Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent Upon Capacity for B Cell Recovery

ByCrossFitDecember 18, 2019

The Diabetes Remission Clinical Trial (DiRECT) demonstrated a four-month, calorie-restricted weight loss diet could reverse diabetes in a significant number of subjects (1). This 2018 analysis compared subjects in whom diabetes was successfully reversed (n = 40, “responders”) to otherwise similar subjects who remained diabetic after successful weight loss (n = 18, “non-responders”).

Weight loss was similar in responders and non-responders (13 to 16 kg). Alongside weight loss, liver fat content decreased dramatically in all subjects, from 16% (liver fat fraction) at baseline to 3% after weight loss, a value similar to healthy controls. Pancreatic fat content similarly decreased from an elevated baseline to healthy levels in all subjects. Previous work by these authors, as well as work featured on, has linked decreased pancreatic and liver fat to improvements in glycemic control and insulin response (2).

Alongside these changes, fasting blood glucose decreased to 102 mg/dL in responders but did not change significantly in non-responders. HbA1c, accordingly, was reduced to healthy levels in responders (5.9%) but did not change significantly in non-responders. Crucially, fasting insulin decreased in all subjects, but the first-phase insulin response — that is, the amount of insulin secreted by the pancreas immediately after an elevation in blood glucose — increased to healthy levels in responders but did not change in non-responders.

Responders and non-responders had similar average age, BMI, and fasting glucose at baseline. Non-responders had lower fasting insulin, higher plasma alanine aminotransferase (ALT), and longer average duration of diabetes than responders.

Taken together, this data indicates significant weight loss leads to liver and pancreatic fat clearance in all subjects. The pancreatic beta cells of some subjects, however, fail to return to normal levels of function even after the pancreas is cleared of fat. In these subjects, the insulin response to a glucose load (i.e., a meal) remains suppressed, so blood glucose levels and HbA1c levels remain elevated and diabetes persists even with weight loss.

Previous research has hypothesized pancreatic beta-cell stress results from high blood glucose, blood lipid, and/or insulin production levels (3). It is widely known that pancreatic beta cell function degrades over time as diabetes persists, whether as a consequence of these stressors or due to other factors.

This study contributes to the research developed in previous trials showing diabetes is reversible in the majority of subjects through the use of a calorie-restricted diet (4). Some (Lim 2011, Steve 2016) have shown a very low-calorie diet can induce diabetes reversal in as little as a few weeks. The DiRECT study builds on these smaller trials, further establishing that diabetes can be reversed through diet alone. Just as importantly, this study reinforces the importance of early intervention, as a diet started soon after diagnosis, before stressors have begun to degrade pancreatic beta-cell function, is more likely to successfully reverse diabetes.


  1. Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomized trial
  2. Pathogenesis of type 2 diabetes: Tracing the reverse route from cure to cause; Pathogenesis of type 2 diabetes: Etiology and reversibility
  3. The molecular mechanisms of pancreatic beta-cell glucotoxicity: recent findings and future research directions; Glucolipotoxicity of the pancreatic beta cell; Beta-cell differentiation in diabetes is important, but what is it?
  4. Reversal of type 2 diabetes: Normalization of beta cell function in association with decreased pancreas and liver triacylglycerol; Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance and hyperglycemia by moderate weight reduction in patients with type 2 diabetes; Very low calorie diet and 6 months of weight stability in type 2 diabetes: Pathophysiological changes in responders and nonresponders; Weight loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes

Comments on Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent Upon Capacity for B Cell Recovery


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Clarke Read
December 20th, 2019 at 5:16 pm
Commented on: Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent Upon Capacity for B Cell Recovery

Going back to the DIRECT trial:

(Unfortunately, it’s paywalled)

The intervention during the weight loss diet was “a low energy formula diet (825 - 853 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fibre) for 3 months followed by structured food reintroduction of 2-8 weeks (about 50% carbohydrate, 35% total fat, and 15% protein). Per the original trial, 46% of subjects following this intervention (which also included cessation of oral anti diabetic and antihypertensive medication) demonstrated remission of diabetes. That initial trial found a close relationship between weight loss and diabetes remission; this trial builds on this by demonstrating a particular biological phenomenon - that is, restoration of pancreatic beta cell function - stratifies those who respond and those who do not.

JR Wild and Richard Feinman are correct to argue this very-low-calorie diet is also a highly carbohydrate restricted diet - in fact, that is part of the reason this study is featured on the site. With the composition above, these subjects would be consuming fewer than 500 calories of carbohydrate per day. If we assume (and this is likely a conservative assumption) they consumed a 2000-kcal 55% carbohydrate diet at baseline, this would be a more than 50% reduction in carbohydrate intake.

