Reduced Glucose Tolerance and Insulin Resistance Induced by Steroid Treatment, Relative Physical Inactivity, and High-Calorie Diet Impairs the Incretin Effect in Healthy Subjects

Aims/Hypothesis: The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect. Methods: The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 +/- 3 yr (mean +/- SD); body mass index 23 +/- 2 kg/m(2); glycosylated hemoglobin 5.4 +/- 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity. Results: The 12-d intervention period resulted in significant increases in body weight [79 +/- 5 vs. 80 +/- 6 kg (mean +/- SD), P = 0.03] and fasting plasma glucose (5.1 +/- 0.1 vs. 5.6 +/- 0.2 mM, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 +/- 1.7 vs. 9.2 +/- 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 +/- 1.1 vs. 7.8 +/- 2.5 mM, P < 0.0001) and area under curve (AUC) (152 +/- 45 vs. 384 +/- 53 mM.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin),(OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 +/- 5 vs. 43 +/- 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation. Conclusions/Interpretation: Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes. (J Clin Endocrinol Metab 95: 3309-3317, 2010)