Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis

Abstract

Background: Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue.

Methodology/principal findings: We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition.

Conclusions/significance: Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess.

Figure 1. Body fat in relation to adipose cell size.

Adipose cell size in relation to body fat in all individuals with (red circles) or without (blue dots) a known genetic predisposition for Type 2 diabetes (A) or overweight/obesity (B). The figures below display the relationships between fat cell size and body fat in lean individuals (BMI<25 kg/m² with (solid lines) or without (broken lines) a diabetes (C) or overweight/obesity heredity (D). Significance of differences between the groups in cell size vs body fat was tested with ANCOVA for those with or without diabetes (F = 5.8, p = 0.019) (C) or overweight/obesity (F = 0.04, p = 0.85) (D) heredity.

Figure 2. Insulin sensitivity in relation to adipose cell size.

(A) Insulin sensitivity, measured with the euglycemic clamp, in non-obese individuals (BMI<28 kg/m²) with a genetic predisposition for Type 2 diabetes in relation mean abdominal adipose cell volume (r = −0.39, p<0.0001) and (B) delta-values (r = 0.35, p<0.0001). The results are expressed as mg glucose infused (GIR)/kg lean body mass (LBM) and minute.