The influence of GLP-1 on glucose-stimulated insulin secretion: Effects on β-cell sensitivity in type 2 and nondiabetic subjects

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 2; pp. 380 - 386
• Main Authors: KJEMS, Lise L, HOLST, Jens J, VØLUND, Aage, MADSBAD, Sten
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2003
• Subjects: Area Under Curve; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; C-Peptide - blood; Care and treatment; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucagon; Glucagon - administration & dosage; Glucagon - pharmacology; Glucagon - physiology; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Kinetics; Male; Medical sciences; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Peptide Fragments - physiology; Physiological aspects; Protein Precursors - administration & dosage; Protein Precursors - pharmacology; Protein Precursors - physiology; Reference Values; Type 2 diabetes; Denmark; Endocrinopathy; Human; Gastrointestinal hormone; Sensitivity resistance; Diabetes mellitus; β Cell; Glucose; Insulin; Endocrine pancreas; Glucagon like peptide 1
• DOI: 10.2337/diabetes.52.2.380
• ISSN: 0012-1797

The intestinally derived hormone glucagon-like peptide 1 (GLP-1) (7-36 amide) has potent effects on glucose-mediated insulin secretion, insulin gene expression, and beta-cell growth and differentiation. It is, therefore, considered a potential therapeutic agent for the treatment of type 2 diabetes. However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2, 4, 6, 8, and 12 mg x kg(-1) x min(-1) over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1). GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 +/- 51 to 975 +/- 198 pmol/kg in the patients with type 2 diabetes and from 711 +/- 123 to 2,415 +/- 243 pmol/kg in the control subjects. The beta-cell responsiveness to glucose, expressed as the slope of the linear relation between ISR and the glucose concentration, increased in proportion to the GLP-1 dose to 6 times relative to saline at the highest GLP-1 dose in the patients and 11 times in the control subjects, but it was 3 to 5 times lower in the patients with type 2 diabetes compared with healthy subjects at the same GLP-1 dose. During infusion of GLP-1 at 0.5 pmol x kg(-1) x min(-1) in the patients, the slope of ISR versus glucose became indistinguishable from that of the control subjects without GLP-1. Our results show that GLP-1 increases insulin secretion in patients with type 2 diabetes and control subjects in a dose-dependent manner and that the beta-cell responsiveness to glucose may be increased to normal levels with a low dose of GLP-1 infusion. Nevertheless, the results also indicate that the dose-response relation between beta-cell responsiveness to glucose and GLP-1 is severely impaired in patients with type 2 diabetes.