Dr. Ben Bikman: How To Reverse Insulin Resistance Through Diet, Exercise, & Sleep

0:00 I unapologetically embrace the view that to some degree insulin

0:04 resistance is a common root cause for most chronic diseases.

0:09 Obviously, type two diabetes, obesity is in there,

0:12 Alzheimer's, fatty liver disease, infertility.

0:15 So, why is that?

0:17 Insulin is one of the few peptide hormones

0:19 that will literally affect every single cell of the body.

0:23 For example, the connection between insulin

0:25 resistance and breast and prostate cancers.

0:27 I'm not saying insulin resistance is the singular contributor, not at all.

0:31 But it is absolutely a contributor.

0:33 I kind of wanted to start out with something a little provocative.

0:36 Right now, there's a big trend in weight loss

0:40 that's made very easy um by taking GLP-1 agonist drugs,

0:44 things like Ozic and Wego V.

0:47 GLP-1 is a naturally produced hormone.

0:49 My concern is that the dose of GLP1 that we're using now,

0:52 it's just a little too much of a good thing.

0:54 What are some of the best strategies people

0:57 can do now to really make a difference?

1:00 The one I like to talk about the most because

1:01 the evidence is so compelling and it's so easy to get.

1:05 My one thing would be welcome back to the podcast.

1:09 I'm very excited to be sitting here with Dr.

1:10 Ben Bickman who is a professor of cell biology at Brigham Young

1:14 University and uh he specializes

1:17 in all things metabolic disorders and metabolism.

1:21 So, I'm pretty excited to have a very well-rounded discussion today, Ben.

1:25 This is this has been a while.

1:26 I've been following your research for some time now.

1:29 So, I'm excited to have this conversation with you.

1:31 I'm too.

1:31 Yeah.

1:31 Thanks.

1:31 This will be great.

1:32 I I kind of wanted to start out with something

1:35 a little provocative and I don't and I want to say surprising.

1:39 Uh this this question for you is a lot

1:42 of people that have normal blood glucose levels quote unquote

1:48 can actually be insulin resistant, right?

1:53 Why is that?

1:54 And what what is this state of like

1:56 pre pre-diabetes and why is it something that is not caught soon?

2:01 Yeah.

2:01 And yet so common, right?

2:03 Right.

2:03 I mean that that adds an extra layer of reason to talk

2:07 about this because it is it's become the most common problem.

2:10 People much of modern clinical care has what I

2:14 call a glucosecentric paradigm when it comes to monitoring

2:17 metabolic health or even cardioabolic health given how

2:19 relevant diabetes and metabolic problems are to cardiovascular disease.

2:24 But the the consequence of the glucosecentric

2:27 paradigm and there's reasons for it.

2:29 So I don't mean to s to state this in any kind of incriminating way.

2:34 They they have their own justification for the glucosecentric paradigm,

2:38 but it's increasingly harder to overlook because

2:43 of what we know with regards to insulin.

2:45 So insulin resistance is the state where insulin levels are higher.

2:50 The body's having to use more and more

2:52 insulin in order to keep glucose in in check.

2:56 Uh but because it is able to keep glucose at that normal range,

3:00 it flies under the clinical radar because of our glucose

3:04 centric paradigm that the the conventional clinician is only measuring

3:07 glucose every time the patient's coming in for an annual

3:10 visit with no regard uh to the patient's insulin levels.

3:15 If we were able to broaden the paradigm a little bit and include insulin,

3:20 then all of a sudden we are measuring the earliest

3:24 signs of insulin resistance because it is insulin itself that ought

3:28 to be measured when we're trying to get that view

3:31 of the patient's not only metabolic health but insulin resistance.

3:35 So to say all that another way,

3:37 type 2 diabetes is when both insulin is high but it's

3:41 starting to really lose the war and now glucose rises as well.

3:45 Then the conventionally trained clinician says a glucose

3:49 is elevated so you have diabetes or pre-diabetes.

3:52 But in its earliest stages the glucose is still

3:55 normal but there's this cold war happening in the body

3:58 where the insulin levels are still two or three

4:01 or four times higher than they used to be.

4:03 it needs to be that high but and it's

4:05 working well enough to keep the glucose in check

4:09 and so the glucosentric paradigm has us miss the earliest

4:15 metabolic canary in the coal mine which is insulin.

4:18 So the sooner our paradigm with modern medicine includes insulin,

4:23 then the earlier we can detect these metabolic problems

4:26 in a person who's progressing towards type 2 diabetes.

4:29 But also it changes the treatment protocol too because not to go

4:35 off on a tangent too soon off the very first question here,

4:39 but if the longer we ignore the insulin,

4:42 the more the clinician may be tempted to push the insulin up

4:44 even higher by giving say a type 2 diabetic an insulin therapy.

4:50 Now they're pushing the insulin from high

4:52 to super physiological all in an effort

4:55 to control the glucose little realizing that in the process you're actually

5:00 killing them faster because so much of what kills the type two diabetic

5:05 is not the hypoglycemia it's

5:07 the in the hyperinsulinemia and the insulin resistance.

5:11 Oh I definitely want to get into that.

5:12 Just just sort of as a follow-up question

5:16 in this world we live in now where gl continuous

5:18 glucose monitors are so becoming very popular many people

5:21 have them without a prescription you can get them.

5:26 Y is there any signs or tests using those that people can do to kind

5:30 of look for this potential problem with you know having perhaps high insulin.

5:36 In fact they're not measuring insulin but glucose.

5:38 Yeah.

5:38 Right.

5:38 Yeah.

5:39 So to answer the first uh the question very directly,

5:42 I'm an enormous advocate of CGM use.

5:45 The more we democratize access to CGMs, I think the better we put individuals

5:51 in a position to be their own coach, you know,

5:54 they don't need to have someone like me or you berating them

5:58 and telling them to change their habits and eat a little better.

6:02 when you see how your body is responding to what you're eating

6:04 and the CGM enables that, you end up making your own lifestyle changes.

6:09 So, with the with the use of the CGM,

6:11 fasting glucose isn't going to be the best indicator.

6:13 It's going to be the dynamic glucose.

6:15 So, if you've eaten a carbohydrate heavy meal or or a simple carbohydrate,

6:20 I shouldn't call it a big meal,

6:22 but a simple carbohydrate like two pieces of bread,

6:25 if your glucose levels aren't back down to normal by about two hours,

6:29 that suggests a problem.

6:30 So in my mind, the greatest utility of the CGM is to monitor

6:34 the dynamic changes rather than the static where am I at every morning.

6:38 That has less value.

6:40 The dynamic changes are what has value.

6:43 But beyond the use of the CGM,

6:44 if a person's curious about their insulin resistance,

6:48 in many instances, you don't even need to get a blood test.

6:51 the the skin is a window to the metabolic soul where if there are two things you

6:56 can observe just on your skin and they're

6:59 both generally going to be right around the neck.

7:01 One of them is a a condition called aanthosis nigricans which is

7:06 when around the little skin fold that most people have around their neck.

7:10 The skin will get darker pigmented which can be harder

7:14 to tell depending on the pigment of the person's skin.

7:17 But what is obvious regardless of pigment is

7:21 the kind of crinkled tissue paper texture of the skin.

7:24 So the skin will be very sort of roughed like crinkled tissue paper.

7:29 So that's echanthosis nigricans around the neck.

7:32 And then the other one people know is called skin tags.

7:36 And that is those little it's not like a rounded little mole

7:39 but rather a distinct little kind of mushroom stock column of skin.

7:45 People probably know what I'm talking about.

7:46 You can see them around the neck.

7:48 Sometimes you can see them around the armpits.

7:50 But again, it's just a teeny little like a little mushroom stock almost of skin.

7:54 Skin tags.

7:55 Both of those are very very strong evidence of insulin resistance.

8:00 And the nice thing is as the insulin sensitivity improves,

8:03 those problems go away just like everything else will.

8:07 So many researchers, including yourself,

8:08 do view insulin resistance as a sort of root

8:14 of causing many different types of chronic diseases,

8:18 age related diseases, obviously type two diabetes,

8:20 obesity is in there, cardiovascular disease,

8:23 Alzheimer's, fatty liver disease, infertility.

8:26 So, so why why why is that Yeah.

8:30 some something that people think as the root cause of so many chronic diseases?

8:33 And again, you know,

8:35 why do you you're talking about insulin resistance being common

8:38 and certainly like this pre pre-diabetic state being pretty common.

8:41 Uh what do you think the reason for that is?

8:43 Yeah.

8:44 Yeah.

8:44 So the first part of the question I

8:46 unapologetically embrace the view that to some degree that's

8:50 italicized wording there to some degree insulin resistance

8:53 is a common root cause for most chronic diseases.

8:57 Uh so I'm not claiming that it's the singular cause.

9:02 For example, the connection between insulin

9:04 resistance and breast and prostate cancers,

9:06 the two most common cancers in men, in women and men respectively.

9:10 I'm not saying insulin resistance is the singular contributor.

9:12 Not at all.

9:13 But it is absolutely a contributor.

9:15 With regards to Alzheimer's disease,

9:18 insulin is not probably the singular contributor, but it is one undeniably.

9:23 And the same goes for polycystic ovary syndrome uh the most common uh

9:28 infertility in women or erectile dysfunction

9:30 in men and fatty liver disease and hypertension.

9:33 So when I in fact this question is the question I asked myself

9:39 as an academic in in at my university when I got tenure I thought

9:44 I looked at the rest at at my future career and I thought do

9:48 I want my career to be defined by the number of peer-reviewed papers I

9:51 publish in science journals and I thought no that's not enough because most

9:55 people will never read those articles no one will ever get a direct benefit

9:59 from them and I thought what would be the one message as a biomedical

10:04 metabolic scientist that I would want to convey to people and it was this one.

10:08 It was that to some degree most of chronic

10:12 disease can be attributed to one common origin.

10:15 And so rather than trimming at the branches of this sick tree

10:19 where we are giving the patient a a drug for their Alzheimer's disease,

10:24 we're giving them a patient for a drug for their hypertension,

10:27 we're giving them a drug for their infertility.

10:30 What if all of those were actually just branches coming off of one tree?

10:36 Let's just cut down the tree.

10:37 So when we can acknowledge a sort of common soil hypothesis,

10:41 it starts to simplify the clinical approach.

10:45 So all of this in my mind is

10:48 a reflection of just how powerful the hormone insulin is.

10:51 Most individuals only think about insulin

10:54 as being a hormone that controls blood sugar, which is fantastically unfair.

10:59 Insulin is one of the few peptide hormones that will literally affect

11:03 every single cell of the body from from brain cells to bone cells,

11:08 lung cells to liver cells, and every cell in between.

11:11 There's no exception.

11:12 Insulin will have an effect at every cell of the body.

11:15 And the the particular pathology with insulin resistance is unique because

11:19 you have some cells that aren't responding very well to insulin.

11:24 Like in the case of erectile dysfunction,

11:26 insulin is less capable at producing nitric

11:29 oxide in the endothelium of the blood vessels.

11:32 So there's less vasoddilation.

11:34 Less vasoddilation means compromised erectile function.

11:37 So on one hand, you have some cells that suffer because they're not responding.

11:42 But on the other hand, you have some cells that are overstimulated

11:46 because insulin resistance is insulin not working

11:50 the same at all cells of the body and blood insulin levels are higher.

11:54 So there's too much insulin.

11:56 Some cells are responding too much to that insulin.

11:59 So with polycystic ovary syndrome, for example,

12:02 that's not a problem of the insulin signal not working well.

12:05 That's a problem of there being too

12:07 much insulin stimulating the ovary to inhibit

12:11 the conversion of testosterone into estrogens

12:14 and thus she manifests with polycystic ovaries.

12:17 So to to some degree most chronic diseases can be connected back

12:21 to insulin resistance and to me that has a a tremendous power.

12:25 That's a reason to focus on that disorder.

12:28 So some researchers think that the high insulin

12:31 is more of a response to ectopic fat accumulation, obesity sort of being

12:38 the underlying cause of the high insulin.

12:41 So how do you kind of differentiate between this cause and effect?

12:45 What what role does ectopic fat accumulation

12:48 have in insulin resistance causing high insulin?

12:51 Yeah, that's a great question.

12:52 In fact, that's a big question.

12:54 Uh, and I already am too longwinded with my answers,

12:56 so I'm going to try to be concise here.

12:59 Um, I look at the origins of insulin resistance as being one of two,

13:03 one of two origins where you have what I

13:06 call fast insulin resistance and then slow insulin resistance.

13:09 And what you're touching on is the slow insulin resistance,

13:12 which I'll come to in just a second.

13:14 Within the fast insulin resistance side,

13:17 there are three what I call primary stimuli that in humans have been

13:21 confirmed and in rodents and in isolated cell cultures that can cause insulin

13:26 resistance quickly like within hours but at the same time if the stimulus

13:30 is removed the insulin resistance is resolved in short order and that is stress.

13:37 So elevated stress hormones whether it's cortisol or epinephrine

13:40 adrenaline will cause acute insulin resistance in humans.

13:44 As that stimulus goes away the problem resolves.

13:47 Next is inflammation.

13:49 If you increase the levels of inflammatory

13:51 cytoines in cells or rodents or humans,

13:54 they will be insulin resistant very quickly.

13:57 In fact, people wearing CGMs may notice

13:59 this, that the CGM may reveal that they're

14:02 starting to get a cold or a flu because they notice that their glucose levels,

14:06 they're having a much harder time controlling

14:08 them even though their habits haven't changed.

14:10 That's often a sign of inflammation.

14:13 But even with autoimmune diseases, uh,

14:15 where you have people where the autoimmune disease will eb and flow,

14:19 so too will the insulin resistance.

14:21 It will track very well with the how active the disease is.

14:24 And then lastly of the primary fast causes

14:28 of insulin resistance is too much insulin itself.

14:32 So we know in humans, rodents and cells,

14:34 I've published my own work on this topic that too

14:37 much insulin will result in a resistance to the stimulus.

14:41 So too much insulin can cause insulin resistance.

14:44 Now none of those touch on what you had mentioned which is the ectopic idea.

14:49 That idea is very important be uh and there's a lot of nuance to it where

14:54 we have to define the the fat first of all and by that I mean what

14:59 of the many of the hundreds of thousands

15:01 of types of molecules that we call a lipid

15:03 or a fat within a cell which are

15:05 the ones that actually matter to insulin resistance.

15:08 Some people will think of just triglycerides which is the main

15:12 form of storing fat and yet triglycerides are totally inert metabolically.

15:16 There was some a case in point.

15:18 Brett Good Pastor and David Kelly 30 years

15:21 ago described this phenomenon of the the athletes

15:26 paradox where they noted that in obesity

15:29 with type two diabetes and insulin resistance,

15:32 if you pull a muscle biopsy, there's really high levels of fat in the muscle

15:35 of triglycerides and they're very insulin resistant.

15:38 And so some people would say and did at the time,

15:41 well, high muscle triglycerides causes insulin resistance.

15:44 And yet when they did muscle biopsies from very lean,

15:48 exceptionally insulin sensitive marathon runners,

15:51 they had just as much fat in their muscle

15:54 in the form of triglycerides as the obese type 2 diabetics did.

15:58 And and again, they were very insulin sensitive.

16:01 So it couldn't be the fat that was being stored in the muscle.

16:04 The same could be said of the liver.

16:06 If the liver has triglycerides,

16:08 it's not the triglycerides that are causing insulin resistance.

16:12 So what is it?

16:14 If there is any lipid that's to blame,

16:16 it's going to be a lipid called ceramides.

16:18 And those do not track the same across these say

16:22 these the lean marathon runner and the obese type two diabetic.

16:25 When you start measuring levels

16:27 of tissue ceramides or its precursor dihydroamides,

16:31 there's still some debate as which of the two matters most.

16:34 I'm very strongly just saying it's one of them.

16:36 And so I'll just say ceramides as a family.

16:39 You can in any biological model cause very strong robust insulin resistance

16:46 just by increasing the ceramides because

16:48 ceramides will block the insulin signal.

16:50 When serum when insulin binds to its receptor then

16:53 you have a series of of of phosphorilation events.

16:56 Ceramides block that very well.

16:58 It's a very well-defined pathway.

17:00 And if you can just do one thing and just resolve the ceramides,

17:04 you correct the insulin signaling.

17:07 So when it comes to ectopic fat,

17:09 it's not a matter of how much triglycerides you're storing,

17:11 but rather what is the entire metabolic millu

17:14 to be promoting ceramides in various tissues throughout the body.

17:18 Interestingly, all of those primary stimuli,

17:21 the quick insulin resistance, all induce ceramide biosynthesis and acrruel.

17:26 But with the slow insulin resistance,

17:29 I still think it's appropriate to invoke fat.

17:33 Um, but but by that it's the fat tissue.

17:35 And I don't want to get ahead of us,

17:37 but my view is that among if you look at tissue level insulin

17:40 resistance is it starting in the muscle or the liver or the fat.

17:44 I'm very much an advocate of the fat first focus

17:46 when it comes to insulin resistance from that slow progressive.

17:50 It settles in over years and it may take,

17:53 you know, weeks to months in order to reverse.

17:56 Yeah.

17:56 Well, this is we we've got a lot to dive into here.

17:59 I mean, it's funny.

18:00 I remember my one of my first projects

18:03 as a budding young scientist was to look at insulin resistance

18:09 like like free fatty acids and and and can

18:12 you make like a little nematode worm insulin resistant and

18:16 you know it it it from my understanding had to do with the atyposite

18:21 cell and this sort of spillover of ceramides that are then attack it

18:25 all had to do with the AKT signaling pathway which you know stopping

18:28 basically the insulin receptor That's exactly

18:30 and that's where in that's where ceramides act.

18:33 You mentioned AKT that's what we would measure and you must have too.

