Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin.
Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin.
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作者：
Matveyenko AV;Dry S;Cox HI;Moshtaghian A;Gurlo T;Galasso R;Butler AE;Butler PC
我们试图确定西格列汀和二甲双胍单用和联合使用在人胰岛淀粉样多肽转基因（HIP）大鼠（2型糖尿病模型）中改善胰岛疾病进展的程度和机制。HIP大鼠接受西格列汀、二甲双胍、西格列汀+二甲双胍治疗，或不接受药物治疗作为对照，持续12周。测量各组的空腹血糖、胰岛素敏感性和β细胞质量、功能和更新。西格列汀联合二甲双胍对保护HIP大鼠β细胞群具有协同作用。二甲双胍比西格列汀更能抑制β细胞凋亡。二甲双胍可增强肝脏胰岛素敏感性;西格列汀可增强肝外胰岛素敏感性，两者联合具有协同效应。西格列汀联合二甲双胍可部分保护β细胞功能。然而，西格列汀治疗与胰腺导管转换增加、导管化生以及一只大鼠的胰腺炎有关。二甲双胍和西格列汀联合用药在2型糖尿病HIP大鼠模型中具有协同作用，可保护β细胞质量和功能，并增强胰岛素敏感性。然而，西格列汀治疗对胰腺外分泌的不良作用引起了需要进一步评价的担忧。
We sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes. HIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and β-cell mass, function, and turnover were measured in each group. Sitagliptin plus metformin had synergistic effects to preserve β-cell mass in HIP rats. Metformin more than sitagliptin inhibited β-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. β-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis. The combination of metformin and sitagliptin had synergistic actions to preserve β-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.
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