Testing The Insulin Model: A Reply To Dr. Ludwig

Dr. David Ludwig, MD, of late published a response to my critique of the carbohydrate-insulin-obesity hypothesis.  This is expert 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 of the thought I tin flaming recall.

Before nosotros dig in, I desire to emphasize that this is science, non tribal warfare.  The destination is to larn far at the best answer, rather than to win an argument.  I'm proceeding inwards expert faith, based on my belief that Ludwig as well as I are both serious people who aid almost scientific discipline as well as human health, as well as I promise my audience volition practice 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 choice betwixt the calories-in, calories-out model (CICO) of obesity, as well as the insulin model.  The CICO model is the thought that our trunk weight is determined past times voluntary decisions almost how much nosotros consume as well as move, as well as inwards lodge to command our trunk weight, all nosotros ask is a petty advice almost how many calories to consume as well as burn, as well as a petty willpower.  The primary defining characteristic of this model is that it assumes that nutrient intake as well as trunk fatness are non regulated.  This model seems to be mostly to brand lean people experience smug, since it attributes their leanness solely to wise voluntary decisions as well as a strong character.

I think at this point, few people inwards the enquiry globe believe the CICO model.  Ludwig as well as I both handgrip that it provides a hapless lucifer for the evidence.  As an alternative, Ludwig proposes the insulin model, which states that the primary drive of obesity is excessive insulin activeness on obese cells, which inwards plow is caused principally past times rapidly-digesting carbohydrate.  According to this model, besides much insulin reduces blood levels of glucose as well as obese acids (the ii primary circulating metabolic fuels), simultaneously leading to hunger, fatigue, as well as obese gain.  Overeating is caused past times a variety of "internal starvation".  There are other versions of the insulin model, but this is the 1 advocated past times Ludwig (and Taubes), so it volition hold upwards my focus.

But there's a 3rd model, non mentioned past times Ludwig or Taubes, which is the 1 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 shout for its release energy status.  Chief amidst these signals is the hormone leptin, but many others play a exercise (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 amongst my scientific mentor Mike Schwartz, titled "Regulation of nutrient intake, release energy balance, as well as 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 as well as obese tissue, as well as betwixt the encephalon as well as the gut.  These are what regulate trunk fatness as well as 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 exercise equally well, acting straight on the encephalon inwards a fashion similar to leptin, although much less powerfully.  As yous tin flaming see, this model doesn't resemble the CICO model-- or the insulin model.

Regulation happens principally equally a termination of the encephalon changing the number of calories entering as well as leaving the trunk (in humans, mostly entering)-- so the much-maligned calorie maintains a key exercise inwards the process.  Even though calories aren't the offset link inwards the causal chain, they are soundless a critical link.

Most people inwards my land also believe that calorie intake is determined both past times hunger (homeostatic eating), as well as factors other than hunger (non-homeostatic eating).  I handgrip amongst them.

So this 3rd model acknowledges the importance of regulation, the importance of unregulated factors, as well as the importance of calories.  Although it's to a greater extent than complex than the insulin as well as 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 land wrong, as well as 2) the insulin model.

I'm non going to practice a point-by-point response to Ludwig's point-by-point response, because that would hold upwards exceedingly cumbersome.  What I'll practice instead is seek to distill out the most of import concepts, as well as hash out those.  In particular, I'll hold upwards focusing on key lines of evidence that take away hold the potential to support-- or falsify-- the insulin model.  This is where the prophylactic meets the route for hypothesis testing.

Is obesity caused past times internal starvation?

In my initial post, I pointed out that people amongst obesity take away hold normal or elevated levels of blood glucose as well as 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), as well as 3) hence this machinery cannot explicate the well-established fact that people amongst obesity tend to consume almost twenty pct 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 hold upwards 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 1 time nosotros compass the obese state, or the fact that the obese Earth persists after internal starvation is no longer occurring.  It hence also requires the existence of ii split upwards mechanisms that drive overeating, 1 involving internal starvation as well as 1 not, as well as requires a hand-off betwixt them at roughly dot inwards time.  I'm non aware of experimental evidence that supports whatever of this.