What I find most compelling about the literature of diabetes remission is that multiple interventions - very-low-calorie diets, highly carbohydrate restricted diets, even (per Aseem Malhotra’s Pioppi diet) a heavily modified Mediterranean diet, alongside the more mainstream solution of bariatric surgery - all drive reversal/remission of a condition that much of the clinical community considers to be chronic, progressive and irreversible. It is not a coincidence that these diets all involve severe restriction of refined carbohydrate and sugar. In other words, we could just as easily frame this literature as a relatively robust data set supporting the clinical efficacy of a single intervention, applied in different ways (specifically, sufficient carbohydrate restriction, with or without calorie restriction, to meaningfully suppress insulin and drive rapid liver fat clearance) to different populations. Given the fact that no pharmaceutical intervention I’m aware of has matched the efficacy of ANY of these dietary interventions, I’d suspect we have a roster of choices to make available to drive diabetes remission. Changes to the composition of the diet (i.e., carbohydrate restriction, independent of calories), quantity of the diet (i.e., calorie restriction), and possibly exercise can be leveraged to achieve this specific metabolic state.

This study helps illustrate what that metabolic state is. As other pieces have shown, liver fat and then pancreatic fat clearance and restoration of beta cell function is coincident with resolution of fasting insulin, then first-phase insulin response, then fasting glucose. As the other two commenters have noted, these biological and biomarker changes are intrinsically linked. This study also shows clearly that in some subjects, the decreases in organ fat content are insufficient to drive complete functional restoration, explaining specifically why these interventions are not universally effective, even within compliant subjects. This, to me, suggests two things - (1) the correlation between overall body weight and diabetes is not causal, but is mediated by the fact that fat gain leads to organ fat storage and (2) ANY intervention that drives rapid organ fat clearance will, in the majority of subjects, also drive rapid diabetes resolution. Current data - clinical and anecdotal - points us to a series of established interventions for #2, but I would suspect any intervention that achieves the same would also be effective. If we’re looking at future research directions, then, they would logically be to establish (A) the full suite of interventions, combining diet and exercise, that can achieve that organ fat clearance, and the markers that may help us predict effectiveness in specific subjects and (B) any tools that may drive restoration of pancreatic beta-cell function in those non-responders.

It would seem we have a cure for diabetes. The question is how best to implement it, both individually and at scale.

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jr Wild
December 19th, 2019 at 11:18 am
Commented on: Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent Upon Capacity for B Cell Recovery

Compared to Virta Health ketogenic approach, this DiRECT fares almost as well. 800kcal "soup" means also less carbs (400kcal) and probably less frequent eating -both good. Re-intro of food happened along "recommendations", and interestingly the weight loss was mainly maintained. Usual care, as usual, was useless in both Virta and DiRECT. The decease is progressing under usual care, everywhere in the world.

The metabolic rate is ca. 4-fold in visceral organs, which would explain nicely, why the fat loss happens first and fast in liver and pancreas after intervention (less insulin messing around). The function of pancreas is least partially.

The loss of insulin secretion gradient likely fails to act as a flip-switch to suppress glucagon = suppress enough the liver glucose release. Prof Noakes referred to a real time baboon portal vein measurement, where they could conclude that liver never stops releasing glucose into circulation, but is being suppressed though. Failure here might lead to constantly higher clugose levels.

Enough with speculation, I have no way of being sure of the above. Prof. Feinman is correct; the establishment likes this "soup" approach better than ketogenic intervention, it is closer to "recommendations". The "pill" here is commercial TDR, with keto there is less control for doctors. Wonder, patients given the informed choice, who would take "soup and hunger" and who "steak without potatoes" ...?


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Richard Feinman
December 19th, 2019 at 3:59 am
Commented on: Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent Upon Capacity for B Cell Recovery

The most important aspect of therapy for type 2 diabetes is the role of low-carbohydrate and ketogenic diets because of the overwhelming effectiveness in bringing about improvement and remission and, at the same time, the resistance of the medical establishment to recommending it or even acknowledging published results. This paper characteristically does not mention the background on low-carbohydrate diets although we usually expect scientific papers to cite previous work by others. (It does mention bariatric surgery however).

The paper is about the effects of a very low calorie diet. How low? Well, it isn't easy to tell. One might expect that a breakthrough approach to diabetes, as this was touted, would have the description of the diet as a salient feature of the report. The information is hard to find in the summary or even in the original study but from the protocol it turns out that on "Week 0-12: a commercial micronutrient-replete 825-853 kcal/d TDR (soups and shakes)...." In other words, the intervention was 12 weeks at about half the caloric level of the Minnesota Starvation experiment ( The astounding thing is that a third of the patient did not respond in terms of glycemic control and remission of diabetes and the current paper is about how great it was anyway. Something is not right here.

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