You Plow 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 skillful because he defends the thought inwards to a greater extent than item 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 destination is to brand it at the best answer, rather than to win an argument. I'm proceeding inwards skillful faith, based on my belief that Ludwig too I are both serious people who aid almost scientific discipline too human health, too I promise my audience volition practise the same. That said, let's larn to it.
Introduction: CICO vs. insulin. Or is at that topographic point a 3rd model?
Similar to Gary Taubes, Ludwig presents a alternative betwixt the calories-in, calories-out model (CICO) of obesity, too the insulin model. The CICO model is the thought that our trunk weight is determined yesteryear voluntary decisions almost how much nosotros swallow too move, too inwards guild to command our trunk weight, all nosotros necessitate is a petty advice almost how many calories to swallow too burn, too a petty willpower. The primary defining characteristic of this model is that it assumes that nutrient intake too 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 too a strong character.
I think at this point, few people inwards the enquiry basis believe the CICO model. Ludwig too I both grip that it provides a miserable agree for the evidence. As an alternative, Ludwig proposes the insulin model, which states that the primary movement of obesity is excessive insulin activeness on obese cells, which inwards plow is caused principally yesteryear rapidly-digesting carbohydrate. According to this model, also much insulin reduces blood levels of glucose too obese acids (the 2 primary circulating metabolic fuels), simultaneously leading to hunger, fatigue, too obese gain. Overeating is caused yesteryear a sort of "internal starvation". There are other versions of the insulin model, but this is the i advocated yesteryear Ludwig (and Taubes), so it volition endure my focus.
But there's a 3rd model, non mentioned yesteryear Ludwig or Taubes, which is the i 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 betoken its unloose energy status. Chief with these signals is the hormone leptin, but many others play a utilization (insulin, ghrelin, glucagon, CCK, GLP-1, glucose, amino acids, etc.).
Here is a simplified schematic overview of how the arrangement works, from a 2012 review newspaper I wrote with my scientific mentor Mike Schwartz, titled "Regulation of nutrient intake, unloose energy balance, too 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: at that topographic point are negative feedback loops betwixt the encephalon too obese tissue, too betwixt the encephalon too the gut. These are what regulate trunk fatness too 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 utilization every bit well, acting direct on the encephalon inwards a mode similar to leptin, although much less powerfully. As yous tin see, this model doesn't resemble the CICO model-- or the insulin model.
Regulation happens principally every bit a outcome of the encephalon changing the number of calories entering too leaving the trunk (in humans, mostly entering)-- so the much-maligned calorie maintains a fundamental utilization inwards the process. Even though calories aren't the outset link inwards the causal chain, they are yet a critical link.
Most people inwards my acre also believe that calorie intake is determined both yesteryear hunger (homeostatic eating), too factors other than hunger (non-homeostatic eating). I grip with them.
So this 3rd model acknowledges the importance of regulation, the importance of unregulated factors, too the importance of calories. Although it's to a greater extent than complex than the insulin too CICO models, it has the wages of beingness supported yesteryear a large trunk of evidence. Let's telephone band 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 every bit a 3rd model so nosotros aren't limiting our choices to 1) a CICO model that is manifestly wrong, too 2) the insulin model.
I'm non going to practise a point-by-point response to Ludwig's point-by-point response, because that would endure exceedingly cumbersome. What I'll practise instead is essay to distill out the most of import concepts, too hash out those. In particular, I'll endure focusing on key lines of evidence that receive got the potential to support-- or falsify-- the insulin model. This is where the prophylactic meets the route for hypothesis testing.
Is obesity caused yesteryear internal starvation?
In my initial post, I pointed out that people with obesity receive got normal or elevated levels of blood glucose too obese acids-- non lower levels every bit 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), too 3) hence this machinery cannot explicate the well-established fact that people with obesity tend to swallow almost 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 endure looking at the weight gain stage instead. Let's think through the implications of this statement. It implies that internal starvation makes us overeat every bit we're gaining weight, but doesn't explicate continued overeating i time nosotros arrive at the obese state, or the fact that the obese terra firma persists after internal starvation is no longer occurring. It hence also requires the existence of 2 dissever mechanisms that movement overeating, i involving internal starvation too i not, too requires a hand-off betwixt them at around dot inwards time. I'm non aware of experimental evidence that supports whatever of this.
