Abstract

Hyperglycemia adversely affects skeletal muscle and hepatic insulin sensitivity (glucotoxicity). However, the effect of prolonged hyperglycemia on glucose and insulin-mediated suppression of glucagon is not known. The aim of the present study was to evaluate effect of a chronic (72 hours) physiologic increase (+45 mg/dl) in plasma glucose concentration on the suppression of plasma glucagon concentration in healthy NGT individuals: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 years, BMI = 27 ± 1 kg/m2) and 8 with FH of T2DM (FH+) (4M/4F, age = 48±2, BMI = 26±1 kg/m2). Subjects received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes) before and after 72-hour glucose infusion. Plasma insulin and C-peptide concentrations were obtained every 2-5 minutes during each hyperglycemic clamp step and plasma glucagon concentrations were measured every 10 minutes. The ratio of insulin/glucagon was measured and used as an index of insulin-medicated suppression of plasma glucagon. FPG concentration increased from 97±4 to 140±4 mg/dl during the 72-hour glucose infusion. Following chronic glucose infusion, plasma insulin levels were significantly higher during the basal state and during each hyperglycemic clamp step (by 59% and 78%) during the 0-80 and 80-160 min time periods, respectively. There was no difference in plasma glucagon levels following chronic glucose infusion. However, the plasma insulin/glucagon ratio was significantly higher during the fasting state (by 76%) and during the first (by 128%) and second (by 178%) hyperglycemic clamp steps. There was no difference in the effect of chronic glucose infusion on glucagon secretion between FH+ and FH-subjects. These results demonstrate that sustained physiologic hyperglycemia for 72 hours (i.e., glucotoxicity) impairs insulin-mediated suppression of glucagon, and could contribute to fasting and post-prandial hyperglycemia in T2DM patients. Disclosure A. Merovci: None. X. Chen: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None. Funding National Institutes of Health

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call