18:36 We would measure a particular protein in AKT for or an amino

18:40 acid residue for phosphorilation and then look at one

18:43 other downstream signal and then we could do some other

18:46 more complicated metrics but that was always the absolute baseline.

18:49 In fact, I've run so many western blots

18:51 measuring phosphoic that next time I if I have

18:54 to have if I ever have to run another

18:56 I'm going to like shove the pipet in my eyeball.

18:58 I'm so tired of it.

18:59 Well, it's just one of those things that, you know,

19:00 when you do experiments and especially when

19:02 it's like something one of your first projects, you kind of remember it.

19:05 And so, you know, as I became interested in nutrition,

19:09 you know, later on down the line and it's like, well,

19:12 it always stuck with me like there's there's

19:13 a role for fatty acids in causing insulin resistance.

19:16 Oh, there is.

19:17 So, so that was something that kind of stuck in my head.

19:19 But um and I think we're going to get we're going

19:21 to get into some of the dietary causes in just a minute,

19:24 but like um beyond you know we're talking

19:27 about you kind of hinted at this earlier.

19:30 Insulin has many roles and oftent times the general public

19:34 thinks about its role in just regulating blood glucose levels

19:38 but maybe you could just talk about some

19:40 of the other roles insulin plays for example in fat accumulation.

19:43 Oh yeah for sure.

19:44 Yeah.

19:44 Uh, in fact, we've I've already touched on a few.

19:47 Like, for example, who would have imagined that insulin regulates the enzyme

19:51 that's responsible for the conversion

19:53 of testosterone to estrogens for goodness sake.

19:55 And yet, it does.

19:56 Insulin has a direct inhibitory role on aromatase,

20:00 that enzyme that mediates the conversion

20:01 and the synthesis of estrogens in men and women.

20:04 It also regulates nitric oxide production,

20:07 regulating dilation of blood vessels and other

20:10 hormones throughout the body that affect water retention,

20:13 salt signaling, neuron conductant of of signals and and more.

20:17 But when the at the fat cell insulin probably has

20:20 its most um powerful effect where the you cannot under

20:27 now we're touching on a broader topic of why do

20:29 we get fat here and I I welcome that topic.

20:33 Uh in fact of all the human tissue I've studied the most in my lab,

20:37 it's fat tissue that we've when we we started doing fat biopsies

20:41 in my lab a few years ago and that's the tissue we study the most.

20:45 So I'm very comfortable talking about atapost tissue physiology.

20:49 There is as much as there is the debate

20:51 in two camps of what makes fat cells grow.

20:54 It's just purely a matter of thermodynamics

20:57 or no it's purely a matter of endocrinology.

20:59 The truth is of course you actually have to have both.

21:02 You cannot under any circumstance make a fat cell get big unless you have both.

21:08 Just to make a put a fine point on that.

21:11 If you have all the calories in the world,

21:13 so I grow fat cells in in petri dishes in my lab right now back at BYU.

21:18 I got students growing fat cells in the incubator.

21:21 Um they are swimming in a culture medium filled with calories.

21:25 Everything the fat cell needs is all the calories

21:28 that fat cell could ever want are around it right now.

21:32 And yet they're teeny little cells.

21:35 They're not getting big at all until we add one thing.

21:38 And the moment we add insulin into that culture,

21:41 now the fat cells start to get big.

21:42 If we check them six hours later, there's a big lipid droplet.

21:46 6 hours still later, it's even bigger.

21:49 So in other words, the fat cell knows what

21:51 to do with the energy that it has access to.

21:53 A cell doesn't have any kind of intuitive intellect to think,

21:57 okay, there's calories here, or more accurately,

21:59 carbons that I can turn into triglycerides,

22:02 and I'm going to take them in and store them.

22:04 But in the context of the body, the fat cell needs to know,

22:08 am I playing nice with the rest of the body?

22:11 How stupid would it be if we got up and went extra, we go out on a jog outside,

22:16 our fat cells are breaking down triglycerides

22:19 as free fatty acids by activating lipolysis.

22:22 and yet at the same time they're pulling them right back in to store them.

22:25 That would be stupid.

22:26 The fat cell wants to cooperate well and be

22:29 part of the orchestra of the of the body.

22:32 And so it will be releasing its fat so that the muscle can take it up.

22:37 But if insulin were elevated,

22:39 so insulin acts as the signal basically telling the fat cell

22:42 when it's time to eat and when it's time to share.

22:44 So to to and then let's if we flip it,

22:48 in fact actually I'll stay there for one more second.

22:50 We even see this.

22:51 Someone could say, "Well, Ben, that's just uh in fat cells." What about humans?

22:56 In fact, humans provide the most convincing evidence of all

22:58 that you cannot get fat unless insulin is elevated.

23:02 Because one of the more common eating disorders among young

23:05 people with type 1 diabetes is a condition called diabelmia,

23:09 which is this terrible tragic scenario where

23:12 the person feels such pressure to be lean.

23:16 And they have learned that that little syringe

23:18 of insulin is the absolute gatekeeper of the fat cell.

23:23 So they will deliberately underdose their insulin

23:26 in order to stay as thin as they want.

23:28 They can eat as much as they want.

23:30 And as long as they underdose their insulin, and it's not even at zero.

23:34 They're just doing a deliberately lower dose.

23:36 They will be as skinny as they want.

23:38 Now there's metabolic hell to pay, right?

23:40 They're hypoglycemic.

23:41 They're getting into keto acidosis.

23:43 So they're dying, but they'll be as thin as they want.

23:46 So as much as people want to say, "No,

23:47 it's just calories." We have a human

23:49 case study that absolutely proves that wrong.

23:52 That it's not just calories.

23:53 Now, having said all that, I'm not claiming calories don't matter.

23:58 Because on the other hand,

23:59 if you just have high insulin in the absence of sufficient calories

24:03 coming in, that's also incompatible with life and the person will die.

24:07 Because if you if you and I were fasting, in fact, Dr.

24:10 George Cahill did these studies about 40 years ago.

24:13 You could never get IRB approval to do it now.

24:15 He would fast men for days and then give

24:19 them an insulin dose and drive their glucose levels down

24:22 to about 20 milligrams per deciliter just to see how

24:25 low could the glucose get and the person maintains consciousness.

24:29 And they did.

24:30 But suffice it to say, if you spike insulin,

24:32 which is telling the body to store energy,

24:35 but there's not energy coming in, then the total

24:38 energy available in the blood drops to essentially zero.

24:41 Glucose goes down to zero.

24:42 Ketones go to zero.

24:43 Fatty acids go to zero because you're you're inhibiting lipolysis.

24:47 You're inhibiting ketogenesis.

24:48 You're stimulating glucose uptake.

24:50 Now, the brain has no energy because it doesn't have a reserve

24:53 of energy like the liver or the fat cells or the muscle.

24:56 And so as blood energy goes to essentially zero, the brain shuts off.

25:00 So coming back to the fat cell, you have to have both.

25:04 You have to have elevated insulin sufficient

25:06 to tell the fat cell to store that energy,

25:09 but then you have to have the energy to store.

25:12 So calories matter, but so too does the insulin

25:16 stimulus because in the absence of the insulin stimulus,

25:18 there is no such thing as fat storage.

25:21 And indeed, the body can't stop breaking down the fat.

25:24 And in fact, that's what ketones are.

25:26 Ketones are nothing more than sign a a sign of the liver

25:31 burning a lot of fat where it's burning so much fat.

25:35 It has such an abundance of acetal COA that it can't it can

25:39 no longer feed the acetal COA into the citrate cycle because it's too full.

25:43 It cannot divert it to lipogenesis because insulin's low.

25:47 So that pathway is inhibited or not activated.

25:50 Then the only other option of all that acetal COA is ketogenesis.

25:54 So ketones are simply sort of this overflow,

25:57 this metabolic release valve of of fat burning,

26:02 but they go one step further if you'll

26:04 allow me where how do we then reconcile it?

26:07 What is it about insulin?

26:08 Like if in I'm not saying calories don't matter.

26:10 I'm not trying to break the laws of thermodynamics.

26:13 In fact, my PhD is bioenergetics.

26:15 I have a unique appreciation for energy in organisms.

26:18 So that those carbons need to be accounted for.

26:22 But the more insulin is low, uh,

26:26 you have two adaptations that allow the body to stay lean

26:30 or to not store that excess as excess that they're eating as fat,

26:35 which is one, a higher metabolic rate by several hundred calories a day

26:39 when insulin goes down as so the body's just burning a little hotter.

26:43 The the engine is revving higher.

26:45 So the overall energy expenditure is up again by 2 to 500 calories a day.

26:50 And when you're in ketosis,

26:52 you're eliminating ketones through the breath and the urine.

26:55 And every ketone that a person's breathing out or urinating

26:58 out has a caloric value roughly similar to glucose.

27:01 So you're just excreting calories from the body.

27:05 So the net effect of all of that can be up

27:07 to 800 or so calories a day that the person's just wasting.

27:12 Okay.

27:12 Um well it's not we're we're really getting

27:14 into this sort of underlying cause of what you

27:18 know what's causing the insulin resistance what I mean

27:22 obviously the what's causing the high insulin as well.

27:26 Yeah.

27:27 And then ultimately obesity is in in that mixture as well.

27:30 And I think you know refined carbohydrates is

27:32 something that you've mentioned and I think a lot

27:34 of people think that refined carbohydrates definitely play

27:37 a role in insulin resistance perhaps the a primary role

27:42 but um aside from the obesity as you're

27:44 talking about obesity being that slow forming insulin resistance

27:49 um what role can we talk a little

27:50 bit deeper about carbohydrates refined carbohydrates saturated fats

27:55 is also something you touched on the camide y you know as well we know palmitate

28:00 yep kind of plays into that pathway.

28:02 And

28:03 so what role do dietary carbs, refined versus maybe complex saturated fats play?

28:11 And then is this all in the the background

28:14 of caloric excess or or you know being in a deficit?

28:18 Does that matter as well?

28:19 The mixture of the two sort of like because there's nuance here.

28:23 Oh yeah, there is kind of get into it.

28:24 In fact, the big a big nuance is the calories.

28:27 And this is where I need to be careful

28:28 because the the degree of studies that have looked

28:31 at these interventions that you're alluding to and I'll

28:34 touch on more now in low calorie or hyperc calorie,

28:37 it's not been fully fleshed out,

28:39 but I would think it's safe to say if there is a caloric deficit,

28:44 then it becomes less relevant um which

28:48 of the the balance of saturated fats to refined carbs.

28:52 Now then someone would say, "Well,

28:53 then let's just always live in a caloric deficit." Yeah, good luck with that.

28:56 I mean, if it were if it were that easy,

28:58 then people would just shrug their shoulders and say,

28:59 "Okay, I'm just going to be on a low calorie diet for the rest of my life." So,

29:02 so if you're in a if you're in a caloric deficit and you're eating,

29:05 you know, some refined carbs, then it's not wiggle room.

29:09 You have more wiggle room for insulin.

29:11 Yeah.

29:11 Yeah.

29:12 Um I I'm I'm comfortable saying that.

29:14 And then again, I just have to counter

29:16 that by saying that's not really feasible long term.

29:18 You know, people get hungry.

29:20 Hunger always wins.

29:21 Yeah, you got to eat nutritious.

29:23 Yeah, you got to eat.

29:24 You got to fuel the body.

29:25 So you can't be in that kind of chronic low calorie state.

29:28 So my view on so saturated fats is one of the more polarizing topics

29:33 and I'm very comfortable talking about it because

29:35 my entire post-doal fellowship was looking at I

29:40 shouldn't say entire my biggest paper ever

29:42 published was looking at the degree to which

29:44 different fatty acids are capable of causing

29:46 insulin resistance through the conversion into ceramides.

29:51 And I'm going to upset some people,

29:54 but in cell cultures and if you treat cells with saturated fat,

29:59 pulmitate, which is the main saturated fat in the body,

30:02 you get insulin resistance very quickly.

30:04 Now, if you block ceramides, you resolve that insulin resistance.

30:08 If you treat those cells with monounsaturated fatty acid, no insulin resistance.

30:13 If you treat those cells with polyunsaturated fatty acid, no insulin resistance.

30:18 So, as much as there is, and I believe it's justified,

30:21 a very heavy focus on seed oils, I I approve of that focus,

30:26 I think they're pathogenic, but I grimace when people invoke them as a primary

30:31 cause of insulin resistance because the data do not support it.

30:35 Again, I think they're very harmful.

30:37 Um, but not when it comes to insulin resistance because you

30:41 can in fact we would treat cells with palmitate cause insulin resistance,

30:46 co- treat them, co-incubate the cells with either oleic acid

30:49 or linoleic acid and we would reverse the insulin resistance.

30:53 Now, I do not mean to give seed oils a pass.

30:57 I think they're highly pathogenic, but not with insulin.

30:59 Well, there's other dietary sources of linoleic acid.

31:01 There are and there you can't even avoid them really.

31:04 Yeah.

31:04 Yeah.

31:05 And and meat, I mean, literally any animal source of of fat,

31:08 any animal food has some linoleic acid in it.

31:11 It's it's it's ubiquitous.

31:13 You would just, you know, want to control it, I guess.

31:16 So, with regards to saturated fat,

31:18 that my own work when I published that paper in uh 2010 maybe,

31:24 um I I left that project with this idea

31:28 that saturated fats are thus a cause of insulin resistance.

31:32 And I had to challenge my own assumptions when I saw the work of Dr.

31:37 Jeff Volic, a friend and a legend in the realm of low

31:40 carbohydrate studies because he published some

31:43 incredibly compelling papers over a few papers.

31:47 He found that I I had to sort of challenge the model

31:52 where I thought all right I was treating cells with saturated fat.

31:55 Is that the same as a human eating it?

31:56 And of course it's not.

31:58 And now to touch on his work,

32:00 you can have uh humans that if if the carbohydrate levels are going down,

32:06 they can eat two or three or four

32:07 times more saturated fat than a high carb group.

32:11 And then they're circulating levels of saturated fat.

32:13 So the saturated fat in some in the plasma is significantly lower.

32:20 That's because most of the saturated fat that's

32:22 flowing through our veins is coming from the liver.

32:25 When the liver is told to make fat through denovo lipogenesis,

32:29 the fat that it makes is palmitate.

32:31 So most of the fat, most of the saturated

32:33 fat we have flowing through our blood that's

32:35 going to get to a cell is going to be coming from what the liver is making,

32:39 not from what we're eating.

32:40 And he showed this very, very well,

32:42 but that's only in the background of low carb.

32:45 Exactly.

32:45 Yeah.

32:46 So, in fact, I won't even elaborate more on that if that point's clear.

32:48 So, the lower carbs are getting,

32:50 the more you can eat saturated fat and appear to have no deficit.

32:55 I'm very comfortable with that.

32:56 No deficit in no problem with insulin resistance.

32:58 Insulin resistance.

32:59 Okay.

33:00 And indeed, but calories aren't an issue in that in that context.

33:04 I don't recall whether they had it in a low calorie context or not.

33:07 I would suspect because insulin is low.

33:10 Once again, you probably have a little more of that metabolic wiggle room

33:13 um with the higher metabolic rate and then the ketone wasting.

33:16 So, it starts to get a little cloudy as to

33:19 because the saturated fat scenario is they

33:22 that there is definitely a pathway to insulin resistance.

33:25 Um, however, it seems as though

33:28 if you're more of a ketogenic type of eater, low carb, ketogenic type of eater,

33:34 that pathway doesn't seem to be relevant

33:37 relevant.

33:37 I I'm very comfortable with that.

33:39 Yeah.

33:39 In fact, that's a great way of stating it that the lower the carbs are getting,

33:42 the less the dietary saturated fat matters.

33:44 Now, in the context of a higher carb diet,

33:48 as much as it pains me to admit because I'm such a defender of saturated fats,

33:52 there are a couple studies that are very well done.

33:54 If I recall, it was some groups in Europe

33:57 um in the European Journal of Clinical Nutrition

33:59 where they had in the context of a high

34:01 carb diet and then manipulating the saturation of fats,

34:05 the high carb and highsaturated fat was

34:07 the worst for insulin resistance and insulin signaling.

34:11 And so when it comes to again the background of high

34:15 carb then I as much as it pains me to admit because

34:18 I'm such a defender of of saturated fats from natural sources I

34:22 I which is where they come from that begins to be problematic.

34:26 I I think it's problematic and not just you

34:29 know for for for metabolic health but cardioabolic health.

34:32 I mean that's where you get small dense LDL particles.

34:34 Again it's the combination of the saturated fat and the refined carbohydrates.

34:40 Are we talking about when you're having, you know,

34:44 a high saturated fat diet in combination

34:46 with what you call carbohydrate, high carb?

34:48 I mean, is this what if you're eating, you know,

34:51 fruits and vegetables and, you know, maybe some oats?

34:56 Is that the same as eating cookies and fruit?

34:59 Yeah.

34:59 No.

35:00 Of course, the easy answer would be no.

35:01 But, but I can't recall the spec the specifics of that study.

35:04 And anytime I can't site a study, I want to be careful in the answer.

35:08 But my view would be what is the underlying insulin effect of those carbs.

35:13 So if these are low glycemic load type carbs

35:15 where the insulin response is going to be very modest, right?

35:19 Insulin itself causes insulin resistance and again

35:23 rapidly and and so what I think

35:25 is if you take the context of an insulin spike with a saturated fat load,

35:30 that's uniquely harmful with regards to insulin resistance.

35:34 So, back to the idea of what are the carbs.

35:36 I think if you're talking about the low glycemic load

35:39 carbs like cruciferous vegetables and berries and citrus fruits, for example,

35:43 now there's almost nothing and then you chase

35:46 that down with a tablespoon of coconut oil,

35:48 the most sat the most concentrated form of saturated fat on the planet.