Let's accept a closer hold off at the weight gain phase, every bit suggested. Is at that topographic point evidence that people who are gaining weight receive got lower glucose too obese acid levels than people who aren't? There is not. I'm non aware of whatever evidence inwards humans or inwards brute models of diet-induced obesity that circulating glucose or obese acid levels are lower during active weight gain. In Mike Schwartz's lab, nosotros receive got done countless glucose measurements inwards mice too rats gaining weight apace due to a fattening diet, too nosotros receive got also measured circulating obese acid levels at times, too neither i 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 every bit hypothalamic lesions inwards rodents (As an aside, Bruce King has shown that the fattening number of VMN lesions does non depend on increased insulin levels (4), too John Brobeck showed inwards the 1940s that these lesions movement voracious overeating every bit presently every bit the anesthesia wears off, non after around catamenia 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, at that topographic point is no direct evidence that internal starvation occurs during 1) weight gain or 2) the overweight/obese state, too at that topographic point is around direct evidence that it does non occur. The internal starvation hypothesis rests solely on indirect evidence that I don't expose especially pertinent.
But let's accept a pace 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 too weight gain? Because if they aren't, too so it's hard to empathize how insulin (or anything else) would Pb to overeating yesteryear reducing obese acid levels. This is testable. To essay out it, nosotros would desire to cut circulating obese acid levels too consider if it provokes a hunger response, too ideally, weight gain. Fortunately for us, this study has been done.
Hideo Makimura too colleagues late published the results of a 6-month randomized, placebo-controlled study inwards which they used a drug called acipimox to chronically cut circulating gratuitous obese acid levels inwards people with obesity (6). The drug caused a substantial (38%) reduction of gratuitous obese acid levels for the duration of the 6-month study.
According the thought of internal starvation, the acipimox grouping should receive got been ravenously hungry too gained obese rapidly, too unloose energy expenditure should receive got declined every bit well. Yet the researchers reported that "caloric too relative macronutrient intake did non alter significantly betwixt groups". Neither group's BMI or trunk composition changed significantly, nor did their unloose energy expenditure. The study was published inwards the Journal of Clinical Endocrinology too Metabolism, a respected magazine inwards my field.
The encephalon monitors a number of signals from the trunk to mensurate unloose energy status, too it uses these to gear upwards your appetite. Apparently, depression circulating obese acid levels are non i of the signals the human encephalon pays attending to when it sets appetite. This seriously undermines the concept of internal starvation, too consequently the insulin model.
In contrast, nosotros receive got strong evidence 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, too reduced unloose energy expenditure. Bringing leptin levels dorsum to normal via injection terminates this starvation response, clearly demonstrating that depression leptin was the principal movement (7, 8, 9, 10, 11, 12, 13). These results don't larn out much room for insulin or obese jail cellphone metabolism to endure involved inwards the body's starvation response (except maybe every bit downstream effectors of leptin).
Do high insulin levels predict obese gain?
This is a straightforward prediction of the insulin model, too nosotros receive got many human studies with which to essay 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 practise non gain to a greater extent than weight or obese over fourth dimension than people with depression insulin levels.
Ludwig countered yesteryear 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 too tissues. Insulin activeness is determined both yesteryear insulin levels too insulin sensitivity (how good tissues "hear" the insulin signal). This is the same declaration I receive got used to query the insulin model, because proponents oftentimes 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), too that insulin action is normal or reduced (as judged yesteryear normal or elevated blood glucose too obese acids, too normal or elevated whole-body lipolysis rates).
In fact, this is just the argue why insulin injections, insulin-producing tumors, too similar non-physiological examples cited yesteryear Ludwig too Taubes are irrelevant to the query at hand. These arguments travail to depict an analogy betwixt non-physiological insulin excess too garden-variety hyperinsulinemia-- but inwards the latter case, at that topographic point is no evidence that insulin action on obese cells is truly increased, too a fair fight of evidence that it isn't.
In whatever case, I grip 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 simply consider studies that measured fasting insulin levels. The studies measured multiple insulin-related variables, including fasting insulin levels, insulin sensitivity, too 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 zip to a greater extent than than speculation at this point.
Ludwig suggests that nosotros should endure looking for the effects of insulin during the weight gain phase. That is exactly what these studies receive got done, too they did non expose that weight gain was consistently associated with a distinct insulin signaling profile inwards whatever measured way.
