Ahrén B, Havel P J, Pacini G, Cianflone K
Department of Medicine, Lund University, Lund, Sweden.
Int J Obes Relat Metab Disord. 2003 Sep;27(9):1037-43. doi: 10.1038/sj.ijo.0802369.
Acylation stimulating protein (ASP) is a hormone produced by adipocytes and is of importance for the storage of energy as fat. We examined whether ASP might also have effects on islet function. In clonal INS-1 cells, ASP dose-dependently augmented glucose-stimulated insulin secretion. The lowest effective dose of ASP at 10 mmol/l glucose was 5 micro mol/l. The effect was glucose-dependent because ASP did not increase insulin secretion at 1 mmol/l glucose but had clear effect at 10 and 20 mmol/l glucose. Similarly, ASP augmented glyceraldehyde-induced insulin secretion but the hormone did not enhance insulin secretion in response to depolarization by 20 mmol/l of KCl. ASP-induced insulin secretion was completely abolished by competitive inhibition of glucose phosphorylation by glucokinase with 5-thio-glucose and was partially inhibited by the calcium channel blocker, nifedipine, and by the protein kinase C inhibitor, GF109203. Furthermore, thapsigargin, an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum, did not affect ASP-induced insulin secretion. ASP (>5 micro mol/l) also augmented glucose-stimulated insulin secretion from islets isolated from C57BL/6J mice, and intravenous administration of ASP (50 nmol/kg) augmented the acute (1 and 5 min) insulin response to intravenous glucose (1 g/kg) in C57BL/6J mice. This was accompanied by an increased rate of glucose disposal. Minimal model analyses of data derived from the intravenous glucose tolerance test revealed that whereas ASP augmented insulin secretion, the hormone did not affect insulin sensitivity (S(I)) or glucose effectiveness (S(G)). We conclude that ASP augments glucose-stimulated insulin secretion through a direct action on the islet beta cells. The effect is dependent on glucose phosphorylation, calcium uptake and protein kinase C. Stimulation of insulin secretion by ASP in vivo results in augmented glucose disposal.
酰化刺激蛋白（ASP）是一种由脂肪细胞产生的激素，对于能量以脂肪形式储存具有重要作用。我们研究了ASP是否也可能对胰岛功能产生影响。在克隆的INS-1细胞中，ASP呈剂量依赖性地增强葡萄糖刺激的胰岛素分泌。在10 mmol/L葡萄糖浓度下，ASP的最低有效剂量为5 μmol/L。该作用依赖于葡萄糖，因为在1 mmol/L葡萄糖浓度下ASP不会增加胰岛素分泌，但在10和20 mmol/L葡萄糖浓度下有明显作用。同样，ASP增强了甘油醛诱导的胰岛素分泌，但该激素不会增强由20 mmol/L KCl去极化引起的胰岛素分泌。用5-硫代葡萄糖竞争性抑制葡萄糖激酶介导的葡萄糖磷酸化可完全消除ASP诱导的胰岛素分泌，钙通道阻滞剂硝苯地平和蛋白激酶C抑制剂GF109203可部分抑制该分泌。此外，内质网中Ca(2+)-ATP酶的抑制剂毒胡萝卜素不影响ASP诱导的胰岛素分泌。ASP（>5 μmol/L）还增强了从C57BL/6J小鼠分离的胰岛的葡萄糖刺激的胰岛素分泌，静脉注射ASP（50 nmol/kg）增强了C57BL/6J小鼠对静脉注射葡萄糖（1 g/kg）的急性（1和5分钟）胰岛素反应。这伴随着葡萄糖处置率的增加。对静脉葡萄糖耐量试验数据的最小模型分析表明，虽然ASP增强了胰岛素分泌，但该激素不影响胰岛素敏感性（S(I)）或葡萄糖有效性（S(G)）。我们得出结论，ASP通过对胰岛β细胞的直接作用增强葡萄糖刺激的胰岛素分泌。该作用依赖于葡萄糖磷酸化、钙摄取和蛋白激酶C。ASP在体内刺激胰岛素分泌导致葡萄糖处置增加。