Let's take away hold a closer expect at the weight gain phase, equally suggested.  Is in that location evidence that people who are gaining weight take away hold lower glucose as well as obese acid levels than people who aren't?  There is not.  I'm non aware of whatever evidence inwards humans or inwards beast 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 as well as rats gaining weight chop-chop due to a fattening diet, as well as nosotros take away hold also measured circulating obese acid levels at times, as well as neither 1 is decreased during active obese gain (3a).

Ludwig acknowledges this lack of evidence inwards his article, but instead focuses on indirect evidence that's non especially relevant to mutual obesity, such equally hypothalamic lesions inwards rodents (As an aside, Bruce King has shown that the fattening lawsuit of VMN lesions does non depend on increased insulin levels (4), as well as John Brobeck showed inwards the 1940s that these lesions drive voracious overeating equally shortly equally the anesthesia wears off, non after roughly catamenia of altered obese tissue metabolism (5).  In whatever case, alterations inwards obese tissue metabolism are the termination 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 evidence that internal starvation occurs during 1) weight gain or 2) the overweight/obese state, as well as in that location is roughly direct evidence that it does non occur.  The internal starvation hypothesis rests solely on indirect evidence that I don't give away especially pertinent.

But let's take away hold a pace dorsum for a minute.  Are depression circulating obese acid levels able to activate the brain's hunger circuits inwards the offset place, leading to increased nutrient intake as well as weight gain?  Because if they aren't, 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 bear witness it, nosotros would desire to trim circulating obese acid levels as well as regard if it provokes a hunger response, as well as ideally, weight gain.  Fortunately for us, this study has been done.

Hideo Makimura as well as colleagues of late published the results of a 6-month randomized, placebo-controlled study inwards which they used a drug called acipimox to chronically trim circulating costless obese acid levels inwards people amongst 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 as well as gained obese rapidly, as well as release energy expenditure should take away hold declined equally well.  Yet the researchers reported that "caloric as well as relative macronutrient intake did non modify significantly betwixt groups".  Neither group's BMI or trunk composition changed significantly, nor did their release energy expenditure.  The study was published inwards the Journal of Clinical Endocrinology as well as Metabolism, a respected magazine inwards my field.

The encephalon monitors a number of signals from the trunk to mensurate release energy status, as well as it uses these to laid upwards your appetite.  Apparently, depression circulating obese acid levels are non 1 of the signals the human encephalon pays attending to when it sets appetite.  This seriously undermines the concept of internal starvation, as well as consequently the insulin model.

In contrast, nosotros take away hold strong evidence that the human encephalon pays closed 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, as well as reduced release energy expenditure.  Bringing leptin levels dorsum to normal via injection terminates this starvation response, clearly demonstrating that depression leptin was the principal drive (7, 8, 9, 10, 11, 12, 13).  These results don't exit much room for insulin or obese jail cellular telephone metabolism to hold upwards involved inwards the body's starvation response (except perchance equally downstream effectors of leptin).

Do high insulin levels predict obese gain?

This is a straightforward prediction of the insulin model, as well as nosotros take away hold many human studies amongst which to bear witness 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 amongst high insulin levels practice non gain to a greater extent than weight or obese over fourth dimension than people amongst 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 genuinely has on cells as well as tissues.  Insulin activeness is determined both past times insulin levels as well as insulin sensitivity (how good tissues "hear" the insulin signal).  This is the same declaration I take away hold used to inquiry the insulin model, because proponents ofttimes assume that high insulin levels automatically imply elevated insulin action.  They to a greater extent than ofttimes than non overlook the fact that people amongst high insulin are almost invariably insulin resistant (including their obese tissue), as well as that insulin action is normal or reduced (as judged past times normal or elevated blood glucose as well as obese acids, as well as normal or elevated whole-body lipolysis rates).

In fact, this is exactly the argue why insulin injections, insulin-producing tumors, as well as similar non-physiological examples cited past times Ludwig as well as Taubes are irrelevant to the inquiry at hand.  These arguments endeavour to describe an analogy betwixt non-physiological insulin excess as well as garden-variety hyperinsulinemia-- but inwards the latter case, in that location is no evidence that insulin action on obese cells is genuinely increased, as well as a fair flake of evidence that it isn't.