So we've measured insulin levels, insulin sensitivity, too the insulin response to carbohydrate. We've measured them inwards people who are gaining weight too people who aren't. We've measured them inwards multiple races too ages. And no clear designing has emerged suggesting that insulin signaling mightiness endure playing an of import utilization inwards the fattening process. Again, it's e'er 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 expose this evidence rather hard to reconcile with 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 too weight/fat gain, too so low-glycemic diets that cut insulin exposure should endure an effective tool for reducing nutrient intake too 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, too 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 normally occurs after (15). He also cited a review newspaper he wrote inwards 2002 suggesting that single-meal studies receive got mostly found that low-glycemic meals are to a greater extent than sating than high-glycemic meals (16). This is a fair point, too the cited evidence does back upwards it (although many of these studies were non controlled for other differences known to acquit upon satiety, such every bit fiber content, palatability, too calorie density). However, findings inwards this surface area haven't been especially consistent, too inwards a few cases high-glycemic foods were truly to a greater extent than sating (17, 18, 19). I practise admit that the weight of the evidence is inwards his military camp on this point.
But inwards whatever case, what nosotros truly aid almost is non what happens at a unmarried meal, but what happens over the long haul. That is the query my 2nd dot addresses. We receive got quite a fight 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 real faithfully, explaining why the diets appear ineffective. While I grip that adherence is e'er a limiting element 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 i thing, adherence is e'er a occupation inwards human diet trials, but they yet oftentimes study weight loss. This has been shown for the low-carb diet, the Paleo diet, the vegan diet, the Mediterranean diet, uncomplicated share control, too fifty-fifty the embattled low-fat diet. Some of these are tough diets that people receive got a hard fourth dimension sticking with, but they silent movement 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 empathize how this would explicate the lack of efficacy.
But let's larn specific. I'd similar to start with a study that may endure the purest essay out of the hypothesis available (27). It was conducted yesteryear Walter Willett too Frank Hu, 2 of Ludwig's colleagues at Harvard.
They randomized 203 good for yous women (average BMI = 27) to i of 2 diets: high-glycemic or low-glycemic. Differences inwards glycemic index were achieved primarily yesteryear eating different types of rice that receive got 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 yesteryear two-fold (40 vs. 79), which implies a large deviation inwards both glucose too insulin exposure. This large deviation 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, at that topographic point was a trivial deviation inwards trunk weight of 0.4 kg favoring the low-glycemic group, but this disappeared yesteryear the terminate of the study. The conclusion is that large too sustained differences inwards post-meal glucose too insulin exposure receive got no meaningful long-term impact on hunger, nutrient intake, or trunk weight inwards women (who were overweight on average).
Let's consider around other study-- the i 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, too fruit, at the expense of refined grains, starchy vegetables, fruit juice, too sweets. The low-fat diet was focused on low-fat grains, vegetables, fruits, too beans, at the expense of of added fats, sweets, too high-fat snacks. The low-glycemic diet was a fight lower inwards saccharide (40% vs 55%), too both diets were fairly high inwards poly peptide (25%). Neither diet was calorie restricted.
Glycemic charge differed substantially on the 2 diets, too a deviation was maintained over the 18-month study, although it narrowed at 12 too xviii months. This implies substantial differences inwards glucose too insulin exposure.
So what happened? Hunger, calorie intake, too player satisfaction didn't differ betwixt groups. Both groups lost weight (4-5 kg at max), but the magnitude too trajectory of weight loss betwixt the 2 groups was virtually identical (see graph below). Substantial differences inwards diet-related glucose too insulin exposure did non outcome inwards detectable differences inwards hunger, calorie intake, weight loss, or weight regain.
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 receive got to hold the finding inwards context. The study wasn't randomized to reply this query (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 for certain endure informative, too there's zip incorrect with conducting too publishing them, but they are improve 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, too consequently your insulin exposure, has no special powerfulness to curtail your appetite or aid yous lose weight. You mightiness every bit good become on a low-fat, high-carbohydrate, high-glycemic diet. This is consistent with the results of the previous study I discussed, too the ease of the literature every bit a whole.
It remains possible that low-glycemic diets are helpful for a subset of people, but electrical current evidence suggests they are non real effective every bit a full general strategy for managing appetite too weight-- counter to what the insulin model predicts.
Conclusion
In summary, several key predictions of the insulin model are non supported yesteryear 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, too the arguments inwards favor of it are based on indirect evidence whose relevance to mutual obesity is oftentimes questionable.