35:52 I think you're fine.

35:53 Well, coconut oil is a bit of a an outlier because so much

35:56 of it's MCT which doesn't follow which is not a substrate for ceramides.

36:01 So, it doesn't quite fit.

36:03 But in that case, no, I think that's would be perfectly fine.

36:06 But you are touching on what is to me the obvious villain.

36:10 As much as we have increasingly two camps of people saying no,

36:13 it's the seed oils and I'm generally more just because I'm

36:16 an insulin resistance guy in the notes refined starches and sugars.

36:20 The fact is they always come together.

36:22 And so the more a person has a dietary

36:24 ideology that's just simply based on the idea

36:26 of don't get your carbs or don't get

36:29 your food from bags and boxes with barcodes,

36:32 you're getting rid of both the refined starches and sugars and the refined oils.

36:37 Anything else is going to be fine for the average for most people.

36:40 Just less bags and boxes with barcodes, mole more whole foods, you're fine.

36:46 And but what about like fructose versus glucose?

36:48 If you're having more fructose in the fruit,

36:50 is that really causing the same insulin response as a refined?

36:52 No, it's not.

36:53 No, it absolutely is not.

36:54 No, fructose itself will not elicit an insulin response whatsoever.

36:58 Now, the body will convert some of that fructose to glucose,

37:01 which is why the diabetic who's gone hypoglycemic can just drink

37:04 a cup of orange juice and within minutes it'll start to, you know,

37:07 that's such a concentrated load of fructose

37:09 that they will see a glycemic excursion.

37:12 But no, fructose isn't the same.

37:14 But even still, depending on the person, you know,

37:16 you and I, we're two lean healthy people.

37:18 We could get away with it.

37:20 If I'm talking to an overweight type two diabetic, then I say, "All right, well,

37:24 the most sugary of the fruits,

37:26 just be more careful with like say mango or a banana." Um,

37:31 then I would say, "All right, you maybe want to be a little more

37:33 careful because your disorder is you don't burn glucose.

37:35 You don't burn sugar very well.

37:37 And so you just be careful with the most sugary of the fruits,

37:41 but then everything else enjoy liberally.

37:44 Um, so with respect to insulin resistance and weight loss

37:51 and obesity and what's causing like the cause of these things, right?

37:54 I mean, this is where we get into there's

37:56 also this sort of war between saturated fat

37:58 versus sort of a high carb diet and can

38:01 you lose weight on one or the other better?

38:04 And that's where Kevin Hall's study was kind of interesting.

38:06 I'd love to get your thoughts because

38:08 so he's published a study back in 2021 NAH did

38:12 a pretty well-controlled study where people were on a high higher

38:17 carb diet or they were on a ketogenic diet and they

38:19 were isocaloric so same calories but if I recall the

38:23 no in fact they were they were able it was ad limitum

38:27 and then they found they found

38:28 that the plant-based group just spontaneously ate less

38:33 so yeah so the 2021 study they one of The powers

38:36 of that study and it's not a perfect one which I can articulate

38:40 was that they allowed them to just eat freely but you got

38:43 to follow these kinds of balance and you follow this pattern you

38:46 follow that pattern and if I recall the plant-based he he

38:50 um rejoiced in the fact that it challenged the carbohydrate insulin theory

38:55 of obesity which I can articulate in a moment because they found

38:59 that the higher carb group spontaneously ate about 700 calories a day less.

39:05 Does that sound right?

39:06 I think that's right.

39:07 So they they just spontaneously were eating less because they could eat freely.

39:11 They just ate and 700 calories a day is a meaningful amount

39:15 to just spontaneously eat less of.

39:18 That did challenge the idea because one view I actually don't like.

39:22 But they lose more fat as well.

39:24 Yeah, they did.

39:25 They did.

39:25 Yeah.

39:26 But it was this is modest.

39:27 I mean to to to to be fair to the study they did a good job controlling it.

39:32 to be a little critical of the study.

39:35 The findings were exceptionally modest.

39:37 This is the kind of thing where it was like one pound versus two pounds

39:41 and it was two weeks and it was a very small study and and a lot

39:45 of what Kevin has done is a lot of these kind of mathematical modeling

39:48 outcomes where they sort of speculate

39:49 or extrapolate beyond the data that they get.

39:52 So they they found that they spontaneously ate 700 calories a day less.

39:56 that challenged one of the central ideas of the carbohydrate insulin model,

40:02 which is if you spike insulin, you get hungry.

40:06 And he was saying, well, they ate all these carbs.

40:08 Mind you, it was mostly plant-based complex carbs.

40:11 Exactly.

40:12 So, that's right.

40:12 And so, it's almost it's a little unfair because that's

40:15 not how most people are getting their carbs these days.

40:18 And and just to put a fine point on that point,

40:21 70% of all calories consumed globally,

40:23 it's about 60% in the US, are carbohydrates.

40:26 And they're not coming from leafy greens

40:29 and berries and and you know, citrus fruits.

40:31 It's coming from bags and boxes with barcodes.

40:33 But nevertheless, that's an interesting finding.

40:37 My my criticism of that is one, it's an extremely short-term study,

40:43 and there are longer studies that we ought

40:45 to highlight just to offset this very short study,

40:49 but at the same time, when you're eating so much fruits and vegetables,

40:53 you're putting a lot of bulk in your stomach.

40:55 And it didn't surprise me that these may be people who within

40:59 just two weeks on this diet were just probably having a lot

41:03 of bloating and gas um from eating a lot of plants when

41:07 they probably weren't eating that many plants before they started the diet.

41:10 So it didn't entirely surprise me that they were spontaneously eating less.

41:15 I would personally enjoy eating more meat than I

41:19 would big leafy greens and and other fruits and vegetables.

41:22 So I would probably eat more calories.

41:24 the fact at the end of the two weeks.

41:26 In fact, what's funny is I looked at the outcome and thought, "Okay,

41:28 the low carb group was eating 700 calories more per day and you're telling me

41:33 they only gained like one more they only

41:35 had one more pound of fat." If anything,

41:39 you could have looked at all that data and said,

41:41 "Wow, there is a metabolic advantage to a low carb diet." And in fact,

41:45 some of the studies Kevin Hall of his own work that he's

41:48 tried to distance himself from is finding that in a ketogenic state,

41:52 people have a significantly higher metabolic rate.

41:55 And so perhaps one outcome of that study is that when a person gets to ketosis,

42:00 they were able to eat 700 calories more per day and only

42:04 had one more pound of fat than the other group did.

42:07 That to me is a pretty big win.

42:09 And that touches on something that's become a theme

42:12 for my lab where if you'll allow me very briefly, I will try to be brief.

42:16 I'm not very good at that, but um uh over a hundred years ago,

42:21 two famous legendary scientists um Francis Benedict,

42:25 who you and I may recall wrote, uh created what's called the Benedict equation,

42:29 which is an equation that is still used to this day

42:32 to try to assess metabolic rate based on someone's body size.

42:36 So the Benedict equation this legend

42:38 of energy expenditure he collaborated with Elliot P.

42:43 Joselyn the who the most famous endocrinology clinic

42:48 in the world the Joslyn diabetes centers named after him.

42:51 So you had these two legends in their own realm who tried to understand

42:54 the metabolism of people in what they called

42:56 severe diabetes which we would call type one.

42:59 They found that their metabolic rate was about 20% too high.

43:03 And then years later when insulin began to be a therapy,

43:07 a group at Minnesota uh the first author is N Share

43:11 N AIR they not only confirmed the findings from 60 or 70

43:16 years earlier that in type 1 diabetes the metabolic rate is too

43:19 high like something's broken they're burning too hot but when you gave

43:23 them insulin within minutes the metabolic rate began to slow down

43:27 and so all of this back to that study from 2021 the reason

43:31 I even brought all of this up is to me That's further

43:34 evidence of the lower insulin gets like with a low carb diet,

43:38 the more metabolic wiggle room a person has where

43:41 energy expenditures up by several hundred calories a day.

43:45 And and we found in human work that part of it is because

43:49 the fat tissue starts having a much

43:51 higher metabolic rate when insulin comes down.

43:53 There's much more mitochondrial uncoupling.

43:55 So the engine is just revving and revving

43:57 and burning energy just to create heat.

43:59 But at the same time, the more you're making ketones,

44:02 the more you're expelling those ketones.

44:03 And ketones are calories.

44:06 And so maybe those 700 calories a day

44:08 that the low carb group was eating in excess,

44:11 the fact that they only had one other pound of fat could be

44:14 that they were just burning the rest off because of these metabolic advantages.

44:18 Well, speaking of wiggle room, I mean,

44:20 we're talking about a variety of scenarios

44:22 here where people can have wiggle room.

44:24 We talked about, you know,

44:25 being in caloric deficit gives you a little more wiggle room.

44:28 Yep.

44:28 being in a ketogenic or, you know,

44:29 close to a ketogenic state seems to give you more wiggle room.

44:32 Um, but what about being like highly physically active?

44:36 Absolutely.

44:36 Yeah.

44:37 Good.

44:37 I love how you're framing that with this context, these themes of wiggle room.

44:41 Where do you have a little bit of margin to work with?

44:44 Yeah.

44:44 Absolutely.

44:45 Exercise is one of those other uh outlet, if you will,

44:50 where if you have energy that you need to account

44:53 for, exercise is going to be a wonderful way to do it.

44:55 Um I I often don't focus so much on ins on exercise because

45:01 I don't want to convey to people that it can outdo the diet.

45:06 There there was a paper published in women where they looked

45:09 at a very structured and intense exercise program with just it

45:14 was I think it was just low carb diet and the low

45:16 carb diet had better metabolic improvements than the strength training did.

45:20 And so diet is going to generally smart smartly done diet.

45:26 So changing nutrition is going to yield

45:27 better long-term benefits with metabolic health.

45:31 However, the I'm an enormous advocate of exercise.

45:35 Uh and to me, you are not going to go

45:39 it's one thing to be metabolically healthy and lean,

45:43 but then it's something else to be lean and sick or or or or weak or frail.

45:48 And that's where to me the exercise comes in.

45:50 So my my view is you eat smart to be lean and metabolically sound.

45:56 You exercise to be strong and capable and metabolically sound.

46:00 So muscle of course is the great glucose consumer.

46:03 When if someone's wearing their CGM and they see the glucose come up and down,

46:08 80% of that coming down is what's going in to fuel the muscle.

46:12 the muscle is just by mass so big and so hungry that the more muscle you have,

46:17 the more you're going to have this big buffer or what we're calling wiggle room

46:21 where you're going to clear uh you're

46:24 going to clear that glucose much much faster.

46:25 So, if you had two people of equal body mass,

46:28 but one having more fat and one having more muscle,

46:31 but otherwise the same, and that's a big difference, though,

46:34 I know they eat the same amount of carbs,

46:36 the guy with more muscle is going to have his glucose curve come up and down,

46:39 and it'll be back down to normal in an hour, maybe 90 minutes.

46:43 the person who has less muscle, even more fat, so same body mass,

46:49 they're it's going to take much much longer

46:50 for that glucose to come down and thus it take longer

46:53 for the insulin to come down because muscle is the main

46:56 place where insulin is going to escort the glucose to.

46:58 And it does so very well if so the more muscle mass a person has,

47:03 the more sort of metabolic wiggle room they have to clear

47:06 that glucose and then the more carbs they can eat.

47:09 As much as I really point the finger at carbs as a primary problem,

47:14 the more they can eat and even to the point where if a person's very active,

47:18 I knew a guy who was training for a marathon,

47:20 he would eat over 200 grams of carbs per

47:22 day and still be in deep ketosis the next morning.

47:26 You'd think, well, no, normally a ketogenic diet is no more than 50 grams.

47:29 Well, unless you're just burning that glucose, right?

47:32 And and also you you mentioned this the study that was

47:35 comparing strength training to to the you know low carb

47:40 right well I think also high-intensity interval training when you're

47:42 doing you know there's there's a lot of work on so

47:45 we're talking about how exercise can improve metabolic health

47:49 and I think it is a really important um le lever

47:52 to pull here because you you're you're activating these glute

47:56 for transporters and it does that like that activation happens

47:59 through lactate the generation of lactate which is happening when

48:02 you're really pushing yourself hard and and so at that point,

48:06 you know, you're you're becoming insulin sensitive, too, right?

48:08 So, you're you're really kind of changing the the the scenario in some ways.

48:13 It doesn't I don't personally think it should give people the um

48:16 justification to go and eat tons of pizzas and, you know,

48:20 ice cream and all all that stuff.

48:22 Um, all you know, cheating once in a while is fine,

48:24 but like I I I think that pe you can't you definitely

48:28 can you can't um out you can out eat exercise in other words.

48:33 So, but you can out exercise badly, right?

48:35 Exactly.

48:35 You can't exercise bad diet.

48:36 But I do think exercise is extremely

48:39 important especially like there's different types of exercises

48:42 that that was kind of another question you

48:44 know the strength training versus like really going

48:46 hard or or the long endurance training right

48:48 so high intensity interval training you can kind

48:51 of get away with doing less time

48:52 but you're going really hard right you're pushing that

48:54 and I am unapologetically an advocate of that as much

48:57 as people may look at their day and say I have one hour I would say

49:01 everyone man old young strength train strength train Um,

49:06 maybe someone I I sometimes question my own motivations where

49:10 I just think if I were in a crisis situation,

49:12 would my ability to run away from the challenge

49:15 be better than my ability to face the challenge?

49:18 No, I don't think so.

49:19 Because I'm going to be with my wife and kids and the fact

49:21 that I can outrun them isn't going to solve the problem.

49:23 And so, I want to be ready to do something if I need to.

49:26 But even beyond that silly dramatic scenario,

49:30 the bigger the muscle, the hungrier the muscle.

49:33 And given the time constraints that most people have,

49:35 but even then there are studies to show that minute form

49:38 minute at that shorter end if a person's spending I think

49:41 it was like 30 minutes a day the strength training group

49:44 had better improvements in insulin sensitivity than the aerobic training group.

49:47 So if you have constrained time and let's

49:49 face it everybody does default to strength training.

49:53 whatever degree of strength training you can get.

49:55 And just your to touch on your point about intensity,

49:58 just try to go to failure at least

50:00 at some point during that overall muscle or that movement.

50:04 Get to it doesn't have to be a high weight, low rep.

50:10 Even if you're doing a lower weight, higher rep, just get to failure.

50:13 Fatigue yourself.

50:14 Yeah.

50:14 Fatigue yourself.

50:14 Yeah.

50:15 Yeah.

50:15 And that's where like if you're in the context of aerobic training,

50:19 I think that's also like there's a spectrum, right?

50:20 Like what were they doing?

50:22 They were they able to talk?

50:23 You know, if they're really going hard, which zone are they in, right?

50:26 You know, it really it does make a difference with respect

50:29 to your how you're pushing that lever for for you know,

50:32 insulin sensitivity and your glute transporters and them sort

50:36 of transllocating up to the muscle and opening the floodgates.

50:39 And so, um, yeah, it's it's nice to know.

50:42 In other words, there's there's many roads to Rome

50:45 and and so I do I I'm just trying to, you know,

50:49 there's there's definitely a lot of diet wars out there and I

50:52 do think it's important to keep in mind that biology is complicated.

50:55 There's a lot of things going on here.

50:56 And yes, having a low carb diet can be very beneficial for insulin sensitivity,

51:02 for staving off insulin resistance,

51:04 but there's also people that are not going to eat

51:06 a low carb diet and they can still be very metabolically healthy,

51:09 particularly if they're avoiding refined carbohydrates.

51:12 they're exercising, they're not overeating, they're not in a caloric surplus.

51:16 Um, and then there's people that hear saturated fats okay

51:19 and they don't quite understand the whole context of it

51:23 and they'll eat a lot of carbs with it

51:25 and that's the worst case scenario where you're combining the two.

51:29 Yeah.

51:29 Well, anytime Yeah.

51:30 To me, highfat, high carb is the worst combination for every outcome.

51:35 You'd mentioned cardioabolic with regards

51:37 to adverse changes in lipoprotein profile.

51:40 Absolutely.

51:41 I agree with that.

51:42 But high carb and highfat just bringing it back to the fat cell.

51:45 You are now giving it a stimulus of insulin which is

51:48 telling the fat cell to get big and the fat cell

51:50 wants to get big most easily just by pulling in fat

51:53 which if you're eating fat it's going to pull in very happily.

51:56 But it won't if insulin's low.

51:59 And so you know that's why you can sort

52:01 of pick which variable you're going to play around with.

52:04 Not that you've asked this but then having

52:06 touched on what causes the growth of the fat.

52:08 Well, naturally, it begs the question, what shrinks the fat cell?

52:11 Well, you look at those two levers,

52:13 the the high insulin and the high calorie, you have to pick one.

52:17 My only worry is, as much as people are so ardently defending the caloric view,

52:21 which they have for a century now.

52:23 Um, if you just cut calories

52:25 without addressing someone's underlying high insulin,

52:28 you're going to make them hungry very quickly.

52:30 And that's one of the reasons why I speak to the insulin side.

52:34 As much as I acknowledge the calorie side, I think that is a step to take.

52:38 It just shouldn't be the first step.

52:40 What I like to see as the first step is control your insulin.

52:44 Okay, how do I do that?

52:45 Well, reduce your consumption of refined carbs.

52:48 So, make sure you're getting a lot of good

52:50 protein and fat and then fruits and vegetables.

52:55 That's going to help your insulin come down.

52:56 Don't worry about your calories yet.

52:58 We'll get there later.

52:59 And just by focusing on the lowering insulin aspect,

53:02 you have the metabolic advantages come into place,

53:04 which is metabolic rate goes up,

53:06 calorie wasting through ketone excretion goes up.

53:08 And so you're going to start to lose weight.

