Insulin Infusion During Normoglycemia Modulates Insulin Secretion According to Whole-Body Insulin Sensitivity.

OBJECTIVE Glucose is the major stimulus for insulin release. Time course and amount of insulin secreted after glycemic stimulus are different between type 2 diabetes mellitus (T2DM) patients and healthy subjects. In rodents, it was demonstrated that insulin can modulate its own release. Previous studies in humans yielded contrasting results: Insulin was shown to have an enhancing effect, no effect, or a suppressive effect on its own secretion. Thus, we aimed to evaluate short-term effects of human insulin infusion on insulin secretion during normoglycemia in healthy humans and T2DM subjects of both sex. RESEARCH DESIGN AND METHODS Hyperinsulinemic-isoglycemic clamps with whole-body insulin-sensitivity (M) and C-peptide measurements for insulin secretion modeling were performed in 65 insulin-sensitive (IS) subjects (45 +/- 1 year, BMI: 24.8 +/- 0.5 kg/m(2)), 17 insulin-resistant (IR) subjects (46 +/- 2 years, 28.1 +/- 1.3 kg/m(2)), and 20 T2DM patients (56 +/- 2 years, 28.0 +/- 0.8 kg/m(2); HbA1c = 6.7 +/- 0.1%). RESULTS IS subjects (M = 8.8 +/- 0.3 mg . min(-1) . kg(-1)) had higher (P < 0.00001) whole-body insulin sensitivity than IR subjects (M = 4.0 +/- 0.2) and T2DM patients (M = 4.3 +/- 0.5). Insulin secretion profiles during clamp were different (P < 0.00001) among the groups, increasing in IS subjects (slope: 0.56 +/- 0.11 pmol/min(2)) but declining in IR (-0.41 +/- 0.14) and T2DM (-0.87 +/- 0.12, P < 0.00002 IR and T2DM vs. IS) subjects. Insulin secretion changes during clamp directly correlated with M (r = 0.6, P < 0.00001). CONCLUSIONS Insulin release during normoglycemia can be modulated by exogenous insulin infusion and directly depends on whole-body insulin sensitivity. Thus, in highly sensitive subjects, insulin increases its own secretion. On the other hand, a suppressive effect of insulin on its own secretion occurs in IR and T2DM subjects.