Mild Physiologic Hyperglycemia Impairs Beta-Cell Function and Induces Insulin Resistance in Healthy Normal Glucose Tolerant Subjects

The aim of the present study was to evaluate effect of a physiologic increase (+45 mg/dl) in plasma glucose concentration on insulin secretion in healthy NGT individuals. 20 NGT subjects: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 years, BMI = 27 ± 1 kg/m²) and 8 with FH (FH+) (4M/4F, Age = 48±2, BMI = 26±1) received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes) followed by IV arginine (5g) bolus. The acute insulin response (AIR_0-10min), 2^nd phase (SP) insulin secretion (IR) (SPIS_10-80 and SIS_90-160 minutes during each hyperglycemic step and following arginine (AIR_Arg) were assessed. Insulin sensitivity was assessed as the glucose infusion rate/steady state plasma insulin (M/I) during the hyperglycemic clamp. FPG concentration increased from 97±4 to 140±4 mg/dl for 48 hours by a variable IV glucose infusion. First phase insulin secretion (0-10 min) and 2^nd phase insulin secretion (10-80 and 90-60 min) increased by 59% and 78%, respectively, following chronic glucose infusion while insulin sensitivity (M/I) during both hyperglycemic clamp steps declined (15± 3.5 to 12±2.8 and 20.8 ± 4.7 to 8.1 ± 2.0, both p<0.02). Consequently, the insulin secretion/insulin resistance (disposition) index declined by 85± 18% (1^st clamp step) and 81±45% (2^nd clamp step) (both p<0.05) following chronic glucose infusion. Similar changes were observed when indices of insulin secretion were measured using C-peptide. There was no difference in the effect of chronic glucose infusion on insulin secretion and insulin sensitivity between subjects with and without FH of T2DM. These results demonstrate that: (i) sustained physiologic hyperglycemia impairs insulin sensitivity (glucotoxicity); (ii) increases absolute insulin secretion; (iii) impairs beta cell function as measured with the disposition index (glucotoxicity).