53:10 And then if you get when you get to that next sort of plateau,

53:13 all right, now we can look at that calorie side because with lower insulin,

53:18 your brain is more accustomed to using ketones

53:20 now and you're more accustomed to you mobilizing fat.

53:24 You have more mitochondria because you've

53:26 been burning more fat with low insulin.

53:29 Now you can start cutting calories and not

53:31 have to worry about hunger kicking you out.

53:34 The most obvious example of the problem with just going

53:38 after calories without addressing a high insulin would be perhaps

53:42 like The Biggest Loser where you never see a reunion

53:45 tour with those poor contestants because they gain everything back, right?

53:51 Hunger always wins.

53:53 It's true.

53:53 Um, I definitely we're going to I want to get more into some of what

53:56 you touched on, but I I kind of want to just complete this um,

54:00 you know, talk about a little bit more

54:01 about what's the underlying cause of insulin resistance.

54:03 We've talked about diet composition.

54:06 Um, that's a big one.

54:09 What about meal frequency?

54:11 So, how often you're eating, if you're a snacker, if you're when you're eating,

54:16 if you're late night eating or if you're a shift worker,

54:19 how does that play a role?

54:20 Yeah.

54:20 Oh well, we pity the the shift workers

54:22 and bless them for everything they're doing for community,

54:25 but that's the worst way to do it.

54:27 So, um, with regards to meal frequency, I think that our the advice that we've

54:34 been giving since the 19 unofficially since the 1960s,

54:38 officially since the late 1970s of high carb diet and then what transitioned

54:43 into with the food guide pyramid and then

54:44 what transitioned into eating multiple small meals per day.

54:47 I think the proof is in the pudding, which is that's how most people eat.

54:51 They eat a starchy, sugary, terrible breakfast,

54:54 then they need a mid-m morninging snack,

54:56 then they need a lunch, then they need an afternoon snack,

54:58 and then dinner, then an evening snack.

55:00 We can see the consequences,

55:02 which is insulin resistance and obesity are the most common problems.

55:06 Even where obesity is not common, insulin resistance is still common.

55:10 Um, not to go on a tangent too much, but even countries like Japan or Singapore,

55:15 my second home, one of my kids was born there.

55:17 I did my fellowship in Singapore.

55:19 Why would the beautiful little island of Singapore care so

55:22 much about diabetes when the average Singaporean is incredibly lean?

55:26 Because their rates of diabetes are higher than ours by a lot.

55:29 We're not even close to the most diabetic country.

55:32 And that actually comes back to how we store fat.

55:35 So with regards to meal frequency and what we eat,

55:39 I think high carb diet with abundant calories and eating

55:45 multiple times a day is the worst way to do it.

55:47 Uh so I would think it'd be better to have fewer meals,

55:50 two to three meals a day where you are controlling carbs.

55:52 So whole fruits and vegetables, enjoy them.

55:55 And then good proteins and fats, enjoy them liberally.

55:59 But this isn't convenient in social or family situations.

56:05 But the more you can stack your meals to be earlier in the day, the better.

56:09 So studies that have looked at humans finding where they do the kind

56:12 of intermittent fasting or timerestricted eating of you

56:15 have one group eat breakfast and lunch,

56:17 one group eat lunch and supper, the lunch and supper group has worse outcomes.

56:23 Not that they're not better.

56:24 I mean, any one of those is better than the standard,

56:27 but when you compare the two,

56:28 the outcomes are better for the meals being earlier in the day.

56:32 Now, you and I are parents.

56:34 How awkward would it be for me to come home and just sit around

56:37 the dinner table and look at my darling wife and kids eat dinner while I'm not?

56:41 I'm not going to do that.

56:43 And so as much as me as a scientist knowing that it would be better

56:47 for me to have breakfast and lunch and fast through later part of the day,

56:51 including supper, I'm not going to do that because I care more about

56:55 being a husband and father than I do about having a six-pack or whatever.

56:58 So I'm going to my own way of doing it

57:00 is well maybe I without I don't need to explain

57:04 my own situation but I think that intermittent finding

57:08 one meal of the day or at a minimum just

57:10 have three meals a day and try to have about

57:12 four hours between those meals and then the most important

57:16 thing I would say and this is where we pity

57:18 the shift workers and thank them it would be evening.

57:22 Do not snack in the evening.

57:24 Especially one of the things I think

57:26 that people don't appreciate is as much as they're

57:28 monitoring their sleep and they're wondering why

57:30 they have night after night terrible sleep habits,

57:33 the most common cause of insomnia is elevated body temperature.

57:37 So they're too hot.

57:39 And one of the most common causes of being too hot is hypoglycemia.

57:43 Most people don't appreciate that.

57:44 When your blood glucose levels spike,

57:47 you you activate your sympathetic nervous system.

57:50 And of all the times of the day

57:52 when your sympathetic nervous system is activated,

57:54 you don't want it to be turned on when you're trying to go to bed.

57:57 That's when you want the parasympathetic to dominate.

58:00 So when someone eats that evening snack of spiking their blood sugar,

58:05 then they go to bed in a hypoglycemic state.

58:07 They're going to have all of the signs and symptoms of anxiety.

58:11 They're going to be laying there hot.

58:13 their heart is going to be beating hard and fast and they're

58:16 going to feel that pulse pounding and wonder what am I anxious about?

58:20 Why can't I just sleep?

58:21 Well, it's not because you have anxiety.

58:23 It's because you went to bed hypoglycemic.

58:25 But unfortunately, that is the one time

58:27 of day where people are at their weakest.

58:29 And I'm very sympathetic to that because I feel the same thing.

58:32 People can walk past treats and junk food all day

58:36 and and and deny themselves that knowing that it's not good for them.

58:39 But the moment 6 o'clock comes around or 7:00

58:43 then all of a sudden the temptation starts

58:46 to take on a new form and they can't they indulge and that is the worst time.

58:50 It would be better for them to indulge in that at lunch

58:52 for example than it would be at that point of the day.

58:54 Not only metabolically and in maintaining

58:56 good insulin sensitivity but not to mention

58:59 sleep then the compounding consequences of poor

59:02 sleep just creates this vicious cycle.

59:05 Yeah.

59:06 Okay.

59:06 So the meal frequency it sounds like you

59:09 know the more you're each time you're elevating each

59:12 time you're having an insulin response that insulin

59:14 is then you're you're getting into the fat storage.

59:17 Yeah.

59:17 And you will get hungry.

59:19 Yeah.

59:19 So so as much as we highlighted that 2021 study what

59:21 I ought to have done is highlight the work of Dr.

59:23 Dr.

59:24 David Lewig um Cara Ebling and others and shy at all in New

59:29 England Journal of Medicine in 2012 where there are there's so many

59:32 decades worth of evidence showing that as much as we had that one

59:35 study suggesting well the insulin higher insulin group didn't had less hunger.

59:39 Yeah.

59:39 There's a lot of evidence showing the opposite.

59:42 So where you you end up creating

59:44 this roller coaster of glycemia and hunger where

59:47 the person eats a starchy sugary breakfast which

59:50 let's face it most breakfasts are these days.

59:52 they have this big spike and then when you go high you inevitably

59:56 go low and then when you go low hunger comes again even though you

59:59 may still literally have food in your stomach and yet your brain is starting

1:00:03 to sense well I'm hungry because the overall amount of energy in the blood

1:00:06 has gone down even though there's plenty of stuff still in the stomach

1:00:09 but it stimulates hunger that's David Lewig's

1:00:12 main contributions so anyway it puts the person

1:00:15 on this roller coaster of glycemia and every time it comes down hunger wants

1:00:19 to push it back up again and so yeah I cut you off though,

1:00:22 but that puts them in a position to eat six or seven times a day.

1:00:25 And if they're not eating, they're drinking something sugary,

1:00:28 either a soda or a sugary fruit juice,

1:00:31 right?

1:00:31 And and the difference between, you know,

1:00:34 this sugary type of like breakfast you're talking about

1:00:36 and perhaps like some something that's more of a complex

1:00:38 carbohydrate would be the fiber is slowing that glucose

1:00:41 response and and causing some satiety as well.

1:00:44 Um, so that would be something that you would contrast.

1:00:47 Not to mention even

1:00:48 in that study in 2021,

1:00:50 they probably were doing more complex carbohydrates and not they were Yeah.

1:00:53 And it was it was plant-based.

1:00:54 And that that's again another reason why I thought we need to be careful.

1:00:57 Not I don't mean to sound overly critical of the study.

1:00:59 I appreciate it, but at the same time,

1:01:01 I think we need to um elaborate on the limitations,

1:01:05 which is most people aren't starting

1:01:06 with a breakfast of a big leafy green salad.

1:01:10 Um but there is an a group uh that found that when you have a breakfast and they

1:01:14 looked at breakfast and the name of the article

1:01:16 was something like more rapid return of hunger.

1:01:19 They it was something like return to hunger was

1:01:21 in the title and if the breakfast isocaloric breakfast

1:01:25 so same number of calories protein was clamped and it

1:01:28 just differed in the ratio of fats to carbs.

1:01:30 The high carb group was hungrier much sooner and then

1:01:34 ate more for their next meal than the low carb group.

1:01:37 And and so I would say as much as we want to be sort of fair with whole plants,

1:01:43 if that breakfast is a mix of whole plants with good proteins and fats,

1:01:48 that's going to be a winning combination of satiety.

1:01:51 And then have a nice lunch and then my view for me personally,

1:01:55 I don't eat breakfast as much as I

1:01:57 said I wouldn't elaborate on my own uh approach.

1:02:01 I eat a big lunch.

1:02:03 um that's my main meal of the day because I want

1:02:05 and then I find if I have a big filling lunch,

1:02:08 it's easy for me to taper through dinner

1:02:10 and then easy to not snack in the evening.

1:02:13 But as much as I know,

1:02:15 one of the great ironies of being

1:02:16 a metabolic scientist and yet a fallible human um

1:02:20 with bad habits sometimes is that evening time

1:02:24 is still my weakest time of the day.

1:02:26 And my kids think that I'm the best dad in the world and I want

1:02:29 them to be healthy and I don't really bring a lot of cereal into the home.

1:02:32 I make breakfast for the kids every morning for the most part

1:02:35 and it's a mix of various meals that I make and they think,

1:02:38 "Wow, my dad just loves me so much." Yes, I do.

1:02:40 I love you all my little darling babies, but I do it because I don't want cereal

1:02:44 in the home because if there's cereal in the home,

1:02:46 daddy is a meth addict when it comes to cereal.

1:02:49 And if it's there, as much as I know,

1:02:53 I will like go through this like I can almost script

1:02:57 it out where I'll put help get the kids to bed.

1:03:00 I'll clean the house, straighten things up, and then everything's quiet,

1:03:03 and then I think, I I need six bowls of cereal right now.

1:03:06 And so then I will eat myself sick.

1:03:08 And like a true addict, I will tell myself, I'll just have one bowl.

1:03:13 What's the problem with one bowl?

1:03:15 And then yet there's this little shoulder angel telling me, "Oh, but you know,

1:03:18 you're not going to stop at one bowl." But then

1:03:20 there's the addiction inside of me saying, "Yeah, I am.

1:03:22 I want this.

1:03:23 I'm just gonna have one bowl.

1:03:24 I never My wife can, though.

1:03:28 My wife has this uncanny alien-like ability to eat something

1:03:32 like this, something sweet like an ice cream or a cereal,

1:03:35 and just have a little bit of it and be done.

1:03:38 I can't do that.

1:03:39 She is a moderator and I am an addict when it comes to these kinds of things,

1:03:43 which is one of the reasons why I don't love a lot of the modern

1:03:49 the most popular modern mantra when it

1:03:52 comes to nutrition is moderation and all things.

1:03:54 What if you can't moderate?

1:03:57 then it would be better not to even start,

1:03:59 right?

1:04:00 Um I want to talk about you talked you sort of alluded

1:04:03 to this and this has to do with the other contributing factors

1:04:07 to insulin resistance and you were talking about this in the context

1:04:10 of if you're if you're late night eating it can disrupt your sleep.

1:04:14 Yeah.

1:04:14 And you know for many reasons you're also you talked

1:04:16 about some very interesting stuff that I hadn't really thought

1:04:18 about before but also you're digesting you know when

1:04:21 your your systems are all activated thermic effective food you're hot.

1:04:25 So I mean it makes it makes perfect sense and um

1:04:28 in fact I remember a friend of mine um Dr.

1:04:30 Sachin Panda he's done a lot of research on timerestricted eating and he's

1:04:33 got this app um my circadian clock where people were you know uploading pictures

1:04:39 of their meals and it was timestamped

1:04:40 and they're putting comments and like the most

1:04:43 one of the most common comments he was getting was um is disrupting sleep.

1:04:47 Eating later was disrupting sleep.

1:04:48 And finally it was like like he's like we got to look into this.

1:04:51 I mean, there's like, you know, dozens of people talking about this and and it's

1:04:55 kind of funny when you kind of get that reverse

1:04:57 thing that you're looking at when you're when you get

1:04:58 the data and then something else kind of pops up.

1:05:00 Wow.

1:05:01 So, eating late at night seems to be disrupting

1:05:03 people's sleep and that's that's that's a real thing.

1:05:05 I'm convinced I'm convinced that given that the natural

1:05:08 uh temptation and inclination people have to indulge before bed.

1:05:12 I'm and and the sleep epidemic, the poor sleep epidemic,

1:05:16 I'm convinced that more of it isn't blue light.

1:05:18 It isn't evening light exposure or evening activities.

1:05:21 It's you're going to bed hypoglycemic and and full.

1:05:24 And you're full.

1:05:24 And so, like you said, your your stomach,

1:05:26 you're bubbling, you're digesting when No,

1:05:28 you ought to have you give yourself at least

1:05:30 a few hours before from your last meal.

1:05:33 Yep.

1:05:34 Before you go to bed.

1:05:35 Yeah.

1:05:35 Exactly.

1:05:36 I mean, it takes like what five how many

1:05:38 hours of digestion that's going on while you're asleep.

1:05:40 Um, that's the one thing, sleep.

1:05:43 So you you were talking about these fast causes of insulin resistance,

1:05:46 inflammation, the the chronic stress, high cortisol,

1:05:50 um and then the last one, insulin, right?

1:05:53 Too much insulin.

1:05:54 Where where does lack of sleep come into that?

1:05:57 Because I have seen I've read studies and we were

1:05:59 talking a little bit about this before before we you know

1:06:01 started the podcast and that is first of all when I

1:06:04 became a new parent and I my sleep was entirely wrecked.

1:06:08 I mean just entirely wrecked.

1:06:10 I mean I aged like 10 years and like but for a good cause but for a good cause.

1:06:14 I would do it all over again in a heartbeat.

1:06:16 Um my my postprandial glucose which is what I was

1:06:21 monitoring at the time with my continuous glucose monitor was

1:06:24 I mean it was not my normal I mean I was pre-diabetic.

1:06:28 It was unreal.

1:06:29 Um and so I started looking into literature and this was

1:06:31 the most surprising thing when I when I wanted to wear a CGM.

1:06:34 I was more like how is watermelon going to affect my glucose?

1:06:37 I was more the fruit and the oh look what a grape did.

1:06:40 this is insane.

1:06:40 And and then and then it was like the disrupted sleep and everything else.

1:06:44 Nothing mattered anymore.

1:06:45 I was like, this is real.

1:06:47 Like this is the real deal here.

1:06:49 Um and I started looking into the literature where sleep,

1:06:52 you know, sleep deprivation after one night,

1:06:55 like half you're getting four hours of sleep instead of eight.

1:06:57 You can be insulin resistant the next day.

1:06:59 And I'm like, what?

1:07:01 Oh yeah.

1:07:02 So I'd love to hear about that and how that's contributing to this, you know,

1:07:06 fast cause of insulin.

1:07:07 Yes.

1:07:07 Well, everything you just said I am nodding to because I I can relate.

1:07:11 Um uh where I when I've worn CGMs,

1:07:14 I absolutely see that the single most predictive variable

1:07:18 of my glycemia in any given day is how did I sleep?

1:07:21 Nothing and that I've played around with nothing has even come close.

1:07:26 So when you get one bad night of sleep,

1:07:28 the stress home so it fits under the stress

1:07:30 category to put a to make it very succinct.

1:07:34 So, of the three primary causes of quick insulin resistance,

1:07:37 it's stress when it comes to sleep deprivation.

1:07:39 One bad night of sleep will result

1:07:41 in a much higher and disrupted rhythm of cortisol.

1:07:45 And and so cortisol is will cause

1:07:48 insulin resistance in every biological model very quickly.

1:07:51 So too will epinephrine.

1:07:53 And epinephrine is another stress hormone, sort of the faster stress hormone,

1:07:57 the cortisol being a little more delayed.

1:07:59 But both of them are higher um with regards to sleep deprivation.

1:08:04 And even even epinephrine,

1:08:05 even adrenaline can cause insulin resistance in humans.

1:08:08 If you do a steady little drip in a human of adrenaline,

1:08:11 they're going to be insulin resistant with demonstrabably

1:08:13 insulin resistant within just an hour or two.

1:08:16 To make so that's how sleep deprivation causes uh insulin resistance.

1:08:21 And to make matters even worse, what is the most common intervention to try

1:08:26 to offset the negative consequences of sleep deprivation?

1:08:29 Well, it's more caffeine.

1:08:30 Well, more caffeine is going to increase epinephrine even more.

1:08:34 Epinephrine causes insulin resistance.

1:08:36 So, even the solution to the sleep deprivation ends

1:08:39 up inadvertently compounding the metabolic

1:08:41 consequences of the sleep deprivation.

1:08:43 Now, that's not to say epinephrine uh it's

1:08:45 not to say caffeine doesn't have some metabolic benefits.

1:08:49 It can when used correctly,

1:08:51 like I would say when used in the context of performance.

