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Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance and Insulin Sensitivity in Healthy Glucose Tolerant Subjects.

The aim of the present study was to evaluate the effect of sustained physiologic increase ∼50 mg/dl in plasma glucose concentration on insulin secretion in normal glucose tolerant (NGT) subjects. Twelve NGT subjects without family history of T2DM (FH-) and 8 NGT with family history of T2DM (FH+) received OGTT and 2-step hyperglycemic clamp (+100 and +300 mg/dl) followed by IV arginine bolus before and after 72 hour glucose infusion. Fasting plasma glucose (FPG) increased from 94±2 to 142±4 mg/dl for 72 hours. First phase insulin secretion (0-10 min) increased by 70%, while second phase insulin secretion during the 1st (10-80 min) and 2nd (90-160 min) hyperglycemic clamp steps increased by 3.8-fold and 1.9-fold, respectively, following 72 hours of physiologic hyperglycemia. Insulin sensitivity (M/I during hyperglycemic clamp) declined by ∼30% and ∼55% (both p<0.05), respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (2nd clamp step) and by 62% following arginine (both p<0.005) following 72 hour glucose infusion. The effect of 72 hour glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 hours of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (p<0.01). These results demonstrate that sustained physiologic hyperglycemia for 72 hours: (i) increases absolute insulin secretion but impairs beta cell function; (ii) causes insulin resistance; (iii) reduces MCR of insulin.