Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients

Objective: First-degree relatives (FDR) of type 2 diabetic patients are often insulin resistant. Visceral obesity is closely linked to both insulin resistance and type 2 diabetes. We therefore hypothesized that the inheritance of an increased tendency to store fat in visceral fat depots may be a characteristic phenotypic feature in FDR contributing to their insulin resistance. Design and methods: We measured fat distribution in 20 FDR and 14 age-, gender- and body mass index (BMI)-matched controls employing dual energy X-ray absorbtiometry (DEXA)- and computed tomography (CT)-scanning. Insulin-stimulated glucose uptake (ISGU) was determined by a hyperinsulinemic clamp and maximal aerobic work capacity (VO 2 max) by a bicycle ergometer test. Baseline lipolysis was measured using [ 3 H]palmitate. The activity level of the hypothalamic-pituitary-adrenal axis was assessed as the 24 h urinary (u)-cortisol/creatinine ratio. Results: All subjects had a normal oral glucose tolerance test (OGTT), but FDR were insulin resistant (ISGU: 6.64±0.48 vs 9.12±0.98 mg/kg ffm/min, P = 0.01). Despite similar BMI (25.2±0.5 vs 24.8±0.7 kg/m 2 , P = 0.61) and overall fat mass (26.4±1.6 vs 24.2±2.1%, P= 0.41) in FDR vs controls, the amount of visceral adipose tissue was substantially increased (65.9±10.0 vs 40.1±11.3 cm 2 . P < 0.05) and VO 2 max was reduced (52.2 ± 3.1 vs 61.3 ± 3.9 ml/kg ffm/min, P < 0.05) in FDR. Visceral adiposity was inversely correlated with ISGU (FDR: r = -0.52, P < 0.05; controls: r = -0.65, P < 0.01) and in multiple regression analysis visceral adiposity (P < 0.01), VO 2 max (P < 0.001) and a family history of type 2 diabetes (P < 0.05) (r 2 = 0.64) all significantly and independently contributed to the level of ISGU. Baseline palmitate appearance (145±10 vs 139 ± 15 μmol/min, P = 0.74) and the 24h u-cortisol/creatinine ratio ((24.9 ± 1.3 vs 27.4±2.0).10 -6 , P = 0.28) were both comparable in the two groups. Conclusion: Healthy but insulin-resistant FDR have enhanced visceral obesity and reduced VO 2 max compared with people without a family history of diabetes, despite similar BMI and overall fat mass. Both the visceral adiposity and reduced aerobic fitness are strongly associated with and may contribute to their insulin resistance.