1:08:54 But for someone who's trying to offset

1:08:56 the consequences of their sleep deprivation,

1:08:58 you may have some increased alertness.

1:09:00 Yes, but the metabolic consequences of the sleep have now just been added on.

1:09:04 Before we continue, I just want to mention something important.

1:09:07 If you're finding these episodes valuable,

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1:09:28 Now, back to the episode.

1:09:30 Um, what about So, we're talking about um other causes of insulin resistance.

1:09:37 You've also kind of looked into some of this other

1:09:39 stuff that's very interesting with respect to environmental toxins.

1:09:44 Yeah.

1:09:44 and how air particulate matter from air pollution perhaps even

1:09:49 plastic associated chemicals or microplastics how those those can

1:09:52 contribute is that something that's meaningful like the sleep deprivation

1:09:56 the cortisol sounds pretty meaningful um are these other talk

1:09:59 about it and whether or not they're pretty meaningful in the

1:10:02 cont yeah yeah super question and really fair of you

1:10:04 to to state it that way because as much as I found

1:10:08 that work and still do really really cool and we're doing

1:10:11 more of it so so to articulate what we've done So far

1:10:14 we've published reports looking at PM2.5 diesel exhaust particles and we

1:10:19 published another report looking at cigarette

1:10:22 smoke with the cigarette smoke particles

1:10:24 that was purely in the context of ceramides forced mitochondrial fision

1:10:29 and insulin resistance and the cigarette smoke did all of those things.

1:10:33 The newer paper that we published about a year or two ago was I think the first

1:10:38 to find that if you just have increased diesel

1:10:42 exhaust particles even when we calorie clamped these we

1:10:45 pair fed these animals and the animals that were

1:10:48 inhaling more of the diesel particles at physiological

1:10:50 levels like at a level that a human could

1:10:52 be exposed to they had much fatter fat cells.

1:10:55 So they had much more atyposite hypertrophy um which accounted for a higher

1:11:01 body fat mass even though they were eating the exact same amount of calories.

1:11:05 Again we pair fed them.

1:11:06 We only let them eat as much calories as the other

1:11:09 group was eating and they still had more fat.

1:11:11 So it does suggest that there are non-nutritive stimuli.

1:11:15 You'd mentioned some others.

1:11:16 We've not done work on microplastics or the plasticizers

1:11:21 those like dethyl stillbsterol and and BPA

1:11:25 but those also have been shown to promote

1:11:27 greater fat expansion in the absence of calorie changes.

1:11:32 That's another reason why I I think that it's

1:11:35 we don't do ourselves any favors when we

1:11:37 only have a calorie centric view of obesity because

1:11:40 there are more variables that come into play here.

1:11:42 Now, to answer the last part of your question,

1:11:44 which is to what degree should the average person be worried about

1:11:47 that I pains me to say this because it's my own work.

1:11:52 I think that's a that's a lower tier concern.

1:11:55 It's also one that some people may not literally be able to do anything about.

1:11:59 You know, like if you are simply living

1:12:01 in an inner city area and there's just pollution,

1:12:04 there's nothing you can really do.

1:12:06 Maybe you can replace your intern your inhome air filter

1:12:09 more frequently and get one and but those aren't cheap either.

1:12:12 So I'm very mindful of the financial constraints

1:12:14 of the person who we may be fictionally talking about.

1:12:17 But I guess other than that would be the only thing

1:12:20 you could do if you could have a better in-home purifier, great.

1:12:23 But for the vast majority of people

1:12:25 who couldn't even quantify their their pollution exposure,

1:12:30 let alone afford an intervention to reduce it,

1:12:33 the good news is that's going to have a much

1:12:35 lower effect than just changing your nutritional and exercise habits.

1:12:39 Yeah, there are there are some more affordable hepailters now that do

1:12:42 seem to kind of u make a dent in reducing particulate matter.

1:12:46 And um but it's interesting that this this air pollution is really it

1:12:52 seems like pretty pervasive like it's not

1:12:54 just metabolic health but it's Alzheimer's disease.

1:12:57 I mean it seems like it's a cardiovascular disease.

1:12:59 I mean it's really affecting lungs of course you know respiratory health.

1:13:04 It's affecting so many different chronic diseases as well.

1:13:06 And so um it is it is important

1:13:08 to keep the context in perspective right obviously diet

1:13:12 you know exercise these things are the most important

1:13:14 when it comes to metabolic health but But but matter

1:13:18 they do and not just for metabolic health

1:13:20 for a variety just our overall health right and

1:13:23 it's interesting of wedding smoking or vaping vaping right

1:13:26 in fact that's the new project that we're starting we have

1:13:28 just what's preliminary data now when we look at the superheated

1:13:32 particles which is what you're inhaling we've we finding we

1:13:36 haven't published this yet so this is unpublished my master

1:13:38 student is this is her thesis project right now so

1:13:40 the data is forthcoming but the early data suggests that it's

1:13:44 it actually at at a relatively controlled um dose matching

1:13:49 it for the cigarette smoke dose that we used previously it's

1:13:52 worse so with now I can't speak to the consequences

1:13:55 of the tumor agenesis effects like maybe the person's going

1:13:59 to have slightly better outcomes with cancer but when we're looking

1:14:02 at forced the outcome we've measured so far is mitochondrial um

1:14:06 outcomes looking at the degree to which the mitochondria can

1:14:08 take in oxygen and convert it to ATP rather than

1:14:12 the oxygen being converted into super oxide radical It's worse

1:14:16 with the superheated particles from the vaping than from the cigarette smoke.

1:14:20 Do you think this is coming down to nicotine or other things in the vape?

1:14:24 I don't know.

1:14:25 So, we have just the whole animal data so far and then

1:14:27 the next step will be isolating individual particles to try to find out

1:14:30 all right which culprit if one culprit is more uh to blame

1:14:35 with regards to the EIG exposure versus

1:14:37 the cigarette because it is different chemicals.

1:14:40 Yeah.

1:14:40 Right.

1:14:41 No, I'd be I'm going to you have to let me know.

1:14:43 I'm in that.

1:14:44 Um I before we get into some solutions here,

1:14:48 I'd also love to touch on one more thing

1:14:50 that I you know you've you've also looked at with respect

1:14:54 to other causes of insulin resistance and and metabolic

1:14:57 health and that is you know commonly prescribed medications.

1:15:00 M and this is something, you know,

1:15:02 that I've I've witnessed firsthand and and friends where they're,

1:15:08 you know, metabolically healthy, lean, lean and metabolically healthy,

1:15:12 and they get on an antid-depressant, for example,

1:15:15 and all of a sudden gain a bunch of weight.

1:15:17 I mean, unbelievable amount of weight, you know, 30 to 40 lbs,

1:15:21 and are no longer metabolically healthy.

1:15:23 So, um, there's a there's a whole host of commonly prescribed medications

1:15:28 out there from lipid lowering medications

1:15:29 like statins to antid-depressants and other neuroscychiatric,

1:15:34 you know, disorders and medications that help with those disorders.

1:15:37 What what what is that something to be concerned about?

1:15:40 Oh, for sure.

1:15:41 Yeah, it absolutely is.

1:15:42 And I'll just mention one that you just mentioned,

1:15:44 which is statins, just because of how common they are.

1:15:47 So, there's no evidence that statins that I'm

1:15:49 aware of are going to create weight gain, but there are metabolic consequences

1:15:52 to messing with cholesterol, lest people forget,

1:15:56 cholesterol is a precursor to an essential

1:15:59 component of the electron transport system.

1:16:01 And so, it's no surprise that if people are waging war on cholesterol synthesis,

1:16:05 the mitochondria may suffer.

1:16:07 And in women, uh, middle-aged and older women have a 50% greater

1:16:12 risk of developing type 2 diabetes when they get on a statin.

1:16:15 That's a meaningful increased risk.

1:16:17 Women appear to be much more susceptible to the consequences of statins,

1:16:21 metabolic consequences of statins.

1:16:23 Not to mention the increased risk of Alzheimer's

1:16:25 and even certain cancers that come with statins.

1:16:27 Now, I'm not intending to sound like I

1:16:29 don't think there's a ever a place for statins,

1:16:31 but I do think they're overprescribed.

1:16:34 Now, more heavily metabolic,

1:16:36 any steroid uh that's been prescribed to control inflammation

1:16:41 is going to be deeply problematic for weight gain.

1:16:44 So if a person has an autoimmune disease or a chronic

1:16:47 inflammatory condition and the clinician has prescribed a corticosteroid,

1:16:51 they're going to gain weight very very quickly because that starts to play

1:16:55 on that stress pathway where the more

1:16:58 cortisol is that pathway is being activated, which is what that's doing,

1:17:01 the more you're going to make the body insulin resistant.

1:17:03 Higher insulin promotes fat gain.

1:17:05 And then just for the sake of time

1:17:07 perhaps I just mention the atypical antiscychotics.

1:17:09 The any drug that ends with an apne um at the end

1:17:13 of it the suffix being apne is generally going to promote weight gain.

1:17:18 That's probably through a central insulin resistance of the hypothalamus.

1:17:23 When the hypothalamus becomes insulin resistant,

1:17:25 you have a reduced satiety signal

1:17:27 and the person's just going to start eating more.

1:17:29 All right.

1:17:30 So, let's kind of shift gears and talk about some solutions here,

1:17:34 protocols to maybe enhance some sensitivity.

1:17:36 People that are, you know, we talked,

1:17:38 we started this conversation talking about people who are

1:17:41 a large population of people that are actually pre pre-diabetic.

1:17:45 They might be, you know,

1:17:46 on their way to insulin resistance or already insulin resistant

1:17:49 and not even really know it.

1:17:51 Um what what are some of the best strategies people can

1:17:55 do now to really make a difference and you know dietary strategies,

1:18:01 you know, stress reduction,

1:18:04 physical activity, but but also how how soon can they

1:18:09 expect to see changes and what should they look at?

1:18:11 Yeah.

1:18:12 To see and monitor those changes.

1:18:13 Yeah.

1:18:13 Well, in fact, I'll I'll start with that last part of your question,

1:18:16 which is how quickly can it turn around.

1:18:18 We published a a clinical report.

1:18:20 So working collaborating with a local clinic in Utah,

1:18:24 we took 11 women with newly diagnosed type 2 diabetes and their A1C was 8.9%.

1:18:30 So very much diabetic range.

1:18:32 And the physician who's very much on board had given these patients two options.

1:18:38 And he said, "You can leave the office

1:18:40 with a prescription for an anti-diabetic drug like metformin

1:18:44 or you can meet with the nutritionist and go

1:18:47 through this lifestyle nutrition counseling." And in just 90 days,

1:18:52 their A1C went down.

1:18:54 The average A1C, the average was 8.9 and it went to 5.6.

1:18:58 So no sign of diabetes whatsoever after just 90

1:19:02 days without a pill popped or a needle injected.

1:19:06 So, I have often taken that 90day span

1:19:09 as a very reasonable amount of time to reverse insulin resistance.

1:19:13 Now, depending on the scope of the problem,

1:19:15 it may take a little longer to get rid

1:19:16 of all of the consequences of the insulin resistance,

1:19:19 but I think 90 days is a very reasonable justified timeline.

1:19:25 Again, I say justified based on our own evidence.

1:19:28 Now, what did we tell them?

1:19:30 That could sort of segue into the first part of your question.

1:19:32 We gave them in fact just three pieces of advice

1:19:36 based on the three macronutrients and I've actually kind of already

1:19:39 alluded to this which the first one is control carbs

1:19:43 and that was simply this admonition to eat whole fruits and vegetables.

1:19:48 You don't even need to count it just whole fruits

1:19:50 and vegetables but in the case of these type 2

1:19:52 diabetics we said try to be mindful of the most

1:19:55 sugary fruits and ve or the starchy fruits and vegetables.

1:19:58 So um the tropical fruits we said

1:20:01 please be careful with like b bananas, pineapples,

1:20:04 mangoes and then the starchy if the vegetable grows

1:20:09 in the ground eat less of it relatively but all other fruits

1:20:12 and vegetables and that's still a lot enjoy liberally and then

1:20:17 prioritize protein and don't fear the fat that comes with that protein.

1:20:21 And that was an important caveat because we didn't want them to be drinking fat,

1:20:25 but we wanted them to acknowledge that in nature all protein comes with fat.

1:20:31 Don't be afraid of that fat.

1:20:33 Um, when humans eat fat with the protein,

1:20:36 we digest the protein better and it's more anabolic.

1:20:40 There's there's studies in humans to show that people work out,

1:20:43 give them protein, they'll have a certain degree of muscle protein synthesis.

1:20:47 If you give them protein and fat,

1:20:49 it's even higher than it was with just the protein alone.

1:20:52 Yeah.

1:20:53 And that's most people don't appreciate that bile when when

1:20:56 the gallbladder from the liver releases the bile into the intestines,

1:21:00 we always just think of that as being

1:21:01 relevant to fat digestion and it's critical for that.

1:21:04 But it also enhances proteolytic enzymes.

1:21:07 It makes the proteolytic enzymes more active uh better.

1:21:11 They work better.

1:21:12 So we digest the protein better and that may be

1:21:14 the mechanism that explains the enhanced

1:21:16 muscle protein synthesis from the combination.

1:21:19 So that was the dietary advice we gave them and I

1:21:21 would just say that for people that manage your macros,

1:21:24 control carbs, prioritize protein, don't fear fat.

1:21:28 And then when it comes to eating time, I mentioned it earlier,

1:21:33 the more you can stack your meals earlier in the day

1:21:36 or at least the bulk of the calories coming earlier in the day,

1:21:39 the better so that you can taper off through evening.

1:21:42 And by all means, or please don't eat

1:21:46 within that 3 to four hour window before bed.

1:21:49 As much as you can, don't don't eat.

1:21:52 And then exercise.

1:21:53 And my view on exercise, as much as we both are,

1:21:56 I am an enormous advocate of exercise.

1:21:58 I was a personal trainer back in the day during my master's degree,

1:22:02 and I hated every minute of it, but I did it.

1:22:04 And I appreciate the role of exercise, and I enjoy exercising every day.

1:22:10 If people are wondering what's the best exercise,

1:22:12 my somewhat pathy answer is the one you'll do.

1:22:15 Just do something.

1:22:17 If you can do the sort of higher intense strength

1:22:21 training that we were talking about, then please do it.

1:22:24 But if this is like some 80-year-old grandma

1:22:26 who just likes walking around with her girlfriends,

1:22:28 just walk around with your girlfriends.

1:22:30 Keep doing that habit.

1:22:31 Whatever exercise you can do and you're going to do, then just do it.

1:22:36 But there is something to be said for timing

1:22:38 it where perhaps you can do your exercise session,

1:22:41 if it is a walk around the block a few times with the gals,

1:22:44 do that after your biggest meal.

1:22:47 where if you just do 10 to 15 minutes

1:22:49 of physical activity after your biggest glucose spiking meal,

1:22:53 you will blunt that glucose excursion by half if not even better.

1:22:58 So what would have been a huge big long glucose

1:23:01 spike and a and a commensurate insulin dose as well,

1:23:05 you're going to cut that down substantially if you did

1:23:08 if you do time that little bit of physical activity.

1:23:10 And maybe that would be one other comment.

1:23:12 If that's not your main exercise,

1:23:13 then have that kind of exercise snack where you had your big meal,

1:23:17 maybe hopefully it was lunch, go on a 10 or 15 minute walk.

1:23:21 Even those of us that, you know, I'm a professor at a university.

1:23:25 I can eat my lunch and still just go on a little walk around the campus.

1:23:28 My building is so big that in bad weather,

1:23:30 I can walk around my building, even like around the hallways.

1:23:33 And so just find a way to get up and do something in little bits,

1:23:37 little bits of activity throughout the day,

1:23:39 but then still as much as a person can

1:23:41 try to have that concentrated time of all right,

1:23:44 I'm working out right now and I'm going

1:23:46 to sweat and I'm going to get tired from it.

1:23:49 Yeah, I love the exercise snacks.

1:23:50 I like to do body weight squats.

1:23:52 Um that's something that I'll, you know, try to do after a meal,

1:23:56 particularly when I'm on vacation and uh get the gelato

1:24:00 that I never ever ever eat unless I'm in Rome.

1:24:03 Yeah.

1:24:03 Well, that's the place to do it.

1:24:04 But um Okay.

1:24:05 Well, that's great.

1:24:05 So, many people ask about these supplements and you know,

1:24:10 are there these supplements that can improve insulin sensitivity?

1:24:12 So, they you know, you hear everything

1:24:14 from magnesium to alphaic acid to bourberine, apple cider vinegar,

1:24:18 and if if there's any merit to that or taking

1:24:20 it before a meal or or is this just

1:24:23 like dropping like a drop of water on the in the pool

1:24:25 to like try to fill the pool up?

1:24:27 Yeah.

1:24:27 Well, in fact, every one you just mentioned works.

1:24:30 Um, frankly, the one I like to talk about the most

1:24:33 because the evidence is so compelling and it's so easy to get.

1:24:37 So, bourberine is undoubtedly effective.

1:24:39 No doubt it works.

1:24:41 Bourberine absolutely works.

1:24:42 I love apple cider vinegar as a personal favorite.

1:24:46 Maybe it's because of my old man palette where

1:24:48 I like really tart things the older I'm getting.

1:24:50 So, I just love the taste when I dilute it in water or sparkling water.

1:24:55 But apple cider vinegar that really that that's the shortest of all short

1:24:59 chain fats that acetic acid and the short chain in the human diet.

1:25:03 As much as we eat a lot of fat, most of it is from seed oils and soybean oil,

1:25:08 but we lose out on the full spectrum of fats

1:25:11 because we don't really eat a lot of fermented foods anymore.

