The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion
Effects on β-Cell Sensitivity in Type 2 and Nondiabetic Subjects
- 1Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
- 2Department of Medical Physiology, the Panum Institute, University of Copenhagen, Copenhagen NV, Denmark
- 3Department of Biostatistics, Novo Nordisk A/S, Bagsvaerd, Denmark
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 β-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 · kg−1 · min−1 over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol · kg−1 · 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 β-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 · kg−1 · 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 β-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 β-cell responsiveness to glucose and GLP-1 is severely impaired in patients with type 2 diabetes.
Address correspondence and reprint requests to Sten Madsbad, MD, Department of Endocrinology, Hvidovre Hospital, Kettegaard Alle, DK-2650 Hvidovre, Denmark. E-mail:.
Received for publication 16 April 2002 and accepted in revised form 29 October 2002.
AUC, area under the curve; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; ISR, insulin secretion rate.