In whatever case, I handgrip amongst Ludwig's basic premise that insulin activeness is what genuinely matters.  Yet if nosotros render to the review newspaper I cited, it didn't but consider studies that measured fasting insulin levels.  The studies measured multiple insulin-related variables, including fasting insulin levels, insulin sensitivity, as well as 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 amongst weight gain.  In fact, I'm non aware of any insulin-related variable that is reliably associated amongst 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 zip to a greater extent than than speculation at this point.

Ludwig suggests that nosotros should hold upwards looking for the effects of insulin during the weight gain phase.  That is exactly what these studies take away hold done, as well as they did non give away that weight gain was consistently associated amongst a distinct insulin signaling profile inwards whatever measured way.

So we've measured insulin levels, insulin sensitivity, as well as the insulin response to carbohydrate.  We've measured them inwards people who are gaining weight as well as people who aren't.  We've measured them inwards multiple races as well as ages.  And no clear designing has emerged suggesting that insulin signaling powerfulness hold upwards playing an of import exercise 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 zip to a greater extent than than speculation at this point.  Currently I give away this evidence rather hard to reconcile amongst the insulin model.

Do low-glycemic diets operate for obese loss?

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

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

But inwards whatever case, what nosotros genuinely aid almost is non what happens at a unmarried meal, but what happens over the long haul.  That is the inquiry my 2d dot addresses.  We take away hold quite a flake of evidence suggesting, fairly consistently, that low-glycemic diets don't operate 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, hapless adherence doesn't explicate the zero results inwards this case.

For 1 thing, adherence is ever a employment inwards human diet trials, but they soundless ofttimes written report weight loss.  This has been shown for the low-carb diet, the Paleo diet, the vegan diet, the Mediterranean diet, elementary share control, as well as 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 drive 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 amongst a study that may hold upwards the purest bear witness of the hypothesis available (27).  It was conducted past times Walter Willett as well as Frank Hu, ii of Ludwig's colleagues at Harvard.

They randomized 203 salubrious women (average BMI = 27) to 1 of ii 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 divergence inwards both glucose as well as insulin exposure.  This large divergence was sustained for the total xviii months of the intervention.

There were no important differences inwards hunger or calorie intake betwixt the ii groups.  At ii months, in that location was a trivial divergence inwards trunk weight of 0.4 kg favoring the low-glycemic group, but this disappeared past times the halt of the study.  The conclusion is that large as well as sustained differences inwards post-meal glucose as well as 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 roughly other study-- the 1 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, as well as fruit, at the expense of refined grains, starchy vegetables, fruit juice, as well as sweets.  The low-fat diet was focused on low-fat grains, vegetables, fruits, as well as beans, at the expense of of added fats, sweets, as well as high-fat snacks.  The low-glycemic diet was a flake lower inwards saccharide (40% vs 55%), as well as both diets were fairly high inwards poly peptide (25%).  Neither diet was calorie restricted.

Glycemic charge differed substantially on the ii diets, as well as a divergence was maintained over the 18-month study, although it narrowed at 12 as well as xviii months.  This implies substantial differences inwards glucose as well as insulin exposure.

So what happened?  Hunger, calorie intake, as well as player satisfaction didn't differ betwixt groups.  Both groups lost weight (4-5 kg at max), but the magnitude as well as trajectory of weight loss betwixt the ii groups was virtually identical (see graph below).  Substantial differences inwards diet-related glucose as well as insulin exposure did non termination 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 ii 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 respond this inquiry (unlike a recent study from Christopher Gardner's group; 29), so this is what's called an "exploratory analysis".  These send less weight than the primary outcomes of a study, which are those that I discussed above.  Exploratory analyses tin flaming sure enough hold upwards informative, as well as there's zip incorrect amongst conducting as well as publishing them, but they are amend 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 amongst obesity, reducing the glycemic charge of your diet, as well as consequently your insulin exposure, has no special powerfulness to curtail your appetite or assist yous lose weight.  You powerfulness equally good larn on a low-fat, high-carbohydrate, high-glycemic diet.  This is consistent amongst the results of the previous study I discussed, as well as the ease of the literature equally a whole.

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

Conclusion

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 evidence that the proposed machinery occurs during or after normal weight gain, a fair amount of direct evidence that it doesn't, as well as the arguments inwards favor of it are based on indirect evidence whose relevance to mutual obesity is ofttimes questionable.

I give thank yous Dr. Ludwig for the chance to clarify my thoughts on this, as well as I wishing him luck inwards his ongoing research.