1:25:13 So we don't get the mediumchain fats and because

1:25:15 we don't eat any much fermentation fermented foods,

1:25:19 we don't get any short- chain fats for the most part.

1:25:22 So short- chain fatty acids, which is what apple cider vinegar is,

1:25:26 is a really it it that's a small

1:25:28 little molecule that punches well above its its weight,

1:25:31 where the acetic acid will reduce

1:25:34 hippatic um gluconogenesis to help control glucose.

1:25:38 Um which is very relevant in a person with diabetes with especially type two.

1:25:42 There's so much glucagon always in their bloodstream,

1:25:45 it's constantly pushing the liver to make more glucose.

1:25:50 Apple cider vinegar will inhibit that and so it

1:25:52 it helps the blood glucose by just having the liver

1:25:54 dump less glucose into the blood but it also

1:25:57 stimulates and you'd mentioned glute 4 at the muscle.

1:26:02 The reason exercise is able to open glute 4 or transllocate

1:26:07 it and get the glucose in without insulin is because of EMPK.

1:26:11 Uh so it's that interesting paradox of exercise where insulin comes down and yet

1:26:16 glucose is taking in more the muscle taking in more glucose than it ever was.

1:26:20 It's because of this kind of backdoor of the muscle exercising.

1:26:24 AMPK gets turned on through a series of events that moves glute 4.

1:26:29 Well, apple cider vinegar will do the same thing in the absence of exercise,

1:26:33 albeit to a more modest degree.

1:26:34 So, that's a couple mechanisms among others,

1:26:37 including mitochondrial biogenesis and a little bit of uncoupling,

1:26:40 where apple cider vinegar is one of my favorites where

1:26:44 if you take a couple tablespoons before your most starchy meal,

1:26:48 you absolutely could compare the glucose curve from one day to the next

1:26:53 and you'll see that it's significantly lower

1:26:55 with just that tart little bit of drinking.

1:26:58 That's fascinating because when you're talking

1:27:00 about the short- chain fatty acid,

1:27:02 you know, and I'm thinking, you know, acetate.

1:27:06 Yep.

1:27:06 So, acetate, acetic acid, we're going from acid base.

1:27:09 Um, I'm thinking of lactate, lactic acid, lactate, lact,

1:27:13 and that's when you're generating with exercise and lactate signaling

1:27:16 is to amkin is it's it's it's very much Yeah.

1:27:20 You know, and then I'm thinking, well, is this like a short chain fatty

1:27:22 acid sort of like they're signaling molecules, right?

1:27:25 They are.

1:27:26 And is there is there something that would be so interesting to look

1:27:29 at to see if there's something going on with lactate acetate malate, right?

1:27:33 Like that's in like a Granny Smith apple

1:27:36 or something like the more sour apple, right?

1:27:38 Yep.

1:27:38 I mean all these different short chain fatty acid well the short chain fatty

1:27:41 acids that you're getting from foods and then

1:27:43 there's another mallet's also in like blueberries

1:27:46 malic acid malic acids in them and then so so I just my my sort of wheels

1:27:51 are turning here when you were mentioning that because

1:27:53 it would be so fascinating to see if there's

1:27:55 a common mechanism like why is the acetic acid

1:27:57 work working we know lactate works too um and so

1:28:01 I think acetic acid I know beta hydroxybutyrate one of the one of the ways

1:28:05 that main ketone not that we've talked about

1:28:07 ketones Some of my work is on ketones.

1:28:10 I've been wonder I've wondered in the past the ketone

1:28:13 is unique because on one hand it's a nutrient.

1:28:15 It's a calorie to be burned but at the other hand it's a signaling molecule

1:28:19 and it is known to elicit some

1:28:21 of its signaling like anti-inflammatory effects and antioxidant effects.

1:28:25 Part of it is through changes elicited because of a groin coupled

1:28:29 receptor where it does have a cell surface receptor that it will activate.

1:28:34 I don't know the degree to which acetic acid may

1:28:36 do the same thing but with regards to beta hydroxybutyrate

1:28:41 even exogenous ketones um that wasn't one you mentioned

1:28:44 but there are increasingly increasing studies showing that you can have

1:28:48 there was just a a study in women with PCOS

1:28:53 the only intervention was to give them exogenous ketones

1:28:56 and every outcome related to metabolic markers and PCOS got

1:29:02 better and the only change was the supplementation with exogenous ketones.

1:29:06 I don't know that that was an effect of the bioenergetics of the ketone.

1:29:10 It was probably more of the signaling effect.

1:29:12 And so that would be another thing

1:29:13 if a person's becoming increasingly curious about ketones.

1:29:17 And that's not without justification.

1:29:19 The evidence supporting the the value of ketones is

1:29:23 growing uh and and growing quickly and it ought to.

1:29:27 I have never in the past wanted to be

1:29:29 seen as a drum beating advocate of a ketogenic diet.

1:29:33 simply knowing that that's not everyone's cup of tea.

1:29:36 But increasingly, I will vigorously defend ketones as very beneficial,

1:29:40 viable signaling molecules in the body.

1:29:43 So even when it comes to uh controlling the metabolic response,

1:29:47 you're probably going to eat less because ketones have

1:29:50 a very satiating effect um more so than say glucose does.

1:29:55 Um but then they also will impact uh mitochondrial

1:29:59 uncoupling and help the body burn through that glucose faster.

1:30:03 No, it's it's it's it's interesting.

1:30:04 Ketone ketones are definitely signaling molecules and I also think there's

1:30:07 a lot of overlap between lactate and beta hydroxybutyrate as well.

1:30:11 I mean, they're activating a lot of the same

1:30:13 like brain drive neurotrophic factor being one that you know

1:30:19 um and and the you know, I've had Dom Dagustinino on the podcast twice.

1:30:22 We talked a lot about ketogenic diets and uh you know, Eric, Dr.

1:30:25 Eric Berden talked about them as well.

1:30:27 Um, I do think they're not the easiest

1:30:31 diet for people to follow for for several reasons.

1:30:34 Um, including, you know, social too, being social.

1:30:36 No, no, they're it's restrictive.

1:30:38 It's definitely restrictive.

1:30:39 Um, but, you know, perhaps cycling them.

1:30:41 I'm I've been interested in in cycling it.

1:30:43 I've I've only done it like a couple of times.

1:30:45 Um, for me, it's also very hard to do as well,

1:30:49 but I'm interested in the brain benefits of ketones.

1:30:52 Yep.

1:30:52 Um, and

1:30:53 this is where exogenous ketones, I think, become so helpful.

1:30:56 Where if you have someone who just says,

1:30:58 "I just don't want to do the ketogenic diet,

1:31:00 but I still would like some of the benefits." Um,

1:31:03 there are so many good options nowadays that I think

1:31:06 I think it becomes a viable approach for someone to say,

1:31:08 "I want the ketones, but I want I don't want ketogenic,

1:31:10 so I'm just going to drink them." Do you think the dose matters?

1:31:14 So like not only in respect to wanting the right dose of ketones to activate,

1:31:19 you know, these beneficial signaling pathways,

1:31:22 but also to make sure that you're not like

1:31:25 dipping too low, like your glucose doesn't go too low where you're kind of like,

1:31:29 what's going on here?

1:31:30 A little bit anxious, a little bit Yeah.

1:31:32 Like you can get I can get, you know,

1:31:34 when I haven't eaten for like many hours, I like forget to eat cuz I'm so busy.

1:31:38 All of a sudden I'll start to get

1:31:39 a little anxious and I'm like, what's going on?

1:31:41 Oh, I haven't eaten, you know?

1:31:43 So

1:31:43 yeah.

1:31:43 Yeah.

1:31:44 So you what's interesting actually even the earlier in our discussion

1:31:47 I mentioned on one of my many tangents Dr.

1:31:50 George Cahill's work and he was really one of the more more

1:31:54 famous prominent what they called at the time starvation scientists we would

1:31:59 call fasting scientists but that same study I mentioned where he they

1:32:04 it made you wonder why was it that these patients who got down

1:32:07 to 20 milligrams per deciliter of glucose many people will say that's

1:32:11 lethal like it'll kill you and yet they not only didn't die

1:32:15 they had no cognitive deficit whatsoever the speculation I don't know whether

1:32:19 it was him or maybe Richard Vch in a sort of follow-up commentary,

1:32:22 a ketone scientist who's also passed away now,

1:32:26 where uh if if the brain has adapted to ketones,

1:32:30 it may be more resilient to tolerate a low glucose,

1:32:35 but most people one haven't adapted to ketones

1:32:39 and two don't even have any ketones.

1:32:41 That's the problem is because the same

1:32:42 intervention for the most part that's going

1:32:45 to drop the glucose in someone like someone

1:32:47 who eats a really sugary meal or drinks

1:32:50 it their glucose is going to come up and the higher it goes usually

1:32:53 the lower it's going to go at the end where you have a rebound hypoglycemia.

1:32:59 You would say well I should be able to weather that drop because I have ketones.

1:33:03 No, because the same thing that's that's helping you reser reverse your glucose,

1:33:08 the high insulin is going to inhibit ketogenesis.

1:33:12 And so you've deprived your brain in that acute moment of its primary fuels,

1:33:17 uh, glucose and ketones.

1:33:18 Although the brain does use lactate

1:33:20 um, as a fuel as well, albeit to lower levels.

1:33:24 But if glucose and ketones have started to go low,

1:33:27 that's going to be a panic at the brain because that is its two primary fuels.

1:33:31 And as I mentioned earlier, the brain doesn't have a reservoir of stored energy,

1:33:35 a very very modest amount,

1:33:36 but its metabolic rate is so high that it it needs constant supply.

1:33:41 Right.

1:33:42 Okay.

1:33:42 Well, let's talk a little bit more about, you know, fat.

1:33:44 And we kind of talked about this a little earlier about, you know,

1:33:48 not all fat being equal and a lot

1:33:51 of people are thinking about fat as just stored calories,

1:33:54 but I mean, there's much more to this picture, right?

1:33:56 So there's there there are different ways

1:33:58 we store fat and there's the subcutaneous way, there's visceral fat.

1:34:02 Um these fats are not the same.

1:34:04 Yeah, I know when you were talking you were talking about liver biopsies,

1:34:07 you kept pointing to the abdominal reg region.

1:34:09 I was wondering if you were talking about

1:34:10 you were getting visceral fat biopsies or probably not.

1:34:13 But um can you talk a little bit about these different types of fat and what

1:34:20 determines whether or not you're going

1:34:21 to store fat subcutaneously versus viscerally?

1:34:24 Yeah.

1:34:24 why visceral fat is so dangerous.

1:34:26 Yeah.

1:34:26 Yeah.

1:34:27 So, a lot of that conversation,

1:34:29 there's so many topics I could take with this and perhaps

1:34:32 just perhaps just to try to bring it to one common theme,

1:34:35 I would describe the two ways in which a human can gain fat mass.

1:34:40 So earlier I'd mentioned and it's a perfect opportunity to bring

1:34:43 in different ethnicities because different

1:34:45 ethnicities will store fat differently.

1:34:47 And this all is underlying the earlier

1:34:50 conversation of the slow insulin resistance where

1:34:53 I said it starts in the fat cell and I very much advocate that view.

1:34:57 So why is it that Singapore 15 years ago was recruiting young scientists

1:35:02 to come do diabetes research where you look at the average body weight

1:35:06 in Singapore and by American US standards they're very lean people and that's

1:35:10 reflective of all East Asians and and most and many South Asians as well.

1:35:16 So India up through Japan and the Koreas.

1:35:19 Um why is it that these are people with such

1:35:21 low body weights and even low body fat levels and yet

1:35:25 their diabetes rates are way higher than we have in the US

1:35:29 and that is the difference in how people store fat.

1:35:32 So if a human body is gaining fat mass,

1:35:34 it will gain that fat mass through two different mechanisms.

1:35:38 It will either be a function of multiplying the fat cells.

1:35:42 So the person will have the ability to make new fat cells.

1:35:45 That's called hyperplasia.

1:35:47 And when the fat is undergoing hyperplasia,

1:35:49 the size of the fat cell is staying very modest.

1:35:52 So the size of the each individual fat cell is small,

1:35:54 there are just a lot more of them.

1:35:56 On the other hand, you could have someone who's storing more

1:35:59 of their fat through hypertrophy where the number of fat cells is not changing,

1:36:04 but the size is the hypertrophic fat cell

1:36:08 is a very sick fat cell for two reasons.

1:36:11 And then I'll explain the ethnic

1:36:13 predisposition predisposition predispositions because of it.

1:36:17 So firstly, the fatter the fat cell gets,

1:36:20 the more insulin resistant it becomes to prevent further fat growth.

1:36:24 So to say that all another way, a fat cell can undergo more expansion than any

1:36:29 other cell in the body that I'm aware of.

1:36:31 It can get 20 times bigger than its original volume.

1:36:34 And as it starts to reach this point of maximum dimension,

1:36:37 it has to start limiting its growth.

1:36:40 And so it becomes insulin resistant to stop growing.

1:36:43 But at the same time, it starts to become hypoxic where the fat

1:36:48 cell has become so big that they've pushed

1:36:50 each other too far from capillaries and now

1:36:53 it can't get the oxygen from the capillaries.

1:36:55 And so it starts releasing a bunch of pro-inflammatory cytoines

1:36:59 because some of them will work like a trail of breadcrumbs

1:37:02 resulting in one capillary having a little budding capillary grow off

1:37:07 and follow the cytoines to the hypoxic or suffocating fat cell.

1:37:12 So the hypertrophic fat cell becomes insulin resistant to stop

1:37:16 growth and it becomes pro-inflammatory to try to correct blood flow.

1:37:21 All of which results in a very insulin

1:37:23 resistant on the course to cardioabolic disease body.

1:37:27 Now back to the various ethnicities.

1:37:29 Some ethnicities like whites and blacks have the ability to make new fat cells.

1:37:35 So these are ethnicities that can be a little fatter than other

1:37:38 ethnicities and yet have lower levels of insulin resistance and type 2 diabetes.

1:37:42 And that's what we see in the US.

1:37:44 High rates of obesity but relatively modest rates of type2 di.

1:37:48 As much as we think the problem is bad here,

1:37:50 I think the US ranks somewhere in the 70s of if you

1:37:54 look at all the countries in the world and how diabetic they are,

1:37:56 we're about number 70.

1:37:58 Whereas Singapore, for example, and Japan is not too far back.

1:38:02 Singapore is I think number nine.

1:38:04 this and and all the countries of the Middle East

1:38:06 are actually numbers one through eight are like Oman, Dubai, Jordan,

1:38:10 these countries in the Middle East and and then the other countries sort

1:38:14 of round out through Southeast Asia and the Middle East are the and the Pacific

1:38:18 Islands the most diabetic places these ethnicities especially so India has among

1:38:24 it is among the highest most diabetic countries on the planet East Asia,

1:38:29 Southeast Asia their fat cells on average are sign there the one

1:38:34 paper I'm recalling where it looked it took Caucasian men and South

1:38:38 Asian men and did an atapose subcutaneous biopsy and it found

1:38:43 that the average South Asian man had atyposytes that were about four times

1:38:48 larger volumetrically than the fat cells in the Caucasian at the same

1:38:52 body size same body fat percent they just had much bigger fat

1:38:56 cells so to say all this another way or to start

1:38:59 to wrap it all up what is more problematic about fat storage storage.

1:39:03 It's not the mass of fat that matters most,

1:39:05 but the size of each fat cell when it comes

1:39:07 to slow insulin resistance and the consequences of too much fat mass.

1:39:12 And this explains why say an East Asian fellow will just

1:39:16 be moderately overweight compared to his obese Caucasian counterpart and yet he

1:39:23 has all of the complications of insulin resistance and this guy

1:39:27 just doesn't look good in his speedo and is otherwise fine metabolically.

1:39:31 It's because his fat cells are small because he has so many of them.

1:39:35 His fat cells are so few, but they're much larger.

1:39:38 And so he has a lower body fat mass,

1:39:40 but it's more harmful because his fat cells are bigger.

1:39:43 And that is the problem with visceral fat.

1:39:46 The main there's nothing inherently pathogenic about visceral fat.

1:39:50 Those fat cells aren't mystically harmful.

1:39:54 It's just that that visceral cavity is so

1:39:57 limited in volume that it only allows fat growth

1:40:01 through hypertrophy because that is a way to limit

1:40:04 the total amount of fat you can grow.

1:40:06 If our visceral fat was able to grow through hyperlasia,

1:40:10 then it may expand so much that it starts to compress our our tissues.

1:40:15 It starts to squeeze the liver or squeeze the intestines or squeeze the kidneys.

1:40:19 And so by only allowing visceral fat to grow through hypertrophy,

1:40:23 you do limit how much it can grow,

1:40:26 but it also becomes much more pro-inflammatory because hypertrophic fat cells

1:40:30 release a lot more pro-inflammatory cytoines than smaller hyperlastic fat cells.

1:40:36 So there's very much a genetic ethnic component to this that influences

1:40:41 how ethnicities are able to stimulate the growth of new fat cells.

1:40:46 And then there is there's absolutely a sex component

1:40:49 to it as well which of course is still genetic where

1:40:52 women because of the effects of estrogens are able to stimulate

1:40:56 a higher degree of hyperplasia than her male counterparts are.

1:41:01 And so women will have that ability

1:41:02 to and this explains why the average woman both

1:41:05 has higher fat than her male counterpart

1:41:08 and yet is healthier in every single cardabolic metric.

1:41:11 If it was just a matter of fat mass,

1:41:13 then women should be dying more from all these cardioabolic diseases.

1:41:16 And yet, they're not.

1:41:17 It's men.

1:41:18 Because women will have more fat cells, but smaller because of estrogens.

1:41:24 Men have relatively lower levels of estrogen.

1:41:26 So, we don't have that hyperplasia as much as the females do.

