Increased Aβ production prompts the onset of glucose intolerance and insulin resistance
Increased Aβ production prompts the onset of glucose intolerance and insulin resistance
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DOI：
10.1152/ajpendo.00500.2011
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发表时间：
2012-06-01
影响因子：
5.1
通讯作者：
Cozar-Castellano, Irene
中科院分区：
文献类型：
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作者：
Jimenez-Palomares, Margarita;Jose Ramos-Rodriguez, Juan;Cozar-Castellano, Irene
Jimenez-Palomares M，Ramos-Rodriguez JJ，Lopez-Acosta JF，Pacheco-Herrero M，Lechuga-Sancho AM，Perdomo G，Garcia-Alloza M，Cozar-Castellano I. A β产生的增加促使葡萄糖耐受不良和胰岛素抵抗的发生。Am J Physiol Endocrinol Metab 302：E1373-E1380，2012.首次发表于2012年3月13日; doi：10.1152/ajpendo.00500.2011.- 2型糖尿病（T2 D）和阿尔茨海默病（AD）是两种具有相似病理生理特征和遗传易感性的流行疾病。AD患者更容易发生T2 D。然而，AD和T2 D之间的分子机制仍不清楚。在这项研究中，我们已经产生了一个新的小鼠模型来测试AD会促使小鼠T2 D发作的假设。为了验证我们的假设，我们将阿尔茨海默病APPswe/PS1 dE 9（APP/PS1）转基因小鼠与瘦素信号传导部分缺陷（db/+）小鼠杂交。监测体重、血糖和胰岛素水平。使用葡萄糖和胰岛素耐量试验进行葡萄糖代谢的表型表征。通过组织形态计量学分析β细胞质量、胰岛体积和胰岛数量。APP/PS1共表达的小鼠与完整的瘦素受体信号没有表现出任何代谢紊乱的葡萄糖代谢或胰岛素敏感性。与此相反，APP/PS1共表达db/+小鼠导致非空腹高血糖症，高胰岛素血症，高胆固醇血症，体重没有变化。相反，空腹血糖和胆固醇水平保持不变。与糖代谢改变相一致，db/+小鼠中APP/PS1共表达导致葡萄糖耐受不良、胰岛素抵抗和胰岛素信号转导受损。此外，胰腺的组织形态计量学分析显示β细胞团增加。总之，这些发现提供了实验证据来支持这样的观点，即异常A β产生可能是AD中胰岛素抵抗和T2 D病理学的潜在机制联系。
Jimenez-Palomares M, Ramos-Rodriguez JJ, Lopez-Acosta JF, Pacheco-Herrero M, Lechuga-Sancho AM, Perdomo G, Garcia-Alloza M, Cozar-Castellano I. Increased A beta production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab 302: E1373-E1380, 2012. First published March 13, 2012; doi: 10.1152/ajpendo.00500.2011.-Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. beta-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented beta-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant A beta production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.