β细胞在临床治疗糖尿病和保存失败。

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β细胞在临床治疗糖尿病和保存失败。

Endocr启2007年4月,28 (2):187 - 218。Epub 2007年3月12日。

PubMed ID

17353295 (在PubMed

]

文摘

有一个渐进恶化在2型糖尿病患者胰腺β-细胞功能和质量。发现胰岛功能正常在诊断时的50%左右,并减少胰腺β-细胞的质量约60%在验尸。减少胰腺β-细胞质量是归因于加速细胞凋亡。β细胞功能进行性损害的主要因素和质量因素包括糖毒性,lipotoxicity,促炎细胞因子,瘦素,与胰岛细胞淀粉样变。β细胞功能受损甚至胰腺β-细胞似乎是可逆的,特别是在疾病的早期阶段的可逆性限制阈值减少胰腺β-细胞质量可能不会被通过。干预中保存或“恢复”细胞,短期强化胰岛素治疗新诊断2型糖尿病将改善β细胞功能,常常导致一个短暂的缓解期。另一个干预是诱导β细胞的选择性激活“休息”ATP-sensitive K + (K (ATP)通道,使用药物如氯甲苯噻嗪。第三种类型的干预是使用抗凋亡药物(如噻唑烷二酮类),和肠促胰岛素模拟和增强剂,它展示了重要的临床证据对人类β细胞功能的影响。服用tzd改善胰岛素分泌能力,减少胰腺β-细胞凋亡,减少与维护新生胰岛淀粉样蛋白。服用tzd的间接影响细胞的胰岛素增敏剂。 The direct effects are via peroxisome proliferator-activated receptor gamma activation in pancreatic islets, with TZDs consistently improving basal beta-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs. Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic beta-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on beta-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating beta-cell proliferation, induction of islet neogenesis, and inhibition of beta-cell apoptosis, thus promoting expansion of beta-cell mass, as observed in rodent diabetes and in cultured beta-cells. Exenatide and liraglutide enhanced postprandial beta-cell function. The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted beta-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial beta-cell function. Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on beta-cells in humans, and there is no clinical evidence that these drugs really have protective effects on beta-cells.

DrugBank数据引用了这篇文章

药物靶点

药物	目标	类	生物	药理作用	行动
Exenatide	Glucagon-like肽受体1	蛋白质	人类	是的	受体激动剂	细节