Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T7 022A Veterinary Research Tower (Box 17), Ithaca, New York 14850, USA Department of Molecular Biosciences, School of Veterinary Medicine Department of Nutrition, University of California Davis, Davis, California, USA Department of Internal Medicine, University of California, Davis, Sacramento, California, USA.
J Endocrinol. 2014 Mar 13;221(1):133-44. doi: 10.1530/JOE-13-0601. Print 2014 Apr.
There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.
需要确定 2 型糖尿病预防策略。因此，我们研究了吡格列酮和阿格列汀单独及联合应用预防 UCD-T2DM 大鼠（多基因肥胖 2 型糖尿病模型）2 型糖尿病发病的疗效。大鼠在 2 个月龄时分为 4 组：对照组、阿格列汀（20mg/kg/天）、吡格列酮（2.5mg/kg/天）和阿格列汀+吡格列酮。每周测量非禁食血糖以确定糖尿病发病。尽管吡格列酮单独及联合阿格列汀治疗导致糖尿病发病延迟 5 个月，但促进了食物摄入和体重（BW）增加。与对照组相比，阿格列汀单独治疗并未延迟糖尿病发病或影响食物摄入或 BW。空腹血糖、胰岛素和血脂浓度降低，脂联素浓度升高 3 倍，吡格列酮治疗组更为显著。所有治疗组在口服葡萄糖耐量试验中葡萄糖耐量和胰岛素分泌均得到改善，阿格列汀+吡格列酮治疗具有附加改善作用。胰岛组织学显示所有治疗组与对照组相比胰岛形态均有改善。吡格列酮治疗还导致棕色和白色脂肪组织中线粒体生物发生标志物的表达增加，而阿格列汀单独治疗动物中观察到轻度升高。吡格列酮通过改善葡萄糖耐量、胰岛素敏感性、胰岛功能和脂肪组织中线粒体生物发生标志物，显著延迟 UCD-T2DM 大鼠 2 型糖尿病的发病；然而，阿格列汀以 20mg/kg/天的剂量添加至吡格列酮治疗并未增强糖尿病发病的预防/延迟作用。
