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Diet and diabetes: exploring the links between obesity and type 2 diabetes

24th November 2021

Obesity is a risk factor for type 2 diabetes but it’s not universally the case that those who are diagnosed are overweight or obese. Two pieces of new research presented at the recent 57th EASD Annual Meeting shed light on the mechanisms behind this, suggesting promising avenues for treatment and prevention. Lisa Buckingham reports.

Effects of a hypercaloric diet on brain insulin sensitivity and liver fat in normal-weight men was the subject of a presentation by Stephanie Kullman, post-doctoral fellow at the Institute for Diabetes Research and Metabolic Diseases of the Helmotz Centre Munich, University of Tübingen.

She first outlined what we already know. When insulin is not appropriately acting in the brain, it is termed brain insulin resistance – this is specifically identified in people with obesity and it has a negative impact on whole-body metabolism. Brain insulin sensitivity is also a predictor of body composition over 10 years and Dr Kullman highlighted a recent study showing that those who are brain insulin resistant gain more weight over 10 years, specifically visceral adipose tissue.

Brain insulin resistance promotes overeating and weight gain and, in animal studies, it’s been shown that even short-term overfeeding can trigger brain insulin resistance. 

The study that was being presented on aimed to find out if overfeeding can trigger brain insulin resistance in healthy humans. A hypercaloric diet (HCD) was used for five days in 29 healthy men – their daily caloric intake was increased by 1500 calories with high caloric snacks and their physical activity was monitored. A control group continued their habitual diet.

Metabolically, they saw very few changes from before and after the intervention. However, there was a significant increase in intrahepatic fat after five days in the HCD group, with a mean change of 53%. The men who were less active in this period had a bigger increase in liver fat.

The team used fMRI to measure regional changes in cerebral blood flow related to the energy use by brain cells before and 30 minutes after applying an intranasal insulin spray – this triggers neural activity that is termed brain insulin action.

There was no significant change in the control group, but the HCD group showed a significant change in insulin responsiveness, specifically in a region called the taste cortex. The HCD diet induced short-term brain insulin resistance as seen in people with obesity from previous research. Brain insulin sensitivity was restored two weeks after the intervention.

Interestingly, those who had the strongest changes in liver fat also had the strongest changes in the brain. Their modelling suggests that the HCD diet induced change in liver fat driven by brain insulin sensitivity.

The conclusion, said Dr Kullman, is that short-term hypercaloric feeding can trigger brain insulin resistance and liver fat accumulation in healthy, normal-weight men. Nutrition can directly modulate brain responses, specifically to insulin, and they think that this can have a tremendous effect on metabolism. Further research is needed to show these causal links.

Can calorie restriction lead to remission in non-obese people?

Preliminary research from the Re-TUNE Study (Reversal of Type 2 Diabetes Upon Normalisation of Energy intake in the non-obese) was presented by Ahmad Al-Mrabeh, a research associate from the University of Edinburgh, although the research was carried out at Newcastle University.

The pathophysiology of diabetes is often assumed to be different in overweight or obese people compared with those of normal body mass index (BMI), said Dr Al-Mrabeh. However, clinical observations suggest that loss of fat can also bring about remission in lean individuals.

The Re-TUNE Study was designed to test this hypothesis – its primary aim was to establish whether weight loss could achieve remission of type 2 diabetes within the non-obese population and investigate the change in metabolic markers. People with early type 2 diabetes and a BMI of less than 27 were recruited.

The study is ongoing with 24 participants in total. It involves three cycles of weight-loss phases over 24 weeks with weight maintenance periods in between. The weight-loss phase is two weeks of calorie restriction (800 calories per day using a liquid formula diet) followed by a six-week phase of stepped food re-introduction and weight loss maintenance.

Preliminary results show that eight out of the 12 participants for which they have full data achieved remission after two cycles (10% weight loss).

The change in fasting insulin went from around 50 pmol/l to around 20 pmol/l. Previous research has shown that fat accumulation in the liver and pancreas determines remission and development of type 2 diabetes in overweight people, said Dr Al-Mrabeh, and they confirm in this study that weight loss is associated with a decrease in liver and intrapancreatic fat. He pointed out that the baseline levels in this non-obese population were below the agreed cut-off for non-alcoholic fatty liver disease (NAFLD).

Total plasma triglycerides was high in the type 2 diabetes cohort at about 1.6% and it decreased sharply after weight loss to be similar to the non-diabetic controls. There was significant improvement in insulin sensitivity index and this was associated with an improvement in beta cell function index, although not clinically significant at this stage in the analysis.

Summary points:

  • Elevation of liver fat, below the diagnostic threshold for NAFLD, can cause metabolic problems in leaner individuals
  • Weight loss (10%) resulted in remission of type 2 diabetes in eight out of 12, with a fall in liver and intrapancreatic fat, and improvement in lipoprotein and β-cell function
  • Two people were eliminated from the study because they were shown to have monogenic or type 1 diabetes, highlighting the importance of accurate diagnosis in non-obese people with diabetes
  • Non-obese people exhibit similar pathophysiology of type 2 diabetes compared with those with overweight; lipoprotein metabolism and intra-organ fat are modulated by weight loss during remission of diabetes

Webcasts from the EASD’s 2021 virtual meeting are now available free to all on the EASD website.

To view the full presentation of these results, see:

OP 07 When men are mice: the study of human physiology in humans

Tuesday 28th September 13.15-14.45!resources/b-effect-of-a-hypercaloric-diet-on-brain-insulin-sensitivity-and-liver-fat-in-normal-weight-men-b


Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.