Cyclic GMP kinase I modulates glucagon release from pancreatic α-cells

Diabetes. 2011 Jan;60(1):148-56. doi: 10.2337/db10-0595. Epub 2010 Oct 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Calcium / physiology
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases / deficiency
  • Cyclic GMP-Dependent Protein Kinases / genetics
  • DNA Primers
  • Gene Amplification
  • Genes, Reporter
  • Glucagon / blood
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / enzymology
  • Glucagon-Secreting Cells / metabolism*
  • Glucose Tolerance Test
  • Guanylate Kinases / metabolism*
  • Homeostasis
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / cytology
  • Luminescent Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / physiology
  • Muscle, Smooth / enzymology
  • RNA / genetics
  • RNA / isolation & purification
  • Recombination, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Blood Glucose
  • DNA Primers
  • Insulin
  • Luminescent Proteins
  • RNA
  • Glucagon
  • Hypoxanthine Phosphoribosyltransferase
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases
  • Prkg1 protein, mouse
  • Guanylate Kinases
  • Calcium