Type 2 diabetes genetically driven in lean patients

Lean patients with type 2 diabetes have a greater genetic disposition to the disease than obese patients, according to an international research study led by the University of Exeter and published in PLoS Genetics.

Researchers studied genetic markers in approximately 5,000 lean patients with type 2 diabetes, 13,000 obese patients with the disease, and 75,000 control subjects. Lean cases were defined as body mass index less than 25; obese cases had a BMI of 30 or more.

It found that lean diabetic cases are enriched for known type 2 diabetes risk alleles compared to obese cases. The study showed that 29 out of 36 type 2 diabetes variants established in Europeans had stronger effects in lean compared to obese cases.

The odds ratio for the 20 percent of lean cases carrying the most risk alleles was more than twice that of the 20 percent of obese cases carrying the most risk alleles.

The obese cases carried a disproportionately low load of confirmed type 2 diabetes risk variants. The authors conclude that the diabetes risk for obese patients is likely to be more heavily influenced by their genetic and environmental predisposition to gaining weight in adulthood.

A genetic variant in the LAMA1 gene was associated with type 2 diabetes in lean cases, an association that was stronger than that in obese cases.

The study also concluded that the variants with the strongest effects on diabetes are associated with reduced beta cell function.

Said John Perry, MD, with University of Exeter and University of Oxford and one of the lead authors of the study:

“This is the first time that a type 2 diabetes gene has been found to act in this way—we do not know why it should be associated in one sub-group of patients and not another. It could point to the fact that type 2 diabetes may not be one disease, but may represent a number of subgroups,”

The authors of the study wrote that “obese cases presumably need fewer diabetes risk variants to push them towards diabetes, as they are already under strain from the physiological impact of obesity and insulin resistance.”

Obesity and overweight are established risk factors for developing type 2 diabetes. Other known risk factors include impaired glucose tolerance or impaired fasting glucose, advanced age over 45 years, family history of diabetes, physical inactivity, low HDL cholesterol or high triglycerides, high blood pressure, ethnicity, and personal history of gestational diabetes.

Sources: University of Exeter, PLoS Genetics, American Diabetes Association

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