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

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 cGKI alpha and I beta rescue mice [alpha/beta RM] 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 alpha- but not in beta-cells in islets of Langerhans. Mice that lack alpha-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 alpha-cells. Diabetes 60: 148-156, 2011