Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats
Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats
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DOI：
10.1530/joe-13-0601
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发表时间：
2014-04-01
影响因子：
4
通讯作者：
Havel, Peter J.
中科院分区：
文献类型：
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作者：
Cummings, Bethany P.;Bettaieb, Ahmed;Havel, Peter J.
有必要确定预防2型糖尿病的策略。因此，我们研究了吡格列酮和阿格列汀单药和联合用药预防UCD-T2 DM大鼠（一种多基因肥胖型2型糖尿病模型）2型糖尿病发作的疗效。在2月龄时，将大鼠分为4组：对照组、阿格列汀（20 mg/kg/天）、吡格列酮（2.5 mg/kg/天）和阿格列汀+吡格列酮组。每周测量非空腹血糖以确定糖尿病发作。吡格列酮单药和与阿格列汀联合给药导致糖尿病发作延迟5个月，尽管促进了摄食量和体重（BW）增加。与对照组相比，单独使用阿格列汀不会延迟糖尿病发作或影响食物摄入或BW。吡格列酮组空腹血糖、胰岛素和血脂浓度较低，脂联素浓度高3倍。在口服葡萄糖耐量试验期间，所有治疗组均显示葡萄糖耐量和胰岛素分泌改善，阿格列汀+吡格列酮组观察到额外改善。胰岛组织学显示，与对照组相比，所有治疗组的胰岛形态均有所改善。吡格列酮给药还导致棕色脂肪组织和白色脂肪组织中线粒体生物发生标志物的表达增加，在阿格列汀单独给药的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、胰岛功能和脂肪线粒体生物生成标志物，显著延迟UCD-T2 DM大鼠2型糖尿病的发作;然而，在吡格列酮治疗中添加20 mg/kg/天剂量的阿格列汀并不能增强预防/延迟糖尿病发作。
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.