Fat Levels in Liver and Pancreas of Key Importance in Driving Type 2 Diabetes

Becky McCall

September 29, 2021

Losing 10-15% of body weight can achieve type 2 diabetes remission in people with normal body mass index (BMI) show findings from the Reversal of Type 2 Diabetes Upon Normalisation of Energy intake in the non-obese (ReTUNE) trial. This is in contrast to the widely held belief that such patients can only be managed with medication.

The findings are similar to results of previous weight loss studies in people with type 2 diabetes who are overweight/obese.

The ongoing ReTUNE study also found that levels of fat in the liver and pancreas fell substantially, and the activity of the insulin-producing cells in the pancreas was restored.

"These results suggest that non-obese people with type 2 diabetes experience similar physiological changes during remission as those who are overweight/obese," said Ahmad Al-Mrabeh, PhD, study co-investigator, from the University of Edinburgh, who presented the work at this year’s virtual Annual Meeting of the European Association for the Study of Diabetes (EASD).

It has long been held that type 2 diabetes harbours a different pathophysiology in people of normal weight, who are "usually not advised to lose weight but tend to start medication, including insulin, earlier," he explained.  

But these results show that in those people with normal BMI, remission can be achieved without drugs - some require 5% weight loss, others need to shed more. "We recommend weight loss with caution in this normal BMI group, so start with modest weight loss," Al-Mrabeh remarked.

Prof Roy Taylor, diabetologist at Newcastle University was ReTUNE’s principal investigator. "These results, while preliminary, demonstrate very clearly that diabetes is not caused by obesity but by being too heavy for your own body.  It's due to having too much fat in your liver and pancreas, whatever your BMI."

He explained that excess fat in the liver prevents insulin from working normally, while in the pancreas, it prevents beta cells from producing insulin. With one-tenth of the UK’s 4.5 million people with type 2 diabetes having normal weight at diagnosis, he added that, "This should be a wake-up call to doctors."

Lucy Chambers, PhD, from Diabetes UK, said she welcomed the study findings. "Internal body fat could be one of the reasons type 2 diabetes develops in people with lower body weights, and the study is testing if a low-calorie, weight loss programme can help to shed internal body fat."

She added that she hopes, "these findings will widen access to the NHS type 2 remission programme".

Diabetes Remission in People of Normal Weight, Overweight, and Obesity 

Previously, the landmark Diabetes Remission Clinical Trial (DiRECT), has provided data showing that intensive weight loss in overweight people can lead to type 2 diabetes remission as well as multiple other benefits including improvements in hypertension, and even restoration of the pancreas.

The ReTUNE trial is similarly looking at type 2 diabetes remission but in those with normal weight.

Twelve people with type 2 diabetes, mean age 58.3 years and mean BMI of 24.5/m2 (all <27 kg/m2) and a mean diabetes duration of 2.5 years were included, and matched with 11 controls, with similar age, BMI (after weight loss), and disease duration.

Participants followed an 800 kcal/day diet of soups and shakes for 2 weeks, followed by 4 to 6 weeks of weight maintenance. This dieting cycle of loss and maintenance was repeated two to three times until remission (HbA1c < 48mmol/mol) was achieved (10-15% of their body weight loss).

Magnetic resonance imaging measured intra-organ fat. Insulin sensitivity and beta cell responsivity after a standard meal were also estimated.

Total Weight and Fat Loss, Liver Fat Reduction, and Disease Remission

Mean weight loss was 8.2kg, from 69kg to 61.8kg, representing 11.9% reduction, while total body fat fell from 33.1% to 27.4% (p<0.001). By comparison, controls had a total body fat of 25.4%.

In those participants who lost weight (10-15% of body weight), both fasting plasma glucose and HbA1c decreased from 7.3 to 6.3 mmol/l, and 53.8 to 48.0mmol/mol respectively (p<0.05 for both). Fasting plasma insulin normalised from 52.2 to 23.7 pmol/L (p=0.007), and plasma triglycerides also fell from1.6mmol/L to 1.0mmol/L, a level similar to controls (p=0.002).

Liver fat at baseline was over twice that of controls (4.4% versus 1.93%, p=0.02), but dropped after the intervention to 1.4% (p=0.004 vs. baseline). Also, pancreas fat lowered from 5.1% to 4.5%, p=0.026), again reflecting control group levels (3.4%, p=0.13).

