Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects

TY - JOUR

T1 - Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects

AU - Hansen, Katrine B

AU - Vilsbøll, Tina

AU - Bagger, Jonatan I

AU - Holst, Jens Juul

AU - Knop, Filip K

PY - 2012/4

Y1 - 2012/4

N2 - 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 comparedwith placebo beforeandafter12dof 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.

AB - 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 comparedwith placebo beforeandafter12dof 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.

KW - Adult

KW - Blood Glucose

KW - C-Peptide

KW - Gastric Inhibitory Polypeptide

KW - Glucagon

KW - Glucagon-Like Peptide 1

KW - Glucose Clamp Technique

KW - Glucose Intolerance

KW - Glucose Tolerance Test

KW - Humans

KW - Incretins

KW - Infusions, Intravenous

KW - Insulin

KW - Insulin Resistance

KW - Insulin-Secreting Cells

KW - Kinetics

KW - Male

KW - Severity of Illness Index

KW - Young Adult

U2 - 10.1210/jc.2011-2594

DO - 10.1210/jc.2011-2594

M3 - Journal article

C2 - 22319034

SN - 0021-972X

VL - 97

SP - 1363

EP - 1370

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -