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Testing The Insulin Model: A Answer To Dr. Ludwig

Dr. David Ludwig, MD, late published a response to my critique of the carbohydrate-insulin-obesity hypothesis.  This is skilful because he defends the thought inwards to a greater extent than particular than I've encountered inwards other written works.  In fact, his slice is the most scientifically persuasive defence forcefulness of the thought I tin recall.

Before nosotros dig in, I desire to emphasize that this is science, non tribal warfare.  The goal is to brand it at the best answer, rather than to win an argument.  I'm proceeding inwards skilful faith, based on my belief that Ludwig in addition to I are both serious people who aid close scientific discipline in addition to human health, in addition to I promise my audience volition exercise the same.  That said, let's larn to it.

Introduction: CICO vs. insulin.  Or is in that location a 3rd model?

Similar to Gary Taubes, Ludwig presents a alternative betwixt the calories-in, calories-out model (CICO) of obesity, in addition to the insulin model.  The CICO model is the thought that our trunk weight is determined past times voluntary decisions close how much nosotros swallow in addition to move, in addition to inwards club to command our trunk weight, all nosotros involve is a niggling advice close how many calories to swallow in addition to burn, in addition to a niggling willpower.  The primary defining characteristic of this model is that it assumes that nutrient intake in addition to trunk fatness are non regulated.  This model seems to be mostly to brand lean people experience smug, since it attributes their leanness alone to wise voluntary decisions in addition to a strong character.

I think at this point, few people inwards the enquiry basis believe the CICO model.  Ludwig in addition to I both handgrip that it provides a miserable gibe for the evidence.  As an alternative, Ludwig proposes the insulin model, which states that the primary motility of obesity is excessive insulin activeness on obese cells, which inwards plough is caused principally past times rapidly-digesting carbohydrate.  According to this model, likewise much insulin reduces blood levels of glucose in addition to obese acids (the 2 primary circulating metabolic fuels), simultaneously leading to hunger, fatigue, in addition to obese gain.  Overeating is caused past times a form of "internal starvation".  There are other versions of the insulin model, but this is the ane advocated past times Ludwig (and Taubes), so it volition locomote my focus.

But there's a 3rd model, non mentioned past times Ludwig or Taubes, which is the ane that predominates inwards my field.  It acknowledges the fact that trunk weight is regulated, but the rule happens inwards the brain, inwards response to signals from the trunk that dot its liberate energy status.  Chief with these signals is the hormone leptin, but many others play a purpose (insulin, ghrelin, glucagon, CCK, GLP-1, glucose, amino acids, etc.).

Here is a simplified schematic overview of how the organisation works, from a 2012 review newspaper I wrote with my scientific mentor Mike Schwartz, titled "Regulation of nutrient intake, liberate energy balance, in addition to trunk obese mass" (1).  This figure summarizes to a greater extent than than a century of enquiry inwards our field:

Here's the gist of it: in that location are negative feedback loops betwixt the encephalon in addition to obese tissue, in addition to betwixt the encephalon in addition to the gut.  These are what regulate trunk fatness in addition to appetite.  The primary known feedback signal that regulates trunk fatness is leptin-- a fact that has remained scientifically unchallenged since shortly after its identification inwards 1994.  Insulin plays a purpose equally well, acting direct on the encephalon inwards a trend similar to leptin, although much less powerfully.  As y'all tin see, this model doesn't resemble the CICO model-- or the insulin model.

Regulation happens principally equally a outcome of the encephalon changing the number of calories entering in addition to leaving the trunk (in humans, mostly entering)-- so the much-maligned calorie maintains a fundamental purpose inwards the process.  Even though calories aren't the outset link inwards the causal chain, they are all the same a critical link.

Most people inwards my acre also believe that calorie intake is determined both past times hunger (homeostatic eating), in addition to factors other than hunger (non-homeostatic eating).  I handgrip with them.

