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

• Published in: The journal of clinical endocrinology and metabolism Vol. 97; no. 4; pp. 1363 - 1370
• Main Authors: Hansen, Katrine B., Vilsbøll, Tina, Bagger, Jonatan I., Holst, Jens J., Knop, Filip K.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.04.2012; Endocrine Society
• Subjects: Adult; Biological and medical sciences; Blood Glucose - analysis; C-Peptide - blood; Diabetes; Diabetes mellitus (non-insulin dependent); Disease resistance; Endocrinopathies; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gastric Inhibitory Polypeptide - administration & dosage; Gastric Inhibitory Polypeptide - blood; Gastric Inhibitory Polypeptide - metabolism; GIP protein; Glucagon; Glucagon - blood; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide 1 - metabolism; Glucose; Glucose Clamp Technique; Glucose Intolerance - blood; Glucose Intolerance - metabolism; Glucose Intolerance - physiopathology; Glucose tolerance; Glucose Tolerance Test; Hormones; Humans; Incretins - administration & dosage; Incretins - blood; Incretins - metabolism; Infusions, Intravenous; Insulin - blood; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Kinetics; Male; Medical sciences; Prednisolone; Risk factors; Severity of Illness Index; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Young Adult; Obesity; Incretin; Pancreatic hormone; Healthy subject; Nutrition; Secretion; Nutrition disorder; Metabolic diseases; Glucose; Insulin; Amplification; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2011-2594

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.