目的:胰高血糖素从胰腺α细胞释放是正常的葡萄糖平衡所必需的,并且在1型和2型糖尿病中都失调。肿瘤抑制因子LKB1(STK11)和下游激酶AMP激活的蛋白激酶(AMPK),调节细胞代谢和生长,而AMPK是抗高血糖药二甲双胍的重要靶点。虽然LKB1和AMPK最近已经成为β细胞量和胰岛素分泌的调节剂,这些酶在控制体内胰高血糖素产生中的作用尚不清楚。
方法:这里,我们烧蚀了LKB1(αLKB1KO),或AMPK的催化α亚基(αAMPKdKO,-α1KO,-α2KO),通过用胰高血糖素前启动子(PPG)Cre删除相应的flox\'d等位基因,选择性地在小鼠45%的α细胞中。
结果:雄性αLKB1KO小鼠的血糖水平在腹腔注射葡萄糖期间较低,氨基咪唑甲酰胺核糖核苷酸(AICAR)或精氨酸耐受性试验,在低血糖钳夹中,葡萄糖输注率增加(p<0.01)。αLKB1KO小鼠也表现出低血糖症诱导的胰高血糖素释放受损。αAMPKα1空小鼠的葡萄糖输注率也升高(p<0.001),低血糖症诱导的血浆胰高血糖素增加倾向于降低(p=0.06)。从分离的胰岛分泌的胰高血糖素对αLKB1KO中葡萄糖的抑制作用敏感,αAMPKdKO,和-α1KO,但不是-α2KO胰岛。
结论:LKB1依赖性信号盒,涉及但不限于AMPKα1,是胰腺α细胞中控制葡萄糖释放胰高血糖素所必需的。
OBJECTIVE: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear.
METHODS: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox\'d alleles with a preproglucagon promoter (PPG) Cre.
RESULTS: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets.
CONCLUSIONS: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.