全球精选文摘 - 转录因子7类似物2调控人类胰岛β细胞的存活及功能

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转录因子7类似物2调控人类胰岛β细胞的存活及功能

Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets

Shu L, Sauter NS, Schulthess FT 2009/8/14 20:26:54

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Diabetes, 2009,

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Objective:
Type 2 diabetes is characterized by impaired insulin secretion in response to increased metabolic demand. This defect in β-cell compensation seems to result from the interplay between environmental factors and genetic predisposition. Genome-wide association studies reveal that common variants in transcription factor 7-like 2 (TCF7L2) are associated with increased risk of type 2 diabetes. The aim of the present study was to establish whether TCF7L2 plays a role in β-cell function and/or survival.

Research Design and Methods:
To investigate the effects of TCFL7L2 depletion, isolated islets were exposed to TCF7L2 small interfering RNA (siRNA) versus scrambled siRNA, and β-cell survival and function were examined. For TCF7L2 overexpression, islets were cultured in glucose concentrations of 5.5–33.3mmol/1 and the cytokine mix interleukin-1β/γ-interferon with or without overexpression of TCF7L2. Subsequently, glucose-stimulated insulin secretion (GSIS), β-cell apoptosis [by transferase-mediated dUTP nick-end labeling assay and Western blotting for poly(ADP-ribose) polymerase and Caspase-3 cleavage], and β-cell proliferation (by Ki67 immunostaining) were analyzed.

Results:
Depleting TCF7L2 by siRNA resulted in a 5.1-fold increase in β-cell apoptosis, 2.2-fold decrease in β-cell proliferation (P<0.001), and 2.6-fold decrease in GSIS (P<0.01) in human islets. Similarly, loss of TCF7L2 resulted in impaired β-cell function in mouse islets. In contrast, overexpression of TCF7L2 protected islets from glucose and cytokine-induced apoptosis and impaired function.

Conclusions:
TCF7L2 is required for maintaining GSIS and β-cell survival. Changes in the level of active TCF7L2 in β-cells from carriers of at-risk allele may be the reason for defective insulin secretion and progression of type 2 diabetes.

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疾病资源中心

高血压	慢性阻塞性肺病
脂肪性肝病	糖尿病
卒中	肺癌
冠心病	子宫内膜异位症
结直肠癌	乳腺癌
心力衰竭	心律失常

病例分析 [栏目介绍]

甲状腺功能亢进合并黄疸

王燕燕王曙

上海交通大学附属瑞金医院内分泌科

患者，女，69岁。2009年1月无明显诱因下出现乏力，当时程度较轻，未予以重视。2009年3月患者乏力症状加重，尿色逐渐加深，大便习惯改变，颜色变淡。4月18日入我院感染科治疗，诉轻度头晕、心慌，体重减轻10kg。无肝区疼痛，无发热，无腹痛、腹泻、腹胀、里急后重，无恶性、呕吐等。入院半月前于外院就诊，查肝功能：ALT 601IU/L，AST 785IU/L，TBIL 97.7umol/L，白蛋白 41g/L，甲状腺功能：游离T3 30.6pmol/L，游离T4 51.9pmol/L，心电图示快速房颤。

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