So this 3rd model acknowledges the importance of regulation, the importance of unregulated factors, in addition to the importance of calories.  Although it's to a greater extent than complex than the insulin in addition to CICO models, it has the wages of beingness supported past times a large trunk of evidence.  Let's telephone telephone it the leptin model, for simplicity's sake.  I won't pass much to a greater extent than fourth dimension on it because it's peripheral to this debate, but I did desire to articulate it equally a 3rd model so nosotros aren't limiting our choices to 1) a CICO model that is apparently wrong, in addition to 2) the insulin model.

I'm non going to exercise a point-by-point response to Ludwig's point-by-point response, because that would locomote exceedingly cumbersome.  What I'll exercise instead is attempt to distill out the most of import concepts, in addition to beak over those.  In particular, I'll locomote focusing on key lines of bear witness that take away hold the potential to support-- or falsify-- the insulin model.  This is where the safe meets the route for hypothesis testing.

Is obesity caused past times internal starvation?

In my initial post, I pointed out that people with obesity take away hold normal or elevated levels of blood glucose in addition to obese acids-- non lower levels equally the insulin model predicts (1a, 1b, 1c).  This suggests that 1) they are non suffering from "internal starvation", 2) they are non suffering from excessive insulin activeness (including on obese cells), in addition to 3) so this machinery cannot explicate the well-established fact that people with obesity tend to swallow close twenty per centum to a greater extent than calories than lean people (2, 3).

Ludwig countered that "static analysis after obesity has developed, rather than during its dynamic stages, are misleading".  In other words, I was focused on the incorrect stage of obesity; nosotros should locomote looking at the weight gain stage instead.  Let's think through the implications of this statement.  It implies that internal starvation makes us overeat equally we're gaining weight, but doesn't explicate continued overeating ane time nosotros orbit the obese state, or the fact that the obese nation persists after internal starvation is no longer occurring.  It so also requires the existence of 2 split upwards mechanisms that motility overeating, ane involving internal starvation in addition to ane not, in addition to requires a hand-off betwixt them at or so dot inwards time.  I'm non aware of experimental bear witness that supports whatever of this.

Let's accept a closer await at the weight gain phase, equally suggested.  Is in that location bear witness that people who are gaining weight take away hold lower glucose in addition to obese acid levels than people who aren't?  There is not.  I'm non aware of whatever bear witness inwards humans or inwards animate beingness models of diet-induced obesity that circulating glucose or obese acid levels are lower during active weight gain.  In Mike Schwartz's lab, nosotros take away hold done countless glucose measurements inwards mice in addition to rats gaining weight speedily due to a fattening diet, in addition to nosotros take away hold also measured circulating obese acid levels at times, in addition to neither ane is decreased during active obese gain (3a).

Ludwig acknowledges this lack of bear witness inwards his article, but instead focuses on indirect bear witness that's non peculiarly relevant to mutual obesity, such equally hypothalamic lesions inwards rodents (As an aside, Bruce King has shown that the fattening outcome of VMN lesions does non depend on increased insulin levels (4), in addition to John Brobeck showed inwards the 1940s that these lesions motility voracious overeating equally presently equally the anesthesia wears off, non after or so flow of altered obese tissue metabolism (5).  In whatever case, alterations inwards obese tissue metabolism are the outcome of the encephalon lesion, showing that the encephalon is influencing obese tissue metabolism inwards these experiments, non the reverse).

So inwards summary, in that location is no direct bear witness that internal starvation occurs during 1) weight gain or 2) the overweight/obese state, in addition to in that location is or so direct bear witness that it does non occur.  The internal starvation hypothesis rests alone on indirect bear witness that I don't let on peculiarly pertinent.

But let's accept a stride dorsum for a minute.  Are depression circulating obese acid levels able to activate the brain's hunger circuits inwards the outset place, leading to increased nutrient intake in addition to weight gain?  Because if they aren't, in addition to so it's hard to sympathize how insulin (or anything else) would Pb to overeating past times reducing obese acid levels.  This is testable.  To attempt out it, nosotros would desire to cut down circulating obese acid levels in addition to consider if it provokes a hunger response, in addition to ideally, weight gain.  Fortunately for us, this study has been done.

