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

摘要

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 (cgkt) 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 cgkia and 1(3 rescue mice [a/prm] 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 ca~(2+) ([ca~(2+)]_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 p-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 [ca~(2+)]_i levels and glucagon release rates of ctr islets at 0.5 mmol/1 glucose, but was without effect on [ca~(2+)]_i or hormone release in cgki-deficient islets. Conclusions-we propose that cgki modulates glucagon release by suppression of [ca~(2+)]_i in a-cells. Diabetes 60: 148-156, 2011