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.


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.
Technische Universität München, Germany.
Veronika
V
Leiss
Andreas
A
Friebe
Andrea
A
Welling
Franz
F
Hofmann
Robert
R
Lukowski
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics; D017931:DNA Primers; D005784:Gene Amplification; D017930:Genes, Reporter; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051528:Guanylate Kinases / Q000378:metabolism*; D006706:Homeostasis; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D009130:Muscle, Smooth / Q000201:enzymology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D008164:Luminescent Proteins; D012313:RNA; D005934:Glucagon; D007041:Hypoxanthine Phosphoribosyltransferase; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D051528:Guanylate Kinases; D002118:Calcium