Hideo Makimura in addition to colleagues late published the results of a 6-month randomized, placebo-controlled study inwards which they used a drug called acipimox to chronically cut down circulating costless obese acid levels inwards people with obesity (6).  The drug caused a substantial (38%) reduction of costless obese acid levels for the duration of the 6-month study.

According the thought of internal starvation, the acipimox grouping should take away hold been ravenously hungry in addition to gained obese rapidly, in addition to liberate energy expenditure should take away hold declined equally well.  Yet the researchers reported that "caloric in addition to relative macronutrient intake did non alter significantly betwixt groups".  Neither group's BMI or trunk composition changed significantly, nor did their liberate energy expenditure.  The study was published inwards the Journal of Clinical Endocrinology in addition to Metabolism, a respected magazine inwards my field.

The encephalon monitors a number of signals from the trunk to stair out liberate energy status, in addition to it uses these to gear upwards your appetite.  Apparently, depression circulating obese acid levels are non ane of the signals the human encephalon pays attending to when it sets appetite.  This seriously undermines the concept of internal starvation, in addition to consequently the insulin model.

In contrast, nosotros take away hold strong bear witness that the human encephalon pays unopen attending to circulating levels of leptin.  When leptin levels are low, whether due to weight loss or mutations inwards the leptin gene, it triggers a full-blown starvation response including increased hunger, increased responsiveness to nutrient cues, in addition to reduced liberate energy expenditure.  Bringing leptin levels dorsum to normal via injection terminates this starvation response, clearly demonstrating that depression leptin was the principal motility (7, 8, 9, 10, 11, 12, 13).  These results don't locomote out much room for insulin or obese jail cellular telephone metabolism to locomote involved inwards the body's starvation response (except mayhap equally downstream effectors of leptin).

Do high insulin levels predict obese gain?

This is a straightforward prediction of the insulin model, in addition to nosotros take away hold many human studies with which to attempt out it.  In my initial post, I cited a systematic review newspaper that summarized the results of 22 prospective studies examining this prediction (14).  Overall, the literature suggests that people with high insulin levels exercise non gain to a greater extent than weight or obese over fourth dimension than people with depression insulin levels.

Ludwig countered past times arguing that what matters isn't insulin levels, but insulin action; inwards other words, how much of an impact the insulin truly has on cells in addition to tissues.  Insulin activeness is determined both past times insulin levels in addition to insulin sensitivity (how good tissues "hear" the insulin signal).  This is the same declaration I take away hold used to interrogation the insulin model, because proponents ofttimes assume that high insulin levels automatically imply elevated insulin action.  They mostly overlook the fact that people with high insulin are almost invariably insulin resistant (including their obese tissue), in addition to that insulin action is normal or reduced (as judged past times normal or elevated blood glucose in addition to obese acids, in addition to normal or elevated whole-body lipolysis rates).

In fact, this is exactly the argue why insulin injections, insulin-producing tumors, in addition to similar non-physiological examples cited past times Ludwig in addition to Taubes are irrelevant to the interrogation at hand.  These arguments endeavor to depict an analogy betwixt non-physiological insulin excess in addition to garden-variety hyperinsulinemia-- but inwards the latter case, in that location is no bear witness that insulin action on obese cells is truly increased, in addition to a fair chip of bear witness that it isn't.

In whatever case, I handgrip with Ludwig's basic premise that insulin activeness is what truly matters.  Yet if nosotros render to the review newspaper I cited, it didn't merely consider studies that measured fasting insulin levels.  The studies measured multiple insulin-related variables, including fasting insulin levels, insulin sensitivity, in addition to the insulin response to a glucose challenge.  Although nosotros could cite private studies to back upwards whatever hypothesis nosotros want, the overall literature suggests that none of these variables are reliably associated with weight gain.  In fact, I'm non aware of any insulin-related variable that is reliably associated with weight or obese gain inwards humans, despite intensive enquiry inwards this area.  Perhaps we're non measuring the correct thing, or non measuring inwards the correct way, but that possibility is cypher to a greater extent than than speculation at this point.