1:41:29 So, if we're getting fatter,

1:41:31 it's more through hypertrophy relative to the to the ladies.

1:41:36 Um so with respect to these hyperplasia versus like hypertrophy fat cells

1:41:41 and I probably should have mentioned the visceral fat the fat lining the organs.

1:41:45 You mentioned the visceral cavity is so this this fats usually like

1:41:48 the lining the organs and you usually find it around the midsection as well.

1:41:52 But um you mentioned the the fact that the the the fat

1:41:58 in the atapost tissue will become insulin resistant

1:42:01 to basically shut down growth like as a response

1:42:04 like an adaptation like okay we got to stop growing.

1:42:07 What about spillover of fat?

1:42:09 like is this feeding into that whole ceramide pathway

1:42:11 that you started to talk about where is is visceral fat

1:42:15 and is this you know this hypertrophy like swollen fat

1:42:18 cell also causing more ceramides to go into your system.

1:42:23 Right.

1:42:23 I'm I'm so happy you brought that up.

1:42:25 I did I deliberately chose not to cuz

1:42:27 I thought I'm already being too long-winded,

1:42:28 but here you are slow pitching the the ball to me anyway.

1:42:32 So yeah, the problem with that hypertrophic fat cell

1:42:35 is that it's becoming insulin is trying to still

1:42:39 force-feed it to store more fat and insulin's main

1:42:42 mechanism of promoting fat storage is by inhibiting lipolysis.

1:42:47 So insulin will promote the growth of the fat cell.

1:42:50 It does enable the feeding to some degree,

1:42:52 but its most powerful effect is blocking the breakdown.

1:42:56 And so the fat cell is saying insulin, I can't keep you keep telling me to grow.

1:43:00 I can't.

1:43:01 If I continue to grow, I mean,

1:43:02 it literally gets to the point where the membrane can start to fray.

1:43:06 It can't hold itself together.

1:43:07 It's like a balloon that's being filled too much.

1:43:09 And so, it becomes insulin resistant,

1:43:13 which is manifested as insulin not being able to inhibit lipolysis.

1:43:18 Now, we have a metabolic millu that's quite odd,

1:43:22 where you have high insulin and high free fatty acids.

1:43:27 That does not happen unless the fat cells are insulin resistant.

1:43:30 So just to make that clear, in a fasted state or a low carb state,

1:43:34 insulin is low and so you have more lipolysis.

1:43:38 So free fatty acids will be higher.

1:43:40 That's a that's a very common feature.

1:43:41 This is the fasted state.

1:43:43 Low insulin, high free fatty acids.

1:43:45 In contrast, the fed state,

1:43:47 especially if it has some carbs, now insulin has gone up.

1:43:50 It's inhibited lipolysis and so free fatty acids will be down.

1:43:54 This is the normal.

1:43:55 It's one or the other.

1:43:57 Unless the fat cells are insulin resistant.

1:43:59 Now you have high insulin reflective

1:44:01 of insulin resistance but it can't inhibit lipolysis.

1:44:05 Thus we have high free fatty acids.

1:44:07 This is a problem back to the ectopic aspect that you'd

1:44:10 mentioned earlier where normally if free fatty acids are high the muscle

1:44:14 will just burn it and the muscle will happily burn free fatty

1:44:18 acids or any tissue any cell with the mitochondria would burn it.

1:44:22 But if insulin's elevated you can't burn fat.

1:44:25 um then fat burning uh beta oxidation has been

1:44:28 inhibited at virtually every single step with high insulin.

1:44:31 So now we are storing more fat

1:44:34 as triglycerides which is the ectopic fat deposition.

1:44:37 So that's where you start to have fatty liver.

1:44:39 In fact the main cause of fatty liver is

1:44:43 spillover from fat from fat cells especially visceral fat.

1:44:47 That's the main origin of all that fat.

1:44:49 As much as we talk about fructose

1:44:50 and other nutritional variables and those matter,

1:44:53 the majority of it is fat that's leaking out

1:44:55 from the fat cell and because insulin's high, it can't burn it.

1:44:59 Normally, the liver would take those fatty acids and just say, "Well,

1:45:02 I'm going to burn it into ketones." But if insulin's elevated, it can't happen.

1:45:06 The liver has to store it.

1:45:08 The pancreas starts to store it.

1:45:09 But as I mentioned earlier,

1:45:11 the triglycerides are not the cause of insulin resistance.

1:45:14 But now we have the high insulin, which is an acute cause of insulin resistance.

1:45:18 and a lot of free fatty acids and where some of those are

1:45:22 going to be palmitate because palmitate is some of the stored triglycerides you

1:45:26 have pulmitate coming out that will

1:45:28 directly be activating TLR4 the receptor that's

1:45:31 going to then drive ceramides bio uh to be synthesized so you have

1:45:36 a lot and not to mention the inflammatory cytoines that are also being

1:45:39 released from the hypertrophic fat cell

1:45:42 at the same time also stimulating ceramide

1:45:45 acrruel thus we end up having the perfect metab metabolic millu to promote

1:45:49 insulin resistance and it all started because the fat cells got too big

1:45:53 and not to mention the the with the cytoine signaling you're talking

1:45:56 about now the chronic inflammation I

1:45:59 mean there's studies now linking visceral fat

1:46:01 to cancer you know and so it's the brain the cancer incidents it's

1:46:06 allosis cactive protein is a better predictor

1:46:09 of heart disease and LDL cholesterol is

1:46:11 and and and the fat cell is the main source of a protein called plasmminogen

1:46:17 activator inhibitor one P AI1 whose main job is to erode clots as they form.

1:46:23 So why is it that bigger fat cells

1:46:25 relate so well with stroke and and cardiovascular disease?

1:46:29 Because you are producing a protein that's inhibiting the breakdown of clots,

1:46:33 making it just more likely that someone's going to have a stroke.

1:46:36 So you talked about genetics and you know someone's sex in terms

1:46:40 of like male or female and how that affects whether or not

1:46:43 they're going to have this you know predispos predisposition to forming more

1:46:47 more fat cells or taking that fat cell and just expanding it.

1:46:51 What what other factors play a role because I mean you know is there a dietary

1:46:57 is there you know some other some other

1:46:59 factors that are that are also contributing to that.

1:47:01 There is yeah just I'll just mention one just

1:47:04 for the sake of time which actually is linoleic acid.

1:47:07 So my view on seed oils is that they can contribute to insulin

1:47:11 resistance through a secondary route by influencing

1:47:14 the dynamics of the fat cell.

1:47:16 Specifically, when linoleic acid is taken into the cell,

1:47:21 one of its peroxide metabolites that it can turn into is a molecule

1:47:25 called 4 H&H has been shown to inhibit the fat cells potential for hyperplasia,

1:47:33 thus forcing the fat cell to only go down hypertrophy.

1:47:37 So if there is some nutritional link that can drive fat cell

1:47:41 storage into one versus the other um linoleic acid does have that effect.

1:47:46 Linoleic acid being converted to 4H and& will inhibit

1:47:50 the atypogenic uh hyperlastic signaling and only enable the hypertrophic signal.

1:47:57 Is that dose dependent?

1:47:58 Like are you going to get that if you're eating

1:47:59 I don't want people to be scared to eat like walnuts.

1:48:03 Yeah I for sure it would be.

1:48:04 I don't know.

1:48:05 I can't quantify the dose but yeah in general my view you

1:48:08 and I were chatting earlier linoleic acid is ubiquitous in nature you need it.

1:48:15 Yes.

1:48:15 Yes.

1:48:16 You have to have it.

1:48:17 So as much as I'm talking about it and invoking it as a problem.

1:48:21 I'm I think it's very appropriate for you to say

1:48:23 yeah but it also like it's in mother's milk for goodness sakes.

1:48:26 It's in every meat source you're and I'm a huge defender of meat.

1:48:30 I think meat is very healthy and yet you're going to have linoleic acid in it.

1:48:34 I would maybe counter or not counter

1:48:36 by just stating that those also in nature when

1:48:39 you have the omega-6 linoleic acid you often

1:48:42 also have an omega-3 that comes with it.

1:48:45 That to me is key that if you're con and often

1:48:48 it'll have some degree even minuscule levels of vitamin E.

1:48:53 Vitamin E will help that linoleic acid not go down the pathway of peroxidation.

1:48:59 It'll help it just go down the pathway of oxidation.

1:49:03 Even Dr.

1:49:04 Steven Kunain, this incredible man, just a delightful individual,

1:49:08 he's done a lot of work documenting the fact

1:49:10 that linoleic acid when it's allowed to just be burned

1:49:14 for fuel burns so high and so rapid that it

1:49:18 create it allows the brain to create its own ketones.

1:49:20 He has a fascinating area of research on this.

1:49:23 So, I've always tried to have a little bit

1:49:25 of a nuanced view of linoleic acid in that it's everywhere,

1:49:29 but when we get it in nature,

1:49:31 it'll come with an omega-3 and it'll come with some amount of often vitamin E,

1:49:36 which will help prevent the linoleic acid from going

1:49:39 down the pathway of becoming a villain, which it can.

1:49:42 Um, linoleic acid will undergo peroxidation very readily and become a very

1:49:47 harmful series of metabolites that are

1:49:49 harmful to cell membranes and mitochondrial membranes.

1:49:52 Is that is that though more because I you know I've

1:49:54 looked a lot at the literature here and I remember I

1:49:57 first was I was submitting a paper and I was going

1:50:00 off about how terrible omega6 high omega6 and you know it

1:50:05 wasn't necessarily from seed oil but it was kind of going

1:50:08 that way and um and a reviewer just kind of just

1:50:12 got me hard and I started to really have to look

1:50:14 at this with a different perspective and go into the literature and

1:50:18 um I really was shocked by how much

1:50:22 of the literature is showing with these, you know,

1:50:25 lenolic acid and even, you know,

1:50:27 switching saturated fat with these polyunsaturated fat seed oils,

1:50:31 um, were either neutral or beneficial,

1:50:34 um, with the exception of like maybe one study,

1:50:36 but like the bulk of them were not showing that.

1:50:39 Yeah.

1:50:39 And it wasn't until I started to really dive deep and see like okay it's like

1:50:43 this heated seed oils and when you start

1:50:46 to heat them especially if you're like heating them

1:50:48 very very high temperatures or you're heating them

1:50:50 over again where they're becoming problematic at least

1:50:54 at least with respect to some of the biomarkers

1:50:56 that were being looked at like inflammatory biomarkers.

1:50:58 Um, so I'm wondering like is is the heating the seed oils

1:51:02 the bigger problem the consuming them

1:51:04 in this really concentrated form and heating them

1:51:07 and the whole package that they're you know

1:51:09 the friends that they're they're bringing along, right?

1:51:11 People are consuming these seed oils in processed foods, right?

1:51:15 They're all in processed foods um versus eating

1:51:17 some like you said meats, you know, walnut.

1:51:20 I I mentioned nuts because they have a higher ratio,

1:51:22 but they also, you know, have omega-3s as well.

1:51:25 So, I do think it's a nuanced topic as well, but I don't want people to like be

1:51:29 so scared of just anything with linoleic acid, right?

1:51:32 No, and I totally agree.

1:51:33 I would also just say I'm also not the person to tackle the seed oil topic.

1:51:39 There would be other people who would be way more articulate on both sides,

1:51:43 attacking and defending.

1:51:44 I've only tried to view that.

1:51:47 I've tried to kind of stay in my lane, which is I'm an insulin mitochondria guy.

1:51:51 And in that that's why I've tried to be a little cautious because

1:51:55 as much as people will invoke linoleic acid for causing all heart disease,

1:52:00 all fatty liver disease, etc.

1:52:02 I just sort of say, okay, great.

1:52:04 That's not my forte.

1:52:05 I'm looking at it in the context here.

1:52:07 Uh, of I'm looking at metabolic outcomes.

1:52:11 So having said all of that, I think what you just said is what I would agree

1:52:16 with in that I think it's appropriate to scrutinize

1:52:20 seed oils because of how we eat them.

1:52:24 Um, we eat them from refined seed oil sources.

1:52:26 Dr.

1:52:27 Christopher Ramston at the NIH a number

1:52:29 of years ago published a report finding that soybean

1:52:32 oil has become the number one consumed source of fat calories in the human diet.

1:52:36 That's not good.

1:52:37 And so I think it's appropriate for us to call them seed

1:52:40 oils rather than linoleic acid coming from all natural animal sourced foods,

1:52:46 which I'm always an advocate of.

1:52:48 Dairy has linoleic acid in it.

1:52:49 Meat has linoleic acid in it.

1:52:51 They all do.

1:52:52 Seeds have linoleic acid in it,

1:52:53 but they also come with other things like a degree

1:52:57 of vitamin E and an omega-3 to some degree.

1:53:00 And those help to varying degrees reduce the pathogenicity.

1:53:04 Even if the linoleic acid was had the potential to be harmful,

1:53:07 which it does through peroxidation more than the other fats do,

1:53:10 these other characters that are coming along with it help it behave and act

1:53:15 in a way that we want it to act because it is everywhere.

1:53:18 It is ubiquitous.

1:53:20 And so I think where you and I would agree and maybe others would disagree,

1:53:24 I don't have a fear of linoleic acid per se as an omega-6 in so

1:53:28 far as it's going to come in every natural source of fat that I'm eating.

1:53:33 But where earlier I'd said control carbs.

1:53:37 If you're controlling your carbs by, and pardon me for repeating again,

1:53:41 not getting your carbs from bags and boxes with barcodes,

1:53:43 you've also eliminated essentially all of those refined

1:53:46 seed oils from your diet, too.

1:53:48 And that's why I also don't like getting caught

1:53:50 up in the is it seed oil or carbs.

1:53:53 They always these refined carbs, they always come together.

1:53:56 So as much as I am the guy who's saying, "Well,

1:53:58 refined starches and sugars are a real

1:54:01 problem." And every someone else would say,

1:54:02 "No, it's the seed oils." And I'd say, "You know what?

1:54:06 Fine.

1:54:06 They're coming together anyway." Uh because it's it's in that it's

1:54:09 you opening up that pack of chips or treats

1:54:12 or some refined snack that's going to have the first ingredient

1:54:17 is going to be a starch that's it's the potato chip,

1:54:20 you know, as it's been fried, but what's it been fried in?

1:54:22 It's been fried in corn oil or whatever.

1:54:25 So you not only have a concentrated source of omega-6,

1:54:27 but it's undergone this superheating and now

1:54:30 it's absolutely gone through some peroxidation.

1:54:33 So, if the person's just eating whole fruits

1:54:35 and vegetables and natural sources of fats and proteins,

1:54:39 you're going to get linoleic acid.

1:54:40 And I would say there's no reason to fear it.

1:54:44 Um, yeah.

1:54:44 I I think also it it can be a distraction if you're if you're not focusing

1:54:48 on like avoiding avoiding the refined carbohydrates,

1:54:51 avoiding the refined sugars, making sure you're getting exercise,

1:54:54 making sure you're not overeating, like all those things.

1:54:57 And then like I look, full disclosure, I don't cook with seed oils.

1:55:01 I don't cook with them.

1:55:02 I don't use them.

1:55:03 Um, but I will say that an unbiased look at the literature,

1:55:08 I still think uh I don't I think cooking them I

1:55:11 think heating them I I would stay away from that for sure.

1:55:14 But um if someone wants to put a little bit of, you know,

1:55:19 of this uncooked oil on their salad,

1:55:20 do I think it's like the worst thing in the world?

1:55:22 I'm not sure that it is.

1:55:23 I don't either.

1:55:24 based on the current evidence, but you know, at the end of the day,

1:55:28 I think that that person's probably already doing things right,

1:55:31 and that's really what matters.

1:55:33 So, that's that's kind of where I'm at.

1:55:35 Well, you'll get someone else on here who can articulate

1:55:37 the seed oil point much more eloquently than I can.

1:55:39 Yeah.

1:55:39 If there's if there's a a researcher doing that, I'll look into that.

1:55:43 Um, but kind of going back to this fat cells and shrinking and you

1:55:46 you were talking about the the atyposites

1:55:48 kind of becoming insulin resistance first, insulin resistant first.

1:55:52 And and that kind of leads into something that I I forgot I

1:55:55 wanted to ask you about as we were talking about some of this before.

1:55:58 And that is, you know,

1:55:59 insulin resistance doesn't happen at the same time in all tissues.

1:56:04 And and so it'd be kind of nice to just talk about

1:56:07 that briefly before we continue on in terms of like the muscle,

1:56:11 the atapost tissue, the liver.

1:56:13 Um what happens when each of those become insulin resistance?

1:56:16 Um insulin resistant and you also talked about atapost tissue.

1:56:20 Yeah.

1:56:20 Maybe first is that then contributing

1:56:22 to the other ones then becoming insulin resistant.

1:56:25 Yeah.

1:56:25 Yeah.

1:56:25 So I absolutely so there are people who would say no the fat is

1:56:28 first when it becomes so what what is the first domino if if it's

1:56:32 a sequence of tissues which is the first to fall when it comes

1:56:36 to here's the person healthy here they're

1:56:38 progressing through insulin resistance with type two diabetes

1:56:41 being the most obvious outcome at the end of it what's the progression some

1:56:46 would say it's the liver some would say it's muscle some would say it's

1:56:49 fat it's the fat uh in my view very strongly it's the fat tissue

1:56:55 Um so insulin resistance in its earliest

1:56:58 stages is high insulin but normal glucose.

1:57:02 The problem with invoking a fat a muscle centric view

1:57:06 or a liver centric view or I need to add one

1:57:09 an alpha cell centric view because that's also relevant of the pancreas

1:57:12 for a reason I'll I'll touch on in a moment.

1:57:15 The moment those become insulin resistant glucose

1:57:18 is not going to be controlled anymore.

