Prandial glucose effectiveness and pasting gluconeogenesis in insulin-resistant first-degree relatives of patients with type 2 diabetes

Impaired glucose effectiveness (i.e., a diminished ability of glucose per s e to facilitate its own metabolism), increased gluconeogenesis, and endogen ous glucose release are, together with insulin resistance and beta -cell ab normalities, established features of type 2 diabetes. To explore aspects of the pathophysiology behind type 2 diabetes, we assessed in ct group of hea lthy people prone to develop type 2 diabetes (n = 23), namely first-degree relatives of type 2 diabetic patients (FDR), 1) endogenous glucose release and fasting gluconeogenesis measured using the (H2O)-H-2 technique and 2) g lucose effectiveness. The FDR group was insulin resistant when compared wit h an age-, sex-, and BMI-matched control group without a family history of type 2 diabetes (n = 14) (M value, clamp: 6.07 +/- 0.48 vs. 8.06 +/- 0.69 m g.kg(-1) lean body weight (lbw).min(-1) P = 0.02). Fasting rates of glucone ogenesis (1.28 +/- 0.06 vs. 1.41 +/- 0.07 mg.kg(-1) lbw.min(-1); FDR vs. co ntrol subjects, P = 0.18) did not differ in the two groups and accounted fo r 53 +/- 2 and 60 +/- 3% of total endogenous glucose release. Glucose effec tiveness was examined using a combined somatostatin and insulin infusion (0 .17 vs. 0,14 mU.kg(-1).min(-1), FDR vs. control subjects), the latter repla cing serum insulin at near baseline levels. In addition, a 360-min labeled glucose infusion was given to simulate a prandial glucose profile. After gl ucose infusion, the integrated plasma glucose response above baseline (1817 +/- 94 vs. 1789 +/- 141 mmol/l per 6 h), the ability of glucose to simulat e its own uptake (1.50 +/- 0.13 vs. 1.32 +/- 0.16 ml.kg(-1) lbw.min(-1)), a nd the ability of glucose per se to suppress endogenous glucose release did not differ between the FDR and control group. In conclusion, in contrast t o overt type 2 diabetic patients, healthy people at high risk of developing type 2 diabetes are characterized by normal glucose effectiveness at near- basal insulinemia and normal fasting rates of gluconeogenesis.