Technische Universität München, Germany.
Diabetes. 2011 Jan;60(1):148-56. doi: 10.2337/db10-0595. Epub 2010 Oct 26.
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 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(+)) 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 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(+) levels and glucagon release rates of CTR islets at 0.5 mmol/l glucose, but was without effect on Ca²(+) or hormone release in cGKI-deficient islets.
We propose that cGKI modulates glucagon release by suppression of Ca²(+) in α-cells.
一氧化氮（NO）/环鸟苷酸（cGMP）信号通路在胰岛中的生理意义尚不清楚。我们假设 cGMP 依赖性蛋白激酶 I 型（cGKI）直接参与胰岛激素的分泌和葡萄糖稳态的调节。
我们研究了缺乏胰岛 cGKI 的基因靶向小鼠（常规 cGKI 突变体和仅在平滑肌中表达 cGKI 的 cGKIα 和 Iβ 拯救小鼠[α/βRM]），并将其与对照（CTR）小鼠进行了比较。通过 Western blot、免疫组织化学和胰岛特异性重组分析来绘制内分泌胰腺中的 cGKI 表达图谱。通过放射免疫测定和 FURA-2 测量分别测定胰岛素、胰高血糖素的分泌和细胞内 Ca²（+）浓度([Ca²（+）]（i））。在体内空腹和葡萄糖刺激（2 g/kg）时分析血清胰岛激素水平。
免疫组织化学显示 cGKI 存在于胰岛的α-细胞中，但不存在于β-细胞中。缺乏α-细胞 cGKI 的小鼠空腹血糖和胰高血糖素水平显著升高，而血清胰岛素水平不变。高葡萄糖浓度强烈抑制 CTR 小鼠的胰高血糖素释放，但对缺乏 cGKI 的胰岛仅有中度影响。8-Br-cGMP 降低了 CTR 胰岛在 0.5 mmol/l 葡萄糖刺激下的[Ca²（+）]（i）水平和胰高血糖素释放率，但对缺乏 cGKI 的胰岛的[Ca²（+）]（i）或激素释放没有影响。
我们提出 cGKI 通过抑制α-细胞中的[Ca²（+）]（i）来调节胰高血糖素的释放。
