Cyclic GMP Kinase I Modulates Glucagon Release From Pancreatic α-Cells
- 1FOR 923, Technische Universität München, München, Germany, and Center for Integrated Protein Science, Ludwig-Maximilians-Universität München, München, Germany;
- 2Institut für Pharmakologie und Toxikologie, Abteilung Pharmakologie und Experimentelle Therapie, Universitätsklinikum Tübingen, Tübingen, Germany;
- 3Lehrstuhl für Physiologie I, Julius-Maximilians Universität Würzburg, Würzburg, Germany;
- 4Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany;
- 5Institut für Pharmazie, Abteilung Pharmakologie, Toxikologie und Klinische Pharmazie, Universität Tübingen, Tübingen, Germany.
- Corresponding author: Robert Lukowski, .
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.
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- Received April 27, 2010.
- Accepted October 7, 2010.
- © 2011 by the American Diabetes Association.
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