Ludwig suggests that nosotros should locomote looking for the effects of insulin during the weight gain phase.  That is exactly what these studies take away hold done, in addition to they did non let on that weight gain was consistently associated with a distinct insulin signaling profile inwards whatever measured way.

So we've measured insulin levels, insulin sensitivity, in addition to the insulin response to carbohydrate.  We've measured them inwards people who are gaining weight in addition to people who aren't.  We've measured them inwards multiple races in addition to ages.  And no clear designing has emerged suggesting that insulin signaling mightiness locomote playing an of import purpose inwards the fattening process.  Again, it's ever possible that nosotros haven't measured the correct variable yet, or haven't measured it inwards the correct way, but that is cypher to a greater extent than than speculation at this point.  Currently I let on this bear witness rather hard to reconcile with the insulin model.

Do low-glycemic diets function for obese loss?

If rapidly-digesting saccharide that markedly elevates insulin levels is a major driver of overeating in addition to weight/fat gain, in addition to so low-glycemic diets that cut down insulin exposure should locomote an effective tool for reducing nutrient intake in addition to trunk weight.  In my initial post, I reviewed bear witness suggesting that 1) the glycemic index doesn't reliably predict the satiety response to mutual foods, in addition to 2) low-glycemic diets are ineffective for weight control.

To the outset point, Ludwig countered that the study I cited only measured the satiety response over a two-hour period, but hunger unremarkably occurs afterward (15).  He also cited a review newspaper he wrote inwards 2002 suggesting that single-meal studies take away hold mostly found that low-glycemic meals are to a greater extent than sating than high-glycemic meals (16).  This is a fair point, in addition to the cited bear witness does back upwards it (although many of these studies were non controlled for other differences known to impact satiety, such equally fiber content, palatability, in addition to calorie density).  However, findings inwards this expanse haven't been especially consistent, in addition to inwards a few cases high-glycemic foods were truly to a greater extent than sating (17, 18, 19).  I exercise admit that the weight of the bear witness is inwards his military camp on this point.

But inwards whatever case, what nosotros truly aid close is non what happens at a unmarried meal, but what happens over the long haul.  That is the interrogation my 2nd dot addresses.  We take away hold quite a chip of bear witness suggesting, fairly consistently, that low-glycemic diets don't function for weight loss (20, 21, 22, 23, 24, 25, 26).

Ludwig countered that these studies "suffer from severe non-compliance, limiting inferences".  In other words, people don't follow the experimental diet really faithfully, explaining why the diets appear ineffective.  While I handgrip that adherence is ever a limiting constituent inwards human trials that don't lock people upwards inwards a enquiry ward, miserable adherence doesn't explicate the zero results inwards this case.

For ane thing, adherence is ever a employment inwards human diet trials, but they all the same ofttimes study weight loss.  This has been shown for the low-carb diet, the Paleo diet, the vegan diet, the Mediterranean diet, elementary part control, in addition to fifty-fifty the embattled low-fat diet.  Some of these are tough diets that people take away hold a hard fourth dimension sticking with, but they soundless motility measurable weight loss despite imperfect adherence.  In diet trials, adherence rates to low-glycemic diets are similar to those of other diets, so it's hard to sympathize how this would explicate the lack of efficacy.

But let's larn specific.  I'd similar to start with a study that may locomote the purest attempt out of the hypothesis available (27).  It was conducted past times Walter Willett in addition to Frank Hu, 2 of Ludwig's colleagues at Harvard.

They randomized 203 salubrious women (average BMI = 27) to ane of 2 diets: high-glycemic or low-glycemic.  Differences inwards glycemic index were achieved primarily past times eating different types of rice that take away hold different digestion speeds, so the study was relatively good controlled for other aspects of diet similar fiber, calorie density, palatability, etc.  The overall glycemic index (and glycemic load) of the diets differed past times two-fold (40 vs. 79), which implies a large departure inwards both glucose in addition to insulin exposure.  This large departure was sustained for the total xviii months of the intervention.

