New Genes Hold Clue to Why Many With Obesity Don't Get Diabetes

Becky McCall

March 19, 2018

LONDON — Seven new genetic variants that could lower a person's risk of developing type 2 diabetes have been identified in an effort to understand why some people who are overweight or obese are at much lower risk of the disease than others.

The researchers, led by Hanieh Yaghootkar, MD, PhD, from the University of Exeter, UK, say that people carrying these genes have a so-called 'favorable' adiposity profile, whereby their extra fat is stored subcutaneously rather than around organs such as the liver (visceral fat).

Using data from the UK Biobank, Yaghootkar and colleagues identified 14 genetic variants associated with obesity but a lower risk of type 2 diabetes; 7 were already known and 7 are novel.

Obesity is a recognized risk factor for type 2 diabetes, but of the overall type 2 diabetes population, around half are normal weight, with some even being quite lean. And among obese patients, many do not have type 2 diabetes, explained the researcher.

"We live at a time when our environment is changing the world's population body size to its upper limit, leading to increased prevalence of type 2 diabetes. Our study provides evidence that people store fat in different places, which is genetically determined," said Yaghootkar, who presented her work here at the Diabetes UK Professional Conference 2018.

"Our study suggests that individuals with these 14 genetic factors are able to store fat in a safer place, so that despite having higher percentage body fat they are protected from type 2 diabetes, heart disease, and hypertension," she observed.

What Confers Protection From Type 2 Diabetes in Some Obese People?

Yaghootkar's work aimed to determine what confers a level of protection from type 2 diabetes in some with obesity, while conversely, what confers higher risk in some normal weight individuals.

"We wanted to know if there were more genetic variants associated with so-called 'favorable' adiposity," she pointed out.

Researchers studied the genetic factors associated with higher percentage body fat in 451,000 UK-based individuals from data collected by the UK Biobank study.

They also used published genome-wide association study (GWAS) data to characterize each genetic variant and narrow down the list of potential genetic factors to those associated with higher adiposity but a favorable metabolic profile, explained Yaghootkar.

A favorable metabolic effect was seen with genetic variants associated with an increase in body fat percentage, adiponectin, sex hormone binding globulin, and high-density lipoprotein cholesterol, as well as variants associated with a decrease in triglycerides, fasting insulin, and alanine transaminase, she reported.

Carrying the 'favorable adiposity' alleles was associated with higher body mass index (0.063 kg/m2, P = 4 x 10−45) but lower risk of type 2 diabetes (odds ratio, 0.95; P = 4 x 10−44, 14,371 cases).

"The 5% of people with most of these genes will be about half a kilogram heavier, for average height, but at about 40% lower risk of type 2 diabetes, 10% lower risk of heart disease, and 10% lower risk of hypertension compared with the 5% of people with the fewest," she emphasized.

Body Fat Storage — Subcutaneous in Those With the 14 Genetic Variants

Of the 14 genetic variants found to be associated with high body fat percentage but lower risk of type 2 diabetes, heart disease, and hypertension, the researchers wondered if the key to the risk was where in the body the fat was stored.

Using MRI data, which they had on 5000 individuals from the UK Biobank, they found that carrying the more 'favorable adiposity' alleles was associated with lower liver fat (P = .0002) and lower visceral-to-subcutaneous adipose tissue ratio in men and women (P = .007), which was driven by association with more subcutaneous fat (P = .007).

The 14 genetic variants were also associated with a favorable body shape in women, which is a lower waist circumference and higher hip circumference.

"But it was different in men," said Yaghootkar. "We found they [the 14 variants] were associated with high waist circumference and higher hip circumference, so it is not due to a favorable body shape in men."

Session moderator Shivani Misra, MD, consultant in metabolic medicine at Imperial College Healthcare NHS Trust, London, UK, complimented Yaghootkar on her work but asked whether she had looked at the role of pancreatic fat and its relationship with risk of type 2 diabetes.

"We are planning to, but it is very difficult to measure with a limited number of individuals available. UK Biobank is planning to do this," Yaghootkar replied.

And Misra also wondered whether the differential expression of these variants in different ethnic groups "might account for some of the variable risk in type 2 diabetes that we see."

"It's a good question, and we are looking at the South Asian population to see if the effect is greater in this population," answered Yaghootkar.

Finally, Misra enquired whether, as a clinician, she should be screening patients for these variants if they are overweight and if there is reason to be concerned about their risk.

"As you know these variants are common in the population with very subtle effects, but they don't have any predictive value in the clinic yet," Yaghootkar concluded.

Yaghootkar and Misra have reported no relevant financial relationships.

Diabetes UK Professional Conference 2019. March 16, 2018; London, UK. Abstract A59.

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