Cai Ying, Lydic Todd A, Turkette Thomas, Reid Gavin E, Olson L Karl
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
Biochem Pharmacol. 2015 May 1;95(1):46-57. doi: 10.1016/j.bcp.2015.03.010. Epub 2015 Mar 20.
Prolonged exposure of pancreatic beta (β) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of β cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, β cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in β cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for β cell failure.
在2型糖尿病中，胰腺β细胞长期暴露于升高的葡萄糖和游离脂肪酸（FFA）会导致β细胞功能丧失和存活能力下降。在Zucker糖尿病脂肪（ZDF）大鼠中，β细胞功能衰竭与三酰甘油（TAG）合成增加以及甘油脂质/FFA（GL/FFA）循环紊乱有关，而GL/FFA循环是葡萄糖刺激的胰岛素分泌（GSIS）的关键环节。本研究的目的是分别使用吡格列酮和/或阿格列汀通过抑制二肽基肽酶来激活PPARγ并增强肠促胰岛素作用，从而确定其对糖尿病前期和糖尿病ZDF大鼠胰岛脂质代谢的影响。对照糖尿病前期ZDF大鼠向糖尿病的转变与血浆胰岛素水平降低、胰岛胰岛素含量和GSIS降低、硬脂酰辅酶A去饱和酶2（SCD 2）表达降低以及含有饱和脂肪酸的胰岛TAG、二酰甘油（DAG）和神经酰胺种类增加有关。联合使用吡格列酮和阿格列汀治疗糖尿病前期ZDF大鼠（而非单独使用）可预防其向糖尿病的转变，并与胰岛TAG和DAG水平显著降低有关。然而，吡格列酮和阿格列汀并未恢复SCD2表达、TAG、DAG或神经酰胺中的脂肪酸饱和度、胰岛胰岛素含量或降低神经酰胺水平。这些发现与PPARγ激活和肠促胰岛素作用增强协同作用以恢复ZDF大鼠β细胞中的GL/FFA循环一致。然而，在不纠正胰岛脂肪酸去饱和、胰岛神经酰胺产生和/或胰岛素敏感性的情况下恢复GL/FFA循环，可能会使这些胰岛面临β细胞功能衰竭的风险。
