The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion

Effects on β-Cell Sensitivity in Type 2 and Nondiabetic Subjects

  1. Lise L. Kjems1,
  2. Jens J. Holst2,
  3. Aage Vølund3 and
  4. Sten Madsbad1
  1. 1Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
  2. 2Department of Medical Physiology, the Panum Institute, University of Copenhagen, Copenhagen NV, Denmark
  3. 3Department of Biostatistics, Novo Nordisk A/S, Bagsvaerd, Denmark

    Abstract

    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.

    Footnotes

    • Address correspondence and reprint requests to Sten Madsbad, MD, Department of Endocrinology, Hvidovre Hospital, Kettegaard Alle, DK-2650 Hvidovre, Denmark. E-mail: sten.madsbad{at}hh.hosp.dk.

      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.

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