I give thank yous Dr. Ludwig for the chance to clarify my thoughts on this, too I want him luck inwards his ongoing research.
Before nosotros dig in, I desire to emphasize that this is science, non tribal warfare. The destination is to brand it at the best answer, rather than to win an argument. I'm proceeding inwards skillful faith, based on my belief that Ludwig too I are both serious people who aid almost scientific discipline too human health, too I promise my audience volition practise the same. That said, let's larn to it.
Baca Juga
Similar to Gary Taubes, Ludwig presents a alternative betwixt the calories-in, calories-out model (CICO) of obesity, too the insulin model. The CICO model is the thought that our trunk weight is determined yesteryear voluntary decisions almost how much nosotros swallow too move, too inwards guild to command our trunk weight, all nosotros necessitate is a petty advice almost how many calories to swallow too burn, too a petty willpower. The primary defining characteristic of this model is that it assumes that nutrient intake too 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 too a strong character.
I think at this point, few people inwards the enquiry basis believe the CICO model. Ludwig too I both grip that it provides a miserable agree for the evidence. As an alternative, Ludwig proposes the insulin model, which states that the primary movement of obesity is excessive insulin activeness on obese cells, which inwards plow is caused principally yesteryear rapidly-digesting carbohydrate. According to this model, also much insulin reduces blood levels of glucose too obese acids (the 2 primary circulating metabolic fuels), simultaneously leading to hunger, fatigue, too obese gain. Overeating is caused yesteryear a sort of "internal starvation". There are other versions of the insulin model, but this is the i advocated yesteryear Ludwig (and Taubes), so it volition endure my focus.
Here is a simplified schematic overview of how the arrangement works, from a 2012 review newspaper I wrote with my scientific mentor Mike Schwartz, titled "Regulation of nutrient intake, unloose energy balance, too 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: at that topographic point are negative feedback loops betwixt the encephalon too obese tissue, too betwixt the encephalon too the gut. These are what regulate trunk fatness too 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 utilization every bit well, acting direct on the encephalon inwards a mode similar to leptin, although much less powerfully. As yous tin see, this model doesn't resemble the CICO model-- or the insulin model.
Regulation happens principally every bit a outcome of the encephalon changing the number of calories entering too leaving the trunk (in humans, mostly entering)-- so the much-maligned calorie maintains a fundamental utilization inwards the process. Even though calories aren't the outset link inwards the causal chain, they are yet a critical link.
Most people inwards my acre also believe that calorie intake is determined both yesteryear hunger (homeostatic eating), too factors other than hunger (non-homeostatic eating). I grip with them.
So this 3rd model acknowledges the importance of regulation, the importance of unregulated factors, too the importance of calories. Although it's to a greater extent than complex than the insulin too CICO models, it has the wages of beingness supported yesteryear a large trunk of evidence. Let's telephone band 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 every bit a 3rd model so nosotros aren't limiting our choices to 1) a CICO model that is manifestly wrong, too 2) the insulin model.
I'm non going to practise a point-by-point response to Ludwig's point-by-point response, because that would endure exceedingly cumbersome. What I'll practise instead is essay to distill out the most of import concepts, too hash out those. In particular, I'll endure focusing on key lines of evidence that receive got the potential to support-- or falsify-- the insulin model. This is where the prophylactic meets the route for hypothesis testing.
Is obesity caused yesteryear internal starvation?
In my initial post, I pointed out that people with obesity receive got normal or elevated levels of blood glucose too obese acids-- non lower levels every bit 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), too 3) hence this machinery cannot explicate the well-established fact that people with obesity tend to swallow almost 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 endure looking at the weight gain stage instead. Let's think through the implications of this statement. It implies that internal starvation makes us overeat every bit we're gaining weight, but doesn't explicate continued overeating i time nosotros arrive at the obese state, or the fact that the obese terra firma persists after internal starvation is no longer occurring. It hence also requires the existence of 2 dissever mechanisms that movement overeating, i involving internal starvation too i not, too requires a hand-off betwixt them at around dot inwards time. I'm non aware of experimental evidence that supports whatever of this.
