Cyclic GMP Kinase I Modulates Glucagon Release From Pancreatic α-Cells

  1. Robert Lukowski1,5
  1. 1FOR 923, Technische Universität München, München, Germany, and Center for Integrated Protein Science, Ludwig-Maximilians-Universität München, München, Germany;
  2. 2Institut für Pharmakologie und Toxikologie, Abteilung Pharmakologie und Experimentelle Therapie, Universitätsklinikum Tübingen, Tübingen, Germany;
  3. 3Lehrstuhl für Physiologie I, Julius-Maximilians Universität Würzburg, Würzburg, Germany;
  4. 4Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany;
  5. 5Institut für Pharmazie, Abteilung Pharmakologie, Toxikologie und Klinische Pharmazie, Universität Tübingen, Tübingen, Germany.
  1. Corresponding author: Robert Lukowski, robert.lukowski{at}uni-tuebingen.de.

Abstract

OBJECTIVE The physiologic significance of the nitric oxide (NO)/cGMP signaling pathway in islets is unclear. We hypothesized that cGMP-dependent protein kinase type I (cGKI) is directly involved in the secretion of islet hormones and glucose homeostasis.

RESEARCH DESIGN AND METHODS Gene-targeted mice that lack cGKI in islets (conventional cGKI mutants and cGKIα and Iβ rescue mice [α/βRM] that express cGKI only in smooth muscle) were studied in comparison to control (CTR) mice. cGKI expression was mapped in the endocrine pancreas by Western blot, immuno-histochemistry, and islet-specific recombination analysis. Insulin, glucagon secretion, and cytosolic Ca2+ ([Ca2+]i) were assayed by radioimmunoassay and FURA-2 measurements, respectively. Serum levels of islet hormones were analyzed at fasting and upon glucose challenge (2 g/kg) in vivo.

RESULTS Immunohistochemistry showed that cGKI is present in α- but not in β-cells in islets of Langerhans. Mice that lack α-cell cGKI had significantly elevated fasting glucose and glucagon levels, whereas serum insulin levels were unchanged. High glucose concentrations strongly suppressed the glucagon release in CTR mice, but had only a moderate effect on islets that lacked cGKI. 8-Br-cGMP reduced stimulated [Ca2+]i levels and glucagon release rates of CTR islets at 0.5 mmol/l glucose, but was without effect on [Ca2+]i or hormone release in cGKI-deficient islets.

CONCLUSIONS We propose that cGKI modulates glucagon release by suppression of [Ca2+]i in α-cells.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Received April 27, 2010.
  • Accepted October 7, 2010.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 60 no. 1 148-156
  1. Online Appendix
  2. All Versions of this Article:
    1. db10-0595v1
    2. 60/1/148 most recent