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Key to type 2 diabetes remission may be loss of half a gram of pancreas fat

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LOS ANGELES — Adults with type 2 diabetes may be able to achieve sustainable remission from the disease by losing weight and decreasing fat in the pancreas and liver, according to data presented at the AACE Annual Scientific and Clinical Congress.

Roy Taylor

Specific measures of 15 kg of total weight loss and a 0.5 g loss of pancreas fat may initiate a reversal of type 2 diabetes, Roy Taylor, MD, FRCP, a professor of medicine and metabolism at Newcastle University in the United Kingdom, said during a plenary presentation.

The ‘twin cycle hypothesis’

A primary factor in determining the validity of these findings is evaluating the robustness of what Taylor calls the “twin cycle hypothesis.” This hypothesis predicts that weight loss following a low-calorie diet will normalize the first phase insulin response in the pancreas.

For those without diabetes, the first phase insulin response occurs with a “rapid shot” approximately 6 minutes after a meal, but such a phenomenon is not present in those with type 2 diabetes. Data from the 2011 Counterpoint study indicated a gradual increase in the peak first phase insulin response in participants with type 2 diabetes who restricted energy intake to 600 kcal per day over an 8-week period. This gradual increase in insulin response ran in parallel to a gradual decrease in pancreas fat, according to Taylor, who said that the beta cells “wake up” during this process.

Determining durability

In the 2016 Counterbalance study, Taylor and colleagues observed that when adults with type 2 diabetes employed a diet of between 624 kcal and 700 kcal per day for 8 weeks and then ate normally for the next 6 months, not only did they lose weight, but they also maintained the lower weight during the follow-up period. As weight loss occurred, HbA1c levels also declined, going from an average of 7.1% at baseline to 5.8% during the 8 weeks of restricted energy intake and holding steady at 5.9% through 6 months of follow-up. Even participants who did not achieve a normal first-phase insulin response after 8 weeks decreased HbA1c levels from 8.4% at baseline to 7.8% at 6 months of follow-up.

Taylor noted that these improvements in HbA1c levels ran in parallel to a decrease in liver and pancreas fat. Liver fat fell from more than 12% at baseline to less than 4% at 10 weeks and 6 months in those who achieved first-phase insulin response normalization, and there was a loss of roughly 0.5 g of pancreas fat between baseline and 10 weeks in this group as well.

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“The bottom line is that type 2 diabetes appears to be caused by a half a gram of fat ... from the pancreas,” Taylor said, while adding that the return to first-phase insulin secretion was maintained during the 6 months of follow-up when participants were asked to return to a normal diet.

While these findings indicate potential remission of type 2 diabetes for anyone with the disease, weight loss is most effective in those with a shorter diabetes duration. For those with a longer duration, over time the “beta cell becomes more and more damaged by the persistent levels of fat,” Taylor said, which adversely affects the ability to achieve fasting plasma glucose levels that equate to diabetes reversal.

Real world treatments

Using these data to inform a potential treatment strategy for type 2 diabetes is the next step, Taylor said. In the Diabetes Remission Clinical Trial (DiRECT), Taylor and colleagues attempted to test the plausibility in a real-world setting of this weight loss strategy and the potential benefits as shown in the smaller Counterpoint and Counterbalance studies.

Participants (n = 298; mean age, 54.4 years; 40.9% women) were randomly assigned to standard care or an energy restriction diet limiting intake to between 825 kcal and 853 kcal per day as well as structured training from a practice nurse on weight maintenance.

Adults with type 2 diabetes may be able to achieve sustainable remission from the disease by losing weight and decreasing fat in the pancreas and liver Shutterstock

At 1 year, the total rate of diabetes remission, as defined by a HbA1c level of less than 6.5%, was achieved by 46% of those who received the intervention and 4% of those who received usual care. These results outstripped estimates made by the researchers prior to study initiation; Taylor noted that they expected roughly 20% of those in the intervention group to achieve remission and 5% of those in usual care to do the same. The remission was maintained over the course of 2 years as well, particularly for those who lost at least 10 kg of baseline body weight, A follow-up study showing that 64% of those who reached such a weight loss remained in remission at 24 months, Taylor said.

Adding to the evidence that more weight loss equals improved outcomes in terms of diabetes reversal, the follow-up in the DiRECT cohort showed that those who achieved remission at both 12 and 24 months lost more weight at each point compared with those who did not achieve remission at all and those who achieved remission at 12 months only.

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“We haven’t gotten this perfectly right yet,” Taylor said. “There is so much more work to do in understanding how to achieve prevention of weight regain. Certainly, other behavioral interventions, certainly, perhaps, GLP-1 agonists, other agents could be used. All of that is to be explored because this is the start of a story, not the end of it.”

Pancreas fat’s role

A final question that needs to be addressed is whether pancreas fat reduction is responsible, at least in part, for these results. This was examined in a 2016 study that compared pancreatic triacylglycerol levels in those with type 2 diabetes and those without who lost similar amounts of weight following bariatric surgery. According to Taylor, despite similar levels of fat mass loss, the study showed that there was “highly significant change” in pancreas fat for those with type 2 diabetes and no significant change in those without diabetes.

The study itself further demonstrated that triacylglycerol levels decreased for those with type 2 diabetes, and the reduction was associated with the diabetes not the loss of body fat, Taylor said. In addition to the reduction in pancreatic fat, the researchers further observed that first phase insulin secretion normalized in those with type 2 diabetes.

In the DiRECT study, according to unpublished data that Taylor presented at AACE, those who responded to intervention increased first-phase and peak insulin response after 4 months and then maintained these levels for 24 months. At 4 months, pancreas fat levels decreased in those who responded to intervention and increased in those who did not.

Taken together, these findings give clear answers to how weight loss and its effect on pancreatic fat could be used to inform treatment with the aim of diabetes remission, Taylor said.

“First of all, that the twin cycle hypothesis appears robust. The return of glucose homeostasis is durable. You can achieve remission for your patients just by training a nurse to carry out procedures of effective weight loss, and it’s all due to the excess fat in the pancreas,” Taylor said. “Type 2 diabetes is a potentially reversible state of excess fat in liver and pancreas.” – by Phil Neuffer

References:

Taylor, et al. Type 2 diabetes remission as a therapeutic goal. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.

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Steven S, et al. Diabetes Care. 2016;doi:10.2337/dc15-0750.

Lim EL, et al. Diabetologia. 2011;doi:10.1007/s00125-011-2204-7.

Lean MEJ, et al. Lancet Diabetes Endocrinol. 2019;doi: 10.1016/S2213-8587(19)30068-3.

Taylor R, et al. Diabetologia. 2019;doi:10.1007/s00125-017-4503-0.

Steven S, et al. Diabetes Care. 2016;doi:10.2337/dc15-1942.

Disclosure: Taylor reports that he is a member of the U.K. government’s working group on low carbohydrate diets and then he receives lecture fees from Novartis and Lilly & Janssen and is on the advisory board for Wilmington Healthcare.