Let's accept a closer hold off at the weight gain phase, every bit suggested. Is at that topographic point evidence that people who are gaining weight receive got lower glucose too obese acid levels than people who aren't? There is not. I'm non aware of whatever evidence inwards humans or inwards brute models of diet-induced obesity that circulating glucose or obese acid levels are lower during active weight gain. In Mike Schwartz's lab, nosotros receive got done countless glucose measurements inwards mice too rats gaining weight apace due to a fattening diet, too nosotros receive got also measured circulating obese acid levels at times, too neither i 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 every bit hypothalamic lesions inwards rodents (As an aside, Bruce King has shown that the fattening number of VMN lesions does non depend on increased insulin levels (4), too John Brobeck showed inwards the 1940s that these lesions movement voracious overeating every bit presently every bit the anesthesia wears off, non after around catamenia 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, at that topographic point is no direct evidence that internal starvation occurs during 1) weight gain or 2) the overweight/obese state, too at that topographic point is around direct evidence that it does non occur. The internal starvation hypothesis rests solely on indirect evidence that I don't expose especially pertinent.
But let's accept a pace 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 too weight gain? Because if they aren't, too so it's hard to empathize how insulin (or anything else) would Pb to overeating yesteryear reducing obese acid levels. This is testable. To essay out it, nosotros would desire to cut circulating obese acid levels too consider if it provokes a hunger response, too ideally, weight gain. Fortunately for us, this study has been done.
Hideo Makimura too colleagues late published the results of a 6-month randomized, placebo-controlled study inwards which they used a drug called acipimox to chronically cut circulating gratuitous obese acid levels inwards people with obesity (6). The drug caused a substantial (38%) reduction of gratuitous obese acid levels for the duration of the 6-month study.
According the thought of internal starvation, the acipimox grouping should receive got been ravenously hungry too gained obese rapidly, too unloose energy expenditure should receive got declined every bit well. Yet the researchers reported that "caloric too relative macronutrient intake did non alter significantly betwixt groups". Neither group's BMI or trunk composition changed significantly, nor did their unloose energy expenditure. The study was published inwards the Journal of Clinical Endocrinology too Metabolism, a respected magazine inwards my field.
The encephalon monitors a number of signals from the trunk to mensurate unloose energy status, too it uses these to gear upwards your appetite. Apparently, depression circulating obese acid levels are non i of the signals the human encephalon pays attending to when it sets appetite. This seriously undermines the concept of internal starvation, too consequently the insulin model.
In contrast, nosotros receive got strong evidence 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, too reduced unloose energy expenditure. Bringing leptin levels dorsum to normal via injection terminates this starvation response, clearly demonstrating that depression leptin was the principal movement (7, 8, 9, 10, 11, 12, 13). These results don't larn out much room for insulin or obese jail cellphone metabolism to endure involved inwards the body's starvation response (except maybe every bit downstream effectors of leptin).
Do high insulin levels predict obese gain?
This is a straightforward prediction of the insulin model, too nosotros receive got many human studies with which to essay 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 practise non gain to a greater extent than weight or obese over fourth dimension than people with depression insulin levels.
Ludwig countered yesteryear 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 too tissues. Insulin activeness is determined both yesteryear insulin levels too insulin sensitivity (how good tissues "hear" the insulin signal). This is the same declaration I receive got used to query the insulin model, because proponents oftentimes 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), too that insulin action is normal or reduced (as judged yesteryear normal or elevated blood glucose too obese acids, too normal or elevated whole-body lipolysis rates).
In fact, this is just the argue why insulin injections, insulin-producing tumors, too similar non-physiological examples cited yesteryear Ludwig too Taubes are irrelevant to the query at hand. These arguments travail to depict an analogy betwixt non-physiological insulin excess too garden-variety hyperinsulinemia-- but inwards the latter case, at that topographic point is no evidence that insulin action on obese cells is truly increased, too a fair fight of evidence that it isn't.
In whatever case, I grip 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 simply consider studies that measured fasting insulin levels. The studies measured multiple insulin-related variables, including fasting insulin levels, insulin sensitivity, too 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 zip to a greater extent than than speculation at this point.
Ludwig suggests that nosotros should endure looking for the effects of insulin during the weight gain phase. That is exactly what these studies receive got done, too they did non expose that weight gain was consistently associated with a distinct insulin signaling profile inwards whatever measured way.
