Lamontagne Julien, Pepin Emilie, Peyot Marie-Line, Joly Erik, Ruderman Neil B, Poitout Vincent, Madiraju S R Murthy, Nolan Christopher J, Prentki Marc
Department of Nutrition and Biochemistry, Molecular Nutrition Unit and Montreal Diabetes Research Center, Université de Montréal, Montréal, Québec, Canada.
Endocrinology. 2009 Aug;150(8):3465-74. doi: 10.1210/en.2008-1557. Epub 2009 Apr 30.
Thiazolidinediones (TZDs) have beneficial effects on glucose homeostasis via enhancement of insulin sensitivity and preservation of beta-cell function. How TZDs preserve beta-cells is uncertain, but it might involve direct effects via both peroxisome proliferator-activated receptor-gamma-dependent and -independent pathways. To gain insight into the independent pathway(s), we assessed the effects of short-term (<or=90 min) exposure to pioglitazone (Pio) (10 to 50 microM) on glucose-induced insulin secretion (GIIS), AMP-activated protein kinase (AMPK) activation, and beta-cell metabolism in INS 832/13 beta-cells and rat islets. Pio caused a right shift in the dose-dependence of GIIS, such that insulin release was reduced at intermediate glucose but unaffected at either basal or maximal glucose concentrations. This was associated in INS 832/13 cells with alterations in energy metabolism, characterized by reduced glucose oxidation, mitochondrial membrane polarization, and ATP levels. Pio caused AMPK phosphorylation and its action on GIIS was reversed by the AMPK inhibitor compound C. Pio also reduced palmitate esterification into complex lipids and inhibited lipolysis. As for insulin secretion, the alterations in beta-cell metabolic processes were mostly alleviated at elevated glucose. Similarly, the antidiabetic agents and AMPK activators metformin and berberine caused a right shift in the dose dependence of GIIS. In conclusion, Pio acutely reduces glucose oxidation, energy metabolism, and glycerolipid/fatty acid cycling of the beta-cell at intermediate glucose concentrations. We suggest that AMPK activation and the metabolic deceleration of the beta-cell caused by Pio contribute to its known effects to reduce hyperinsulinemia and preserve beta-cell function and act as an antidiabetic agent.
噻唑烷二酮类药物（TZDs）通过增强胰岛素敏感性和维持β细胞功能，对葡萄糖稳态具有有益作用。TZDs如何维持β细胞功能尚不确定，但可能涉及过氧化物酶体增殖物激活受体γ依赖性和非依赖性途径的直接作用。为了深入了解独立途径，我们评估了短期（≤90分钟）暴露于吡格列酮（Pio）（10至50微摩尔）对INS 832/13β细胞和大鼠胰岛中葡萄糖诱导的胰岛素分泌（GIIS）、AMP激活的蛋白激酶（AMPK）激活以及β细胞代谢的影响。Pio导致GIIS剂量依赖性曲线右移，使得在中等葡萄糖浓度下胰岛素释放减少，但在基础或最大葡萄糖浓度下不受影响。在INS 832/13细胞中，这与能量代谢改变有关，其特征是葡萄糖氧化、线粒体膜极化和ATP水平降低。Pio导致AMPK磷酸化，其对GIIS的作用被AMPK抑制剂化合物C逆转。Pio还减少了棕榈酸酯化为复合脂质的过程，并抑制了脂解作用。至于胰岛素分泌，在高葡萄糖浓度下，β细胞代谢过程的改变大多得到缓解。同样，抗糖尿病药物和AMPK激活剂二甲双胍和黄连素也导致GIIS剂量依赖性曲线右移。总之，在中等葡萄糖浓度下，Pio可急性降低β细胞的葡萄糖氧化、能量代谢以及甘油脂质/脂肪酸循环。我们认为，Pio引起的AMPK激活和β细胞代谢减速有助于其降低高胰岛素血症、维持β细胞功能并作为抗糖尿病药物的已知作用。