1:57:20 and and so then you skip a step because insulin resistance if

1:57:23 you look at the progression of the person towards type two diabetes

1:57:26 the insulin has come up first and then the glucose is normal

1:57:30 and the glucose will start to climb and that's when we detect the problem.

1:57:34 So my view is the fat cell falls first.

1:57:37 It's the first tissue to become insulin resistant

1:57:40 as it starts to experience some degree of hypertrophy.

1:57:44 That then starts to facilitate the other tissues becoming insulin resistant.

1:57:50 And at that point, there's no order in my mind.

1:57:52 It'd be hard to distinguish if there's another order.

1:57:56 But I actually when I teach this very idea to my students,

1:57:58 I one of my undergraduate assignments is a class called pathophysiology.

1:58:02 And these kids are fortunate enough to learn

1:58:04 the true origins of type two diabetes from an expert.

1:58:07 But I actually show the fat cell first and then the next step I say I teach it

1:58:13 in this concept of all right well what flips

1:58:15 the switch from pre-diabetes insulin resistance to type 2 diabetes.

1:58:19 What is it that makes the glucose go up?

1:58:21 That is then when the muscle becomes insulin resistant

1:58:24 you have lost access of the main glucose consumer.

1:58:28 So you are you're clearing the glucose out far of the blood

1:58:32 far worse less readily than you were before resulting in a hypoglycemia.

1:58:36 When the liver becomes insulin resistant

1:58:38 insulin can no longer inhibit glycogenolysis.

1:58:42 So normally one of the mechanisms whereby the liver

1:58:45 works with insulin is by storing glucose as glycogen.

1:58:50 Insulin inhibits the breakdown of that glycogen

1:58:53 unless the liver has become insulin resistant.

1:58:56 Now the liver is breaking down glycogen and releasing it as glucose even

1:58:59 when insulin is attempting to tell it

1:59:01 not to thereby further compounding the hypoglycemia.

1:59:05 Then the last one is the most overlooked

1:59:08 but absolutely relevant which is the alpha cell.

1:59:12 The alpha cell is the yin to the beta cell's yang where the beta

1:59:16 cell releases insulin and insulin's most famous job is to lower blood glucose.

1:59:21 The alpha cell releases glucagon and its

1:59:24 most famous job is to increase blood glucose.

1:59:26 So it's very important for fasting and exercise.

1:59:29 The opposite of when insulin would be up basically.

1:59:32 But the alpha cell knows when to not

1:59:36 release glucagon when the beta cell is releasing

1:59:38 a lot of insulin because insulin and their nextoor

1:59:41 neighbors within the eyelets of the pancreas.

1:59:44 Insulin will flood the beta cell with or rather ins

1:59:48 the beta cell will flood the alpha cell with insulin and insulin

1:59:52 will inhibit the production of glucagon which is good because then

1:59:55 that helps insulin overall affect blood glucose to bring it down.

1:59:59 But the alpha cell can become insulin resistant.

2:00:01 Dr.

2:00:02 Roger Unger at UT Southwestern over years published a series of mind-blowingly

2:00:07 cool papers finding that in type 1 diabetes if you just

2:00:12 control the glucagon excess you don't even need to give the patient

2:00:16 insulin that you could correct all hypoglycemia by just inhibiting the glucagon.

2:00:21 So that's just a weird little feature of the fact that when

2:00:24 the alpha cell becomes insulin resistant and it does it starts

2:00:28 releasing uncontrolled glucagon which comes to the liver and once again is

2:00:33 telling the liver to make glucose and release it into the bloodstream.

2:00:36 So the fat tissue becomes insulin resistant first that facilitates

2:00:42 the insulin resistance of the glucose controlling tissues muscle,

2:00:47 liver and the alpha cells.

2:00:48 And when those start to become insulin resistant in any particular order,

2:00:52 that's when you start to see the gl the glucose start to climb.

2:00:55 But we know decades potentially before

2:00:59 the person ever starts to have hypoglycemia, they have hyperinsulinemia.

2:01:04 That's why I think the fat cell is subtle enough in its

2:01:07 metabolic demands that it doesn't really need a lot of glucose.

2:01:10 Its metabolic rate is so modest.

2:01:13 So it can become insulin resistant

2:01:14 without really affecting fasting glucose levels.

2:01:18 So the person's fasting glucose levels can stay normal.

2:01:21 But once the glucose handling tissues like the three

2:01:24 I've already articulated become insulin resistant now glucose is uncontrolled.

2:01:29 Going back to the this fat cell hyperplasia like a lot of you know

2:01:33 forming lots of different fat cells versus

2:01:35 this you know swelling of it the hypertrophy.

2:01:38 If a person loses weight,

2:01:40 like let's let's say they're they're on a weight loss diet.

2:01:43 They're, you know, doing restricting their calories, they're doing low carb,

2:01:47 they're exercising, any of the combination of those.

2:01:51 What happens to the fat cells?

2:01:53 Do they shrink?

2:01:54 They shrink.

2:01:55 They shrink.

2:01:56 Do you ever do they ever die?

2:01:58 They do.

2:01:58 Yeah, they do.

2:01:59 Yeah.

2:01:59 But they shrink.

2:02:00 So, I actually say when I talk about this in my class,

2:02:02 I say the patient's on a fat cell shrinking journey.

2:02:05 That's exactly how I describe it because that is weight loss.

2:02:08 All weight loss is shrinking of the fat cells.

2:02:12 Now, however, a fat cell has a lifespan of about 10 years.

2:02:16 And so, depending on the utility of that fat cell,

2:02:18 it may not be replaced or it may be replaced.

2:02:21 And so, you can over time lose fat cell number.

2:02:24 And indeed, you do.

2:02:25 At around 60 years old, 60 to 70 a person.

2:02:29 So, during infancy, childhood, puberty, we're making fat cells.

2:02:33 And then for the most part the number of fat cells we have is set.

2:02:38 Now women have a little buffer like I said earlier but even then you could

2:02:41 have a person who gains a hundred more pounds or 200 more pounds in adulthood.

2:02:46 For the the for the average individual

2:02:48 that's hypertrophy not a result of hyperplasia.

2:02:52 But then when we get to older age

2:02:53 then the number of fat cells stop turning over.

2:02:56 So as they start dying at their 10year lifespan we don't replace them.

2:03:00 And so at the end of life we have a little drop off in the number of fat cells.

2:03:04 Uh um so no so weight loss is shrinking the size not changing the number.

2:03:09 And in fact if you force artificial weight loss

2:03:13 by sucking out fat cells where you are just

2:03:16 sucking out the fat cells and reducing fat cell

2:03:19 number then you don't improve any cardioabolic outcome whatsoever.

2:03:23 So there's many studies that show that you can have people lose a significant

2:03:27 amount of fat through liposuction and there not a single outcome has improved.

2:03:31 Whereas if that same person had lost that 20

2:03:34 pounds of fat through normal lifestyle interventions like you'd mentioned,

2:03:38 they would have had improvements in every cardabolic outcome.

2:03:41 But you don't do that with liposuction because

2:03:43 you haven't changed the size of the fat cell.

2:03:46 The size of your fat cells is the same.

2:03:47 You've just sucked out a lot, but the remaining ones are still there.

2:03:51 And now in fact you've put a greater pressure on them

2:03:55 because a person an adult doesn't make new fat cells very readily.

2:03:59 So what will happen is the remaining fat cells will be forced to grow through

2:04:02 size because they can't share the burden

2:04:04 with their other neighbors that you've sucked out already.

2:04:07 So when a person starts to regain

2:04:09 weight the cardioabolic outcomes are amplified.

2:04:13 When when people do um lose weight and they're shrinking their fat cell size,

2:04:18 are those fat cells like let's say someone was even insulin resistant, right?

2:04:22 And there's a problematic fat cell and it shrinks in size.

2:04:27 They lose weight, it shrinks in size.

2:04:28 I mean, is it still problematic?

2:04:31 No.

2:04:32 No.

2:04:31 No.

2:04:31 In fact, that's why with the slow insulin resistance,

2:04:34 the reversal of that like over the 90 days in the type

2:04:38 2 diabetic patients that we had in our published case series,

2:04:42 uh that would have been not that we measured this, but it

2:04:44 would have been because of a shrinking of the fat cell.

2:04:47 Now, let's say they grow those fat cells again,

2:04:51 the same problems will come back.

2:04:53 So whatever intervention, one of the problems I have with diet,

2:04:56 whatever the intervention is, low carb or, you know,

2:04:59 calorie restricted, whatever, people will complain and they'll say, "Well,

2:05:03 but it's only short term." Yeah, of course it is.

2:05:07 Um, whatever a person has done to reverse their metabolic problems

2:05:10 will only persist as long as they adhere to those changes.

2:05:14 Uh, the more they go back to their old habits,

2:05:17 the more the same consequences will return because

2:05:20 it was those old habits that caused it.

2:05:23 with respect to the visceral fat and I mean I particularly the visceral

2:05:27 fat since it's the fat that's really got that expansion of the fat cells

2:05:31 you can only go through hypertrophy

2:05:32 right only going through hypertrophy what what sort of targeted diet lifestyle

2:05:38 interventions would be suggested or evidence-based

2:05:42 to to actually decrease the visceral fat

2:05:44 yeah that's a great question so visceral adiposites are more

2:05:48 responsive to the lipolytic signal the fat breakdown signal of epinephrine.

2:05:53 So, anything that increases epinephrine will

2:05:56 have sort of poundfor-pound or sight for sight visceral versus subcutaneous is

2:06:01 going to have a better visceral response.

2:06:04 Um, so the more the epinephrine is being targeted,

2:06:06 so that's going to be things like exercise and like cold therapy,

2:06:10 for example, cold immersion, talked about an epinephrine spike.

2:06:14 So anytime you're really activating the sympathetic nervous system,

2:06:17 you're going to be sort of molecule for molecule,

2:06:20 cell for cell, targeting the visceral more than the subcutaneous.

2:06:24 So it is more responsive to that sympathetic tone than subcutaneous fat is.

2:06:30 Interesting.

2:06:30 So epinephrine, high-intensity interval training

2:06:32 is really like more intense exercise.

2:06:34 Again, back to that and then yeah, deliberate cold exposure.

2:06:37 Another one.

2:06:37 Great.

2:06:38 And I'm a big advocate of cold immersion.

2:06:41 Great.

2:06:41 Yeah.

2:06:41 Okay.

2:06:42 Well, that's interesting.

2:06:42 Um, I didn't know about the ep the the fact

2:06:44 that epinephrine was was linked to that as a as a mechanism.

2:06:48 Okay.

2:06:48 So, uh, a little bit about we talked

2:06:50 a little bit about the the muscle mass and I

2:06:52 think just the the the one thing that was kind of on my mind was that sort of

2:06:58 anabolic paradox of insulin.

2:07:01 Yeah.

2:07:00 And and kind of what your thoughts are with respect

2:07:02 to like you know some bodybuilders are injecting insulin, right?

2:07:05 Um, so how Yeah.

2:07:08 like let's let's talk about a little bit like reconciling insulin's role

2:07:11 as being this you know anabolic versus

2:07:14 you know storing fat being metabolically problematic.

2:07:17 Yeah.

2:07:17 Yeah.

2:07:17 So I want to be careful in answering this because

2:07:19 I'm an insulin guy but I'm not a muscle cell guy.

2:07:22 Um but because I'm familiar with insulin

2:07:25 I'm comfortable enough answering this question.

2:07:28 So there was a group in fact I think it was

2:07:30 the same guy I mentioned earlier Shrinire NI at Minnesota at the time.

2:07:35 They published a paper finding that insulin

2:07:39 wasn't necessary for muscle protein synthesis.

2:07:42 So, so you have the here we have the muscle and we

2:07:44 have the protein formed giving the the bulk of the muscle.

2:07:48 There's you have to look at both the stimulus

2:07:51 building it and the signals that are breaking it down.

2:07:54 They documented that insulin was not necessary for muscle protein

2:07:58 synthesis but it was very helpful for inhibiting the breakdown.

2:08:02 So it they suggested that insulin's main effect on muscle

2:08:05 is an anti-p proteolytic effect rather than a stimulating effect.

2:08:11 So that my general view is that that's where insulin is going to be favorable.

2:08:15 But it also didn't take a lot of insulin to inhibit the proteolysis.

2:08:18 So I do not think it's at all justified to take

2:08:22 insulin as an intervention to try to promote muscle growth.

2:08:26 And in fact, just as a very unscientific observer,

2:08:30 when I compared the physiques of Arnold and Lou from the old 1980s bodybuilders

2:08:35 to the modern-day bodybuilders and the almost

2:08:37 bizarre phenotype of this like bubble belly, do you know what I'm talking about?

2:08:42 Anyone listening probably knows what I'm talking about, but I want to be polite.

2:08:45 You know, these are real guys.

2:08:47 But we can all agree that there's an odd physique.

2:08:50 You know, whereas Arnold and Lou were extremely tapered,

2:08:54 very, very narrow waist.

2:08:57 Modern bodybuilders, yes, they're more jacked,

2:08:59 but they're also oddly distended with their abdomen.

2:09:04 I can't help but wonder whether

2:09:05 insulin has been somehow facilitative to promoting

2:09:08 some degree of visceral growth because insulin wants to promote fat growth.

2:09:13 It wants to, no matter, it's like a fertilizer for fat cells.

2:09:16 And so someone who's who's wanting to overdose on insulin in an effort

2:09:21 to promote muscle when you're just

2:09:22 maybe enhancing some proteolytic antipolytic effect,

2:09:26 I'd say there are better ways to do it.

2:09:28 Like not that I'm endorsing any intervention like this, but you'd be better

2:09:32 off just focusing on growth hormone

2:09:33 than you would injecting yourself with insulin.

2:09:35 So I am not a fan.

2:09:37 Now I appreciate some big yolked bodybuilder looking

2:09:39 at relatively spelty small Ben Bickman and saying, "Well, what do you know?

2:09:43 Maybe I don't know a lot." Um, no, I I think I think that was a that's

2:09:47 a really good those are great points that you made.

2:09:50 For sure.

2:09:50 For sure.

2:09:51 Um, I think we covered a lot of the muscle effects on insulin and, you know,

2:09:56 how exercise is so important,

2:09:58 growing muscle tissue and exercise is important for, you know,

2:10:01 allowing the muscle to be that, you know, site of glucose disposal.

2:10:04 Um, but let's kind of then shift gears and talk about this weight loss.

2:10:08 And obviously I think right now there's a big

2:10:13 trend in rapid weight loss and and weight

2:10:16 loss that's made very easy um by taking GLP1 agonist drugs like Ozic and Wiggov.

2:10:24 And I I'd love to to know what your thoughts are on maybe

2:10:29 first you can explain just you know generally how these GLP1 agonists work

2:10:35 and why they're causing weight loss and how they affect metabolic

2:10:39 health but also whether they're addressing the underlying root cause of obesity.

2:10:47 Yeah.

2:10:47 And you know if if or if there's sort of shortcutting around that.

2:10:50 Right.

2:10:50 Well, there's no no no question.

2:10:51 It's it's a bit of a shortcut and I am I'm worried about the long-term effects.

2:10:56 So, with GLP1, I have had my finger on the pulse of GLP-1 probably since well,

2:11:03 not since the its inception, but since the late 90s, early 2000s.

2:11:07 My PhD lab was one of the first labs funded

2:11:11 in the US looking at the study of incrretins by a drug company.

2:11:15 And so I've I've long been familiar with GLP-1 and the other incrretins.

2:11:19 Incrretin being a word to describe

2:11:21 these gut derived hormones that have metabolic effects.

2:11:25 But it's been interesting for me to note

2:11:27 the evolution in their use because originally they

2:11:31 were only used as anti-diabetic drugs and then

2:11:35 the what was considered kind of an offtarget

2:11:38 effect of controlling satiety is now the mechanism

2:11:42 of action at these much higher doses

2:11:44 as the dose has been multiplied up to the kind of current WGO weight loss dose.

2:11:49 So it's really just been an evolution

2:11:50 in the dose of this of semiglutide for the most

2:11:53 part although there are other glutides that fit

2:11:56 in this as well but semiglutide is the main one.

2:11:59 So at the lower dose originally used

2:12:03 these GLP1 activators worked actually by inhibiting glucagon.

2:12:08 So back to the alpha cell that I mentioned earlier,

2:12:10 it's we come back to them now where in type two diabetes,

2:12:14 the insulin resistance of the alpha cell results

2:12:17 in a chronic elevation of glucagon chronically then

2:12:21 telling the liver to be releasing glucose leading

2:12:23 to the hypoglycemia that defines the diabetic state.

2:12:27 At this low dose, semiglutide inhibits the alpha cell.

2:12:31 It inhibits glucagon and by inhibiting glucagon,

2:12:34 you're helping correct blood glucose.

2:12:35 So it was an effective anti-diabetic.

2:12:38 Now some people have the very mistaken view

2:12:41 that semiglutide or GLP-1 activators also release insulin.

2:12:45 That is not true.

2:12:47 That has been shown to happen in isolated cell cultures.

2:12:51 But in humans there's no evidence.

2:12:53 And the authority on the subject is a guy named Arie.

2:12:56 A r nestrop.

2:12:58 A s t rup p.

2:13:00 Arie ostrop in uh in Denmark.

2:13:03 He's one of the absolute authorities on this topic.

2:13:05 He's published multiple papers in humans showing

2:13:08 that no amount of GLP-1 elicits an insulin release.

2:13:12 So that we need to put that idea to bed.

2:13:14 In humans, that does not happen.

2:13:15 GLP-1 does not act as what's called an insulin secret or a hormone

2:13:20 that a drug that forces the beta cell to make insulin.

2:13:24 GLP-1 inhibits glucagon, which helps correct blood glucose.

2:13:28 Now as the dose starts to go up higher just I