Diabetes · 2010
Cyclic GMP kinase I modulates glucagon release from pancreatic α-cells.
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Leiss Veronika, Friebe Andreas, Welling Andrea, Hofmann Franz, Lukowski Robert
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsBlood GlucoseCalciumCyclic GMP-Dependent Protein Kinase Type ICyclic GMP-Dependent Protein KinasesDNA PrimersGene AmplificationGenes, ReporterGlucagonGlucagon-Secreting CellsGlucose Tolerance TestGuanylate KinasesHomeostasisHypoxanthine PhosphoribosyltransferaseInsulinInsulin SecretionIslets of LangerhansLuminescent ProteinsMiceMice, Inbred C57BLMice, KnockoutMuscle, SkeletalMuscle, SmoothRNARecombination, GeneticReverse Transcriptase Polymerase Chain Reaction