Raile K, Klammt J, Laue S, Garten A, Blüher M, Kralisch S, Klöting N, Kiess W
University Hospital for Children and Adolescents, Oststr. 21-25, 04317 Leipzig, Germany.
Diabetologia. 2005 Sep;48(9):1798-809. doi: 10.1007/s00125-005-1860-x. Epub 2005 Jul 29.
AIMS/HYPOTHESIS: Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion.
We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation.
In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high- and low- glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICAR-regulated mRNA expression of both receptors in INS-1E cells.
CONCLUSIONS/INTERPRETATION: We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.
目的/假设：葡萄糖以及肽类生长因子胰岛素、胰岛素样生长因子-I（IGF-I）和胰岛素样生长因子-II（IGF-II）对β细胞量具有强烈的调节作用。此外，IGF-I受体（Igf1r）和胰岛素受体（Insr）在β细胞中的表达对于胰岛素分泌的多个步骤是必不可少的。
我们推测葡萄糖浓度可能调节胰岛和β细胞中Igf1r、Insr以及胰岛素受体相关受体（Insrr）的表达。此外，由于ATP:ADP的比值是参与胰岛素分泌的最重要的细胞内机制，且ATP的消耗会导致AMP积累，因此我们评估了AMP激活的蛋白激酶（AMPK）在葡萄糖依赖性受体调节中的作用。
在大鼠胰岛中，与24小时后的中等葡萄糖浓度（6.2 mmol/L）或低葡萄糖浓度（1.6 mmol/L）相比，高葡萄糖暴露（25 mmol/L）可增加Igf1r、Insr和Insrr的基因表达，但也会增加代谢糖酵解基因肝型丙酮酸激酶（Pklr）的表达。在大鼠INS-1Eβ细胞中，与胰岛情况一样，只有Pklr的表达受到低葡萄糖的抑制，而Insr和Insrr的表达受到高葡萄糖的抑制，低葡萄糖水平则使其增加。Igf1r的表达受到高葡萄糖和低葡萄糖浓度的抑制。5-氨基咪唑-4-甲酰胺核苷（AICAR，0.5 mmol/L）激活AMPK可抑制Pklr的表达，但强烈刺激Igf1r、Insr和Insrr的基因表达。胰岛素受体（IR）和IGF-IR的蛋白表达反映了INS-1E细胞中两种受体的葡萄糖和AICAR调节的mRNA表达。
结论/解读：我们得出结论，葡萄糖直接与胰岛和β细胞中生长因子受体的表达相互作用，这些受体对于β细胞生长和胰岛素分泌都是必不可少的。AMPK激活剂AICAR对Igf1r和Insr基因表达的刺激可能表明AMPK参与了β细胞中Igf1r、Insr和Insrr表达的调节。
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