Peripheral adipose tissue storage capacity may underpin diabetes vulnerability
medwireNews: The same genetic variants that predict insulin resistance and cardiometabolic disease are also linked to a reduced ability to expand peripheral fat storage, shows research published in Nature Genetics.
“We’ve long suspected that problems with fat storage might lead to its accumulation in other organs such as the liver, pancreas and muscles, where it causes insulin resistance and eventually diabetes, but the evidence for this has mostly come from rare forms of human lipodystrophy,” study author Stephen O’Rahilly (University of Cambridge, UK) said in a press statement.
“Our study suggests that these processes also take place in the general population.”
Using data from up to 188,577 people, the team identified 53 genomic regions that were associated with higher fasting insulin and triglyceride levels, and lower levels of high-density lipoprotein cholesterol, independently of body mass index (BMI).
Ten of these have been previously linked to insulin resistance, but 43 associations are newly identified. The loci contained genes including that encoding lipoprotein lipase, as well as the PPARG, PIK3R1, and INSR genes, mutations in which have previously been associated with severe monogenic forms of insulin resistance.
A risk score generated from these 53 loci was significantly associated with insulin resistance in an additional 6101 individuals, and with gold-standard measures of insulin resistance, such as euglycemic clamp, in 2764 people.
Applying the risk score to 45,836 patients with cardiometabolic disease and 230,358 controls, the researchers found that each standard deviation increase in the score (equivalent to having about an additional 4.5 risk alleles) was associated with a significant 12% increase in the likelihood of having type 2 diabetes. It was also associated with a smaller but still significant 5% increase in the likelihood of having coronary artery disease.
But despite being associated with insulin resistance – commonly linked to increased adiposity – a higher genomic risk score was associated with a significantly lower BMI and percentage body fat and a higher waist-to-hip ratio. It was associated with less fat in the arms, legs, android, and gynoid compartments, but not in the trunk.
Among 9150 participants of the EPIC-Norfolk cohort who gained weight during follow-up, those who had more of the 53 risk alleles had smaller increases in hip circumference for a given amount of overall weight gained.
“Overall, these association analyses suggest that individuals genetically predisposed to insulin resistance via the 53 loci have a relative inability to expand their peripheral fat compartment when challenged by a positive energy balance and that this incapacity results in higher cardiometabolic disease risk,” say the researchers.
Of note, the 53 loci were overrepresented in women with pathogenesis of familial partial lipodystrophy type 1, a condition in which patients develop severe insulin resistance despite a loss of adipose tissue in the arms and legs.
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