High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling.
High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling.
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作者：
So WY;Cheng Q;Chen L;Evans-Molina C;Xu A;Lam KS;Leung PS
糖尿病患者循环成纤维细胞生长因子21 （FGF21）水平升高，与糖代谢异常直接相关，而药理学上给予FGF21可以改善高血糖。胰岛是FGF21的靶点，但在正常和糖尿病情况下，FGF21在胰岛中的作用尚不完全清楚。本研究通过研究db/db小鼠胰岛对外源性FGF21的反应，葡萄糖对FGF21信号传导的直接影响，以及过氧化物酶体增殖物激活受体γ (PPARγ)在FGF21通路激活中的作用，研究了高葡萄糖对糖尿病小鼠胰岛FGF21作用的影响。结果表明，体外高糖处理的成年db/db小鼠胰岛和正常胰岛均表现出β-klotho表达降低、FGF21抗性和PPARγ表达降低。罗格列酮，一种抗糖尿病的PPARγ配体，改善了这些作用。我们的数据表明，2型糖尿病患者的高血糖可能导致胰岛FGF21抵抗，可能是通过降低PPARγ的表达，这为葡萄糖介导的胰岛功能障碍提供了一种新的机制。
Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator–activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucose-mediated islet dysfunction.
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DOI：
10.1111/j.1463-1326.2010.01299.x
发表时间：
2010-12
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Gupta D;Kono T;Evans-Molina C
通讯作者：
Evans-Molina C
影响因子：
7.7
作者：
Hojman P;Pedersen M;Nielsen AR;Krogh-Madsen R;Yfanti C;Akerstrom T;Nielsen S;Pedersen BK
通讯作者：
Pedersen BK
影响因子：
8.2
作者：
Dubois, M;Pattou, F;Lefebvre, J
通讯作者：
Lefebvre, J
影响因子：
--
作者：
Chuang, Jen-Chieh;Cha, Ji-Young;Repa, Joyce J.
通讯作者：
Repa, Joyce J.
影响因子：
5.6
作者：
Kharitonenkov, Alexei;Dunbar, James D.;Shanafelt, Armen B.
通讯作者：
Shanafelt, Armen B.