β-cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes
β-cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes
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DOI：
10.2337/db05-1672
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发表时间：
2006-07-01
期刊：
影响因子：
7.7
通讯作者：
Butler, Peter C.
中科院分区：
文献类型：
--
作者：
Matveyenko, Aleksey V.;Butler, Peter C.
2 型糖尿病的特点是胰岛素分泌和作用缺陷，并且先出现空腹血糖受损 (IFG)。 IFG 和 2 型糖尿病的胰岛解剖结构显示，β 细胞质量有类似的 50% 和 65% 的缺陷，β 细胞凋亡和源自胰岛淀粉样多肽 (IAPP) 的胰岛淀粉样蛋白增加。胰岛素作用缺陷包括肝脏和肝外胰岛素抵抗。导致 2 型糖尿病的 β 细胞质量、β 细胞功能和胰岛素作用变化之间的关系尚未解决，部分原因是无法在体内测量 β 细胞质量，而且大多数可用的动物模型不能重现 2 型糖尿病的胰岛病理学。我们评估了 HIP 大鼠，这是一种人类 IAPP 转基因大鼠模型，其在 2 个月（非糖尿病）、5 个月（患有 IFG）和 10 个月（糖尿病）时发展出与人类 2 型糖尿病患者相当的胰岛病理学，以前瞻性地检查胰岛形态变化与胰岛素分泌和作用之间的关系。我们报告说，在 IFG 发生之前，β 细胞凋亡增加和第一相胰岛素分泌受损，这与 β 细胞质量 50% 的缺陷和肝脏胰岛素抵抗的发生相一致。糖尿病的特征是 β 细胞质量减少约 70%、进行性肝脏和肝外胰岛素抵抗以及高胰高血糖素血症。我们得出结论，IAPP 诱导的 β 细胞凋亡会导致胰岛素分泌和 β 细胞质量缺陷，首先导致肝胰岛素抵抗和 IFG，然后导致肝外胰岛素抵抗、高胰高血糖素血症和糖尿病。我们得出的结论是，特定的 β 细胞缺陷可以概括 2 型糖尿病的代谢表型，并指出 2 型糖尿病中的胰岛素抵抗可能至少部分是继发于 β 细胞衰竭的。
Type 2 diabetes is characterized by defects in insulin secretion and action and is preceded by impaired fasting glucose (IFG). The islet anatomy in IFG and type 2 diabetes reveals an similar to 50 and 65% deficit in beta-cell mass, with increased beta-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Defects in insulin action include both hepatic and extrahepatic insulin resistance. The relationship between changes in beta-cell mass, beta-cell function, and insulin action leading to type 2 diabetes are unresolved, in part because it is not possible to measure beta-cell mass in vivo, and most available animal models do not recapitulate the islet pathology in type 2 diabetes. We evaluated the HIP rat, a human IAPP transgenic rat model that develops islet pathology comparable to humans with type 2 diabetes, at age 2 months (nondiabetic), 5 months (with IFG), and 10 months (with diabetes) to prospectively examine the relationship between changes in islet morphology versus insulin secretion and action. We report that increased beta-cell apoptosis and impaired first-phase insulin secretion precede the development of IFG, which coincides with an similar to 50% defect in beta-cell mass and onset of hepatic insulin resistance. Diabetes was characterized by similar to 70% deficit in beta-cell mass, progressive hepatic and extrahepatic insulin resistance, and hyperglucagonemia. We conclude that IAPP-induced beta-cell apoptosis causes defects in insulin secretion and beta-cell mass that lead first to hepatic insulin resistance and IFG and then to extrahepatic insulin resistance, hyperglucagonemia, and diabetes. We conclude that a specific beta-cell defect can recapitulate the metabolic phenotype of type 2 diabetes and note that insulin resistance in type 2 diabetes may at least in part be secondary to beta-cell failure.