There were no important differences inwards hunger or calorie intake betwixt the 2 groups.  At 2 months, in that location was a trivial departure inwards trunk weight of 0.4 kg favoring the low-glycemic group, but this disappeared past times the destination of the study.  The conclusion is that large in addition to sustained differences inwards post-meal glucose in addition to insulin exposure take away hold no meaningful long-term impact on hunger, nutrient intake, or trunk weight inwards women (who were overweight on average).

Let's consider or so other study-- the ane from Ludwig's grouping that I cited previously (28).  This 18-month randomized trial pitted a low-glycemic-load diet against a low-fat diet inwards 73 obese immature adults.  The low-glycemic diet was focused on whole foods similar vegetables, beans, in addition to fruit, at the expense of refined grains, starchy vegetables, fruit juice, in addition to sweets.  The low-fat diet was focused on low-fat grains, vegetables, fruits, in addition to beans, at the expense of of added fats, sweets, in addition to high-fat snacks.  The low-glycemic diet was a chip lower inwards saccharide (40% vs 55%), in addition to both diets were fairly high inwards poly peptide (25%).  Neither diet was calorie restricted.

Glycemic charge differed substantially on the 2 diets, in addition to a departure was maintained over the 18-month study, although it narrowed at 12 in addition to xviii months.  This implies substantial differences inwards glucose in addition to insulin exposure.

So what happened?  Hunger, calorie intake, in addition to player satisfaction didn't differ betwixt groups.  Both groups lost weight (4-5 kg at max), but the magnitude in addition to trajectory of weight loss betwixt the 2 groups was virtually identical (see graph below).  Substantial differences inwards diet-related glucose in addition to insulin exposure did non outcome inwards detectable differences inwards hunger, calorie intake, weight loss, or weight regain.
18-month weight changes inwards Ebbeling et al. Note the p-value of 0.99,
indicating that the 2 trajectories are statistically indistinguishable.
In his response to my post, Ludwig pointed out that subjects who had a greater insulin response to a glucose challenge at baseline experienced to a greater extent than weight loss on the low-glycemic-load diet.  This is true, but nosotros take away hold to maintain the finding inwards context.  The study wasn't randomized to reply this interrogation (unlike a recent study from Christopher Gardner's group; 29), so this is what's called an "exploratory analysis".  These ship less weight than the primary outcomes of a study, which are those that I discussed above.  Exploratory analyses tin sure as shooting locomote informative, in addition to there's cypher incorrect with conducting in addition to publishing them, but they are meliorate suited for generating hypotheses than for testing hypotheses.  And they never trump the primary outcomes of a study.

The most straightforward interpretation of the study is that if you're a immature adult with obesity, reducing the glycemic charge of your diet, in addition to consequently your insulin exposure, has no special powerfulness to curtail your appetite or aid y'all lose weight.  You mightiness equally good larn on a low-fat, high-carbohydrate, high-glycemic diet.  This is consistent with the results of the previous study I discussed, in addition to the repose of the literature equally a whole.

It remains possible that low-glycemic diets are helpful for a subset of people, but electrical flow bear witness suggests they are non really effective equally a full general strategy for managing appetite in addition to weight-- counter to what the insulin model predicts.


In summary, several key predictions of the insulin model are non supported past times the evidence, explaining why this model doesn't larn much traction inwards my field.  There is essentially no direct bear witness that the proposed machinery occurs during or after normal weight gain, a fair amount of direct bear witness that it doesn't, in addition to the arguments inwards favor of it are based on indirect bear witness whose relevance to mutual obesity is ofttimes questionable.

I give thank y'all Dr. Ludwig for the chance to clarify my thoughts on this, in addition to I want him luck inwards his ongoing research.



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