Impaired Incretin-Induced Amplification of Insulin Secretion after Glucose Homeostatic Dysregulation in Healthy Subjects

Feb 10, 2012The Journal of clinical endocrinology and metabolism

Reduced boost to insulin release by gut hormones after blood sugar imbalance in healthy people

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Abstract

The intervention increased insulin resistance from 1.2 ± 0.2 to 2.6 ± 0.5 (P = 0.01) in healthy subjects.

Glucose tolerance deteriorated significantly, with the area under the curve for plasma glucose rising from 730 ± 30 to 846 ± 57 mm after 12 days (P = 0.021).
Subjects increased their insulin responses by 2.9 ± 0.5-fold during saline infusion post-intervention (P = 0.001).
Insulin responses to incretin hormones GIP and GLP-1 were significantly lower, showing insignificant increases of 1.78 ± 0.3 and 1.38 ± 0.3-fold, respectively (P value not significant).
The findings suggest that the impairment of insulinotropic effects of GIP and GLP-1 may result from insulin resistance and glucose intolerance rather than being a primary factor in type 2 diabetes.

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OBJECTIVE: The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects.

RESEARCH DESIGN AND METHODS: The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d.

RESULTS: The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as assessed by the area under curve for plasma glucose during a 75-g oral glucose tolerance test (730 ± 30 vs. 846 ± 57 mm for 2 h, P = 0.021). The subjects compensated for the change in insulin resistance by significantly increasing their postintervention insulin responses during saline infusion by 2.9 ± 0.5-fold (P = 0.001) but were unable to do so in response to incretin hormones (which caused insignificant increases of only 1.78 ± 0.3 and 1.38 ± 0.3-fold, P value not significant).

CONCLUSIONS: These data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotropic effect of the incretin hormones observed in type 2 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.

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Impaired Incretin-Induced Amplification of Insulin Secretion after Glucose Homeostatic Dysregulation in Healthy Subjects

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