Cyclic GMP kinase I modulates glucagon release from pancreatic ?-cells.

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.Gene-targeted mice that lack cGKI in islets (conventional cGKI mutants and cGKI? and I? rescue mice [?/?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.Immunohistochemistry showed that cGKI is present in ?- but not in ?-cells in islets of Langerhans. Mice that lack ?-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.We propose that cGKI modulates glucagon release by suppression of [Ca²(+)](i) in ?-cells.     «

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.Gene-targeted mice that lack cGKI in islets (conventional cGKI mutants and cGKI? and I? rescue mice [?/?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 W...     »