Weight loss-induced remission (off medication), was achieved in 67% (8/12) of intervention participants. "This is a similar result to that seen in studies of weight loss in overweight and obese participants," remarked Al-Mrabeh.

High Fat in the Vital Organs – Liver and Pancreas Key to Type 2 Diabetes

Our data demonstrate clearly that if you have type 2 diabetes, your body has high fat deposition within the vital metabolic organs, notably the liver and pancreas.

When subcutaneous adipose tissue stores are full or become dysfunctional, fat will spill over into ectopic sites, explained Al-Mrabeh.  "These are places where fat is not normally found, of note, the pancreas, heart, and muscles. Individuals have a certain capacity to store fat, known as the ‘personal fat threshold’, once exceeded then metabolic dysfunction will develop over several years."

Al-Mrabeh hopes that by understanding more about the origin of fat build-up within the pancreas and liver, novel, more targeted therapies, other than weight loss, for prevention and remission of type 2 diabetes will be developed. "We want to know how this is modulated by weight loss to bring about remission of diabetes."

Commenting at the session, Christian Heinz Anderwald, associate professor, Department of Internal Medicine Medical University of Vienna, Austria asked whether the effect seen was really remission of type 2 diabetes, or just an amelioration of the disease. 

"Weight loss can achieve remission of type 2 diabetes, but this is different to a cure," Al-Mrabeh answered. "The definition of remission has been agreed in a recently published [American Diabetes Association/EASD/Diabetes UK] consensus document and these were satisfied by all who returned to normal HbA1c - all were still in remission at 12 months. Remission is a term that defines a new metabolic state." 

Also providing comment, Olga Ramish, from the German Institute of Human Nutrition Potsdam-Rehbruecke asked if weight loss was maintained at study end, and in those that regained weight, what happened to the glycaemic control?

"Weight regain at 12 months was minimal," said Al-Mrabeh. "People of normal weight had far less trouble avoiding weight regain than heavier people. Our earlier studies suggest that weight will be regained if eating habits aren’t controlled…glucose control will deteriorate and diabetes will return." 

Liver Fat Reduction After Weight Loss in Obese and Normal Weight People With Type 2 Diabetes

Taylor, Al-Mrabeh and colleagues from Newcastle also presented other findings at the meeting looking at fat loss from the liver and pancreas in people with type 2 diabetes and a mean BMI of 35.1 kg/m2 (DiRECT trial). These were compared to people with type 2 diabetes and a mean BMI of 24.3 kg/m2 (ReTUNE trial) both before and after weight loss.  

Both groups lost 10-15% of body weight and MRI scans were used to measure levels of fat in the liver and pancreas before and after weight loss. Results were compared to a group of controls - people without diabetes who were matched for age, sex, and BMI.

Liver and pancreatic fat was higher in all patients with type 2 diabetes, irrespective of BMI, and after weight loss. Those with obesity dropped from a mean of 16% liver fat to 3%, while those of normal BMI dropped from 4.7% to 1.4%.  Overweight controls without diabetes had liver fat of 5.5%, and normal weight controls had liver fat of 1.9%.

Pancreatic fat levels also dropped in both groups. In those with obesity, it fell from 8.5% to 7.6% (control, 6.8%), and in those with normal weight from 5% to 4.5% (control, 3.4%).

Both obese and normal BMI groups achieved remission at 60% and 67% respectively.  

At present, it is assumed that a liver fat level of less than 5.5% is healthy whatever a person's BMI, said Taylor. "It is clear that if an individual has type 2 diabetes, they have more fat inside their body than they can cope with, even if they seem to be slim," he said.

"These results also show that levels of liver fat vary with weight and that levels currently considered to be healthy can actually be harmful in lighter people. We need to change the way we assess liver fat, to take into account BMI."

Presented at the online meeting of the Annual Meeting of the European Association for the Study of Diabetes (EASD),  Tuesday 27 September, 2021.  Abstracts 41 and 110

COI: Dr Al-Mrabah has declared no financial disclosures. Professor Taylor has received lecture fees from Novo Nordisk, Lilly and Janssen. He is the author of the book Your Simple Guide To Reversing Type 2 Diabetes.

Both studies were funded by Diabetes UK.

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