So we've measured insulin levels, insulin sensitivity, too the insulin response to carbohydrate. We've measured them inwards people who are gaining weight too people who aren't. We've measured them inwards multiple races too ages. And no clear designing has emerged suggesting that insulin signaling mightiness endure playing an of import utilization inwards the fattening process. Again, it's e'er 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 expose this evidence rather hard to reconcile with 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 too weight/fat gain, too so low-glycemic diets that cut insulin exposure should endure an effective tool for reducing nutrient intake too 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, too 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 normally occurs after (15). He also cited a review newspaper he wrote inwards 2002 suggesting that single-meal studies receive got mostly found that low-glycemic meals are to a greater extent than sating than high-glycemic meals (16). This is a fair point, too the cited evidence does back upwards it (although many of these studies were non controlled for other differences known to acquit upon satiety, such every bit fiber content, palatability, too calorie density). However, findings inwards this surface area haven't been especially consistent, too inwards a few cases high-glycemic foods were truly to a greater extent than sating (17, 18, 19). I practise admit that the weight of the evidence is inwards his military camp on this point.
But inwards whatever case, what nosotros truly aid almost is non what happens at a unmarried meal, but what happens over the long haul. That is the query my 2nd dot addresses. We receive got quite a fight 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 real faithfully, explaining why the diets appear ineffective. While I grip that adherence is e'er a limiting element 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 i thing, adherence is e'er a occupation inwards human diet trials, but they yet oftentimes study weight loss. This has been shown for the low-carb diet, the Paleo diet, the vegan diet, the Mediterranean diet, uncomplicated share control, too fifty-fifty the embattled low-fat diet. Some of these are tough diets that people receive got a hard fourth dimension sticking with, but they silent movement 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 empathize how this would explicate the lack of efficacy.
But let's larn specific. I'd similar to start with a study that may endure the purest essay out of the hypothesis available (27). It was conducted yesteryear Walter Willett too Frank Hu, 2 of Ludwig's colleagues at Harvard.
They randomized 203 good for yous women (average BMI = 27) to i of 2 diets: high-glycemic or low-glycemic. Differences inwards glycemic index were achieved primarily yesteryear eating different types of rice that receive got 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 yesteryear two-fold (40 vs. 79), which implies a large deviation inwards both glucose too insulin exposure. This large deviation 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, at that topographic point was a trivial deviation inwards trunk weight of 0.4 kg favoring the low-glycemic group, but this disappeared yesteryear the terminate of the study. The conclusion is that large too sustained differences inwards post-meal glucose too insulin exposure receive got no meaningful long-term impact on hunger, nutrient intake, or trunk weight inwards women (who were overweight on average).
Let's consider around other study-- the i 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, too fruit, at the expense of refined grains, starchy vegetables, fruit juice, too sweets. The low-fat diet was focused on low-fat grains, vegetables, fruits, too beans, at the expense of of added fats, sweets, too high-fat snacks. The low-glycemic diet was a fight lower inwards saccharide (40% vs 55%), too both diets were fairly high inwards poly peptide (25%). Neither diet was calorie restricted.
Glycemic charge differed substantially on the 2 diets, too a deviation was maintained over the 18-month study, although it narrowed at 12 too xviii months. This implies substantial differences inwards glucose too insulin exposure.
So what happened? Hunger, calorie intake, too player satisfaction didn't differ betwixt groups. Both groups lost weight (4-5 kg at max), but the magnitude too trajectory of weight loss betwixt the 2 groups was virtually identical (see graph below). Substantial differences inwards diet-related glucose too insulin exposure did non outcome inwards detectable differences inwards hunger, calorie intake, weight loss, or weight regain.
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| 18-month weight changes inwards Ebbeling et al. Note the p-value of 0.99, indicating that the 2 trajectories are statistically indistinguishable. |
The most straightforward interpretation of the study is that if you're a immature adult with obesity, reducing the glycemic charge of your diet, too consequently your insulin exposure, has no special powerfulness to curtail your appetite or aid yous lose weight. You mightiness every bit good become on a low-fat, high-carbohydrate, high-glycemic diet. This is consistent with the results of the previous study I discussed, too the ease of the literature every bit a whole.
It remains possible that low-glycemic diets are helpful for a subset of people, but electrical current evidence suggests they are non real effective every bit a full general strategy for managing appetite too weight-- counter to what the insulin model predicts.
Conclusion
In summary, several key predictions of the insulin model are non supported yesteryear 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, too the arguments inwards favor of it are based on indirect evidence whose relevance to mutual obesity is oftentimes questionable.
I give thank yous Dr. Ludwig for the chance to clarify my thoughts on this, too I want him luck inwards his ongoing research.
