Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction
Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction
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DOI：
10.2337/diabetes.45.8.1094
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发表时间：
1996-08-01
期刊：
影响因子：
7.7
通讯作者：
Butler, PC
中科院分区：
文献类型：
--
作者：
Couce, M;Kane, LA;Butler, PC
胰岛淀粉样多肽衍生的胰岛淀粉样蛋白（Islet amyloid derived from islet amyloid polypeptide，IAPP）是II型糖尿病的一个公认特征，但胰岛淀粉样蛋白形成的机制尚不清楚。体外研究表明，人而非小鼠的IAPP氨基酸残基20-29赋予淀粉样蛋白形成性，这与小鼠不存在自发性胰岛淀粉样变性一致。几项临床和体外研究表明，IAPP的合成速率增加易患IAPP-淀粉样变性。在本研究中，我们试图检验以下假设：在人LAPP转基因（TG）小鼠中药理学诱导胰岛素抵抗将诱导胰岛淀粉样蛋白和β细胞功能障碍，TG和非转基因（N-TG）对照小鼠用大鼠生长激素（12 μ g/天）和地塞米松（0.24 mg/天）（dex/GH）或不接受治疗4周，之后处死动物以检查胰岛形态。与对照小鼠相比，用dex/GH治疗引起TG小鼠的高血糖症（7.3 +/- 0.4 vs，5.2 +/- 0.1 mmol/l，TG vs，N-TG，P < 0.001），并伴有血浆胰岛素浓度降低（595 +/- 51 vs，996 +/- 100 pmol/l，TG vs，N-TG，P < 0.05）。胰岛淀粉样蛋白在治疗的TG小鼠中诱导，但在对照小鼠中不诱导。胰岛淀粉样蛋白在细胞内和细胞外沉积物中均被鉴定，前者与β细胞变性的证据相关。我们的结论是，dex/GH治疗人类IAPP的小鼠TG诱导IAPP衍生的胰岛淀粉样蛋白，高血糖症和胰岛功能障碍。本模型概括了II型糖尿病的胰岛形态和表型。
Islet amyloid derived from islet amyloid polypeptide (IAPP) is a well-recognized feature of type II diabetes, However, the mechanism of islet amyloidogenesis is unknown, In vitro studies suggest that amino acid residues 20-29 in human, but not mouse, IAPP confer amyloidogenicity consistent with the absence of spontaneous islet amyloidosis in mice. Several clinical and in vitro studies suggest that increased synthetic rates of IAPP predispose to IAPP-amyloidosis, In the present study, we sought to test the hypothesis that pharmacological induction of insulin resistance in a mouse transgenic (TG) for human LAPP would induce islet amyloid and beta-cell dysfunction, TG and non-transgenic (N-TG) control mice were treated with both rat growth hormone (12 mu g/day) and dexamethasone (0.24 mg/day) (dex/GH) or received no treatment for 4 weeks, after which animals were killed to examine islet morphology. Treatment with dex/GH caused hyperglycemia (7.3 +/- 0.4 vs, 5.2 +/- 0.1 mmol/l, TG vs, N-TG, P < 0.001) associated with a decreased plasma insulin concentration (595 +/- 51 vs, 996 +/- 100 pmol/l, TG vs, N-TG, P < 0.05) in TG versus control mice. Islet amyloid was induced in treated TG mice but not in control mice. Islet amyloid was identified in both intra- and extracellular deposits, the former being associated with evidence of beta-cell degeneration. We conclude that dex/GH treatment in mice TG for human IAPP induces IAPP-derived islet amyloid, hyperglycemia, and islet dysfunction. The present model recapitulates the islet morphology and phenotype of type II diabetes.