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Some obesity-related genes protect people from type 2 diabetes

Some obesity-related genes protect people from type 2 diabetes, while others increase risk: New research presented today at the Diabetes UK Professional Conference 2023 and funded by Diabetes UK has pinpointed five unique combinations of genes that either help protect people living with obesity and overweight from developing type 2 diabetes or increase their risk.

Researchers identified that obesity-related genes that increased risk of type 2 diabetes were linked to higher levels of liver fat, and vice versa. The findings indicate that patterns of fat storage – in particular, fat in the liver – play a crucial role in determining whether people with obesity are likely to develop type 2 diabetes or not.

Type 2 diabetes is a complex condition with many risk factors including genetics, age, ethnicity and bodyweight, and around 90% of adults with type 2 diabetes aged under 80 live with overweight or obesity1.

Almost 7% of all UK adults have a diagnosis of type 2 diabetes2, but the number living with overweight or obesity is much greater, at nearly two thirds of the UK adult population3. It is not yet understood why the majority of people with overweight and obesity do not develop type 2 diabetes.

The liver plays an important role in maintaining blood sugar levels and to function well it should contain little or no fat. Previous research by Dr Hanieh Yaghootkar at Brunel University London has found that having higher levels of fat in the liver can increase the risk of type 2 diabetes.

In the study presented today, Dr Yaghootkar and a team of researchers from the University of Westminster and Calico Life Sciences, analysed data from the UK Biobank to understand the exact mechanisms by which combinations of obesity-related genes protect against, or increase the risk of type 2 diabetes.

The team identified three combinations of obesity-related genes that increase the risk of type 2 diabetes, and two that lower it. Combinations that increased risk of type 2 diabetes were also linked to high levels of fat in the liver, insulin resistance, problems in the way the body changes food into energy (metabolism) and higher risk of heart disease. The two protective genetic combinations were linked to lower levels of liver fat, better insulin sensitivity, a healthy metabolism and lower risk of heart disease.

All five gene combinations were associated with a history of childhood obesity, higher BMI and higher levels of fat under the skin, and in the pancreas and muscles.

The findings reveal five distinct groups of genes that each impact where fat is stored in the body in unique ways, which in turn directly influences risk of type 2 diabetes in people with overweight or obesity.

Dr Hanieh Yaghootkar at Brunel University London, said:

“There is increased focus on weight loss to manage type 2 diabetes. However, individuals with the same total levels of body fat have different risks for weight-related health conditions such as type 2 diabetes, hypertension and cardiovascular disease.

“Identifying different patterns of fat distribution in the body and their relationship with type 2 diabetes is important for improving risk assessment, understanding underlying mechanisms, developing personalised medicine, and preventing the condition and its complications.

In this study, we used precise measures of fat in different parts of the body, muscle quality and organ size and provided genetic evidence for distinct biological mechanisms that causally link higher adiposity with risk of type 2 diabetes.”

Dr Elizabeth Robertson, Director of Research at Diabetes UK, which funded the study, said:

“Type 2 diabetes is a complex condition with many risk factors, and while living with obesity or overweight is a major risk factor, not everyone with a higher bodyweight will develop the condition. This research takes us a step closer to understanding the role that genetically determined patterns of fat storage play in obesity and type 2 diabetes, revealing why some people with higher bodyweights develop type 2 diabetes, whereas others are naturally protected.

“It’s important to remember that people with obesity who have genes that increase their type 2 diabetes risk can still take steps to reduce it, including by losing weight to reduce levels of fat in their liver.

“Early and accurate identification of those who are at greater risk of type 2 diabetes could help improve the way we predict, prevent and treat the condition, and identify those who might benefit from targeted treatment approaches.”

To find out your risk of developing type 2 diabetes and the support available to help to reduce it, visit Diabetes UK’s Know Your Risk tool.

1. Around 90% of people aged under 80 with type 2 diabetes are living with overweight or obesity. Percentage based on those with a recorded BMI. Data based on NDA Young People with Type 2 Diabetes, 2019-20 Report.
2. Almost 7% of all UK adults have a diagnosis of type 2 diabetes: Estimate based on UK prevalence data for 2021-22 suggests 6.6% of UK adults are living with a type 2 diabetes diagnosis.
3. Nearly two thirds of the UK adult population are living with overweight or obesity. Data based on National health data available for England, Scotland, Wales and Northern Ireland.

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