Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet antyloid deposition in mice expressing the gene for human islet antyloid polypeptide
Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet antyloid deposition in mice expressing the gene for human islet antyloid polypeptide
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DOI：
10.2337/diabetes.54.7.2235
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发表时间：
2005-07-01
期刊：
影响因子：
7.7
通讯作者：
Kahn, SE
中科院分区：
文献类型：
--
作者：
Hull, RL;Shen, ZP;Kahn, SE
2型糖尿病胰岛淀粉样蛋白沉积与β细胞质量减少有关。因此，旨在减少胰岛淀粉样蛋白形成的干预措施可能有助于保持2型糖尿病患者的p细胞质量。罗格列酮和二甲双胍通过不同的机制改善胰岛素敏感性，从而减少p细胞分泌需求，导致胰岛素和胰岛淀粉样蛋白多肽（IAPP）的释放减少，IAPP是胰岛淀粉样蛋白沉积物的独特成分。我们假设p细胞分泌需求的减少会导致胰岛淀粉样蛋白形成的减少。人类IAPP （MAPP）转基因小鼠，胰岛淀粉样蛋白模型，用罗格列酮(1.5 mg (.) kg(-1) （.) day(-1), n = 19）、二甲双胍(1 g(.) kg(-1) （.) day(-1), n = 18）或对照组（n = 17）治疗12个月。在研究结束时，测定了胰岛淀粉样蛋白患病率（含有淀粉样蛋白的胰岛百分比）和严重程度（淀粉样蛋白占据的胰岛面积百分比）、胰岛质量、p细胞质量和胰岛素释放。胰岛淀粉样蛋白患病率（对照组、二甲双胍组和罗格列酮组分别为44.8%、13.4%和11.3%）和严重程度（对照组、二甲双胍组和罗格列酮组分别为9.2 +/- 3.0、0.22 +/- 0.11和0.10 +/- 0.05%）在罗格列酮（两组均P < 0.001）和二甲双胍组均显著降低（两组均P < 0.001）。两种治疗均与胰岛素释放降低相关，评估为静脉注射葡萄糖的急性胰岛素反应（对照组、二甲双胍组和罗格列酮组小鼠分别为2,189 857、621 256和14 158 pmol/l；二甲双胍组与对照组相比P < 0.05，罗格列酮组与对照组相比P < 0.005），与分泌需求降低一致。同样，对照组、二甲双胍组和罗格列酮组小鼠的胰岛质量（分别为33.4 +/- 7.0、16.6 +/- 3.6和12.2 +/- 2.1 mg）与二甲双胍组无显著差异（P = 0.06），但罗格列酮组的胰岛质量显著低于对照组（P < 0.05）。考虑到胰岛质量的降低，罗格列酮和二甲双胍处理的小鼠胰岛淀粉样蛋白相关的β细胞质量下降（P细胞质量/胰岛质量百分比）得到改善（对照组、二甲双胍和罗格列酮处理的小鼠分别为57.9 +/- 3.1%、64.7 +/- 1.4%和66.1 +/- 1.6%；与对照组相比，二甲双胍或罗格列酮组P < 0.05）。总之，罗格列酮和二甲双胍保护β细胞免受胰岛淀粉样蛋白的有害影响，这种作用可能有助于这些治疗减轻2型糖尿病中β细胞质量和功能的逐渐丧失。
Islet amyloid deposition in type 2 diabetes is associated with reduced beta-cell mass. Therefore, interventions aimed at reducing islet amyloid formation may help preserve P-cell mass in type 2 diabetes. Rosiglitazone and metformin act by different mechanisms to improve insulin sensitivity and thereby reduce P-cell secretory demand, resulting in decreased release of insulin and islet amyloid polypeptide (IAPP), the unique constituent of islet amyloid deposits. We hypothesized that this reduced P-cell secretory demand would lead to reduced islet amyloid formation. Human IAPP (MAPP) transgenic mice, a model of islet amyloid, were treated for 12 months with rosiglitazone (1.5 mg (.) kg(-1) (.) day(-1), n = 19), metformin (1 g (.) kg(-1) (.) day(-1), n = 18), or control (n = 17). At the end of the study, islet amyloid prevalence (percent islets containing amyloid) and severity (percent islet area occupied by amyloid), islet mass, P-cell mass, and insulin release were determined. Islet amyloid prevalence (44 8, 13 4, and 11 3% for control, metformin-, and rosiglitazone-treated mice, respectively) and severity (9.2 +/- 3.0, 0.22 +/- 0.11, and 0.10 +/- 0.05% for control, metformin-, and rosiglitazone-treated mice, respectively) were markedly reduced with both rosiglitazone (P < 0.001 for both measures) and metformin treatment (P < 0.001 for both measures). Both treatments were associated with reduced insulin release assessed as the acute insulin response to intravenous glucose (2,189 857, 621 256, and 14 158 pmol/l for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin vs. control and P < 0.005 for rosiglitazone vs. control), consistent with reduced secretory demand. Similarly, islet mass (33.4 +/- 7.0, 16.6 +/- 3.6, and 12.2 +/- 2.1 mg for control, metformin-, and rosiglitazone-treated mice, respectively) was not different with metformin treatment (P = 0.06 vs. control) but was significantly lower with rosiglitazone treatment (P < 0.05 vs. control). When the decreased islet mass was accounted for, the islet amyloid-related decrease in beta-cell mass (percent P-cell mass/islet mass) was ameliorated in both rosiglitazone and metformin-treated animals (57.9 +/- 3.1, 64.7 +/- 1.4, and 66.1 +/- 1.6% for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin or rosiglitazone vs. control). In summary, rosiglitazone and metformin protect beta-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of beta-cell mass and function in type 2 diabetes.