The alpha-cell as target for type 2 diabetes therapy.
The alpha-cell as target for type 2 diabetes therapy.
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DOI：
10.1900/rds.2011.8.369
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发表时间：
2011-01-01
期刊：
影响因子：
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通讯作者：
Knop, Filip K
中科院分区：
文献类型：
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作者：
Christensen, Mikkel;Bagger, Jonatan I;Knop, Filip K
胰升糖素是胰腺α细胞的主要分泌产物。这种多肽激素的主要功能是在禁食期间为大脑和其他重要器官提供持续的葡萄糖供应。这是通过肝细胞中特定的G蛋白偶联受体刺激肝脏葡萄糖产生而起作用的。2型糖尿病患者的特点是胰高血糖素水平升高，这对这些患者的高血糖起决定性作用。越来越多的证据表明，靶向胰腺α细胞及其主要分泌产物胰高血糖素是治疗2型糖尿病的一种可能方法。一些临床前证据已经为药物的开发铺平了道路，这些药物可以抑制胰高血糖素的分泌或拮抗胰高血糖素受体。本文就胰升糖素的生理作用及其在2型糖尿病病理生理学中的作用作一综述。此外，还讨论了拮抗胰升糖素受体或抑制胰升糖素分泌在治疗2型糖尿病中的潜在优势和局限性，重点讨论了已经上市的药物和临床开发中的药物。结论：新的胰升糖素受体拮抗剂的开发面临着几个安全问题。目前，基于GLP-1的葡萄糖依赖的降糖作用的现有药物是对2型糖尿病患者的α细胞施加限制的最有利的方法。
Glucagon is the main secretory product of the pancreatic alpha-cells. The main function of this peptide hormone is to provide sustained glucose supply to the brain and other vital organs during fasting conditions. This is exerted by stimulation of hepatic glucose production via specific G protein-coupled receptors in the hepatocytes. Type 2 diabetic patients are characterized by elevated glucagon levels contributing decisively to hyperglycemia in these patients. Accumulating evidence demonstrates that targeting the pancreatic alpha-cell and its main secretory product glucagon is a possible treatment for type 2 diabetes. Several lines of preclinical evidence have paved the way for the development of drugs, which suppress glucagon secretion or antagonize the glucagon receptor. In this review, the physiological actions of glucagon and the role of glucagon in type 2 diabetic pathophysiology are outlined. Furthermore, potential advantages and limitations of antagonizing the glucagon receptor or suppressing glucagon secretion in the treatment of type 2 diabetes are discussed with a focus on already marketed drugs and drugs in clinical development. It is concluded that the development of novel glucagon receptor antagonists are confronted with several safety issues. At present, available pharmacological agents based on the glucose-dependent glucagonostatic effects of GLP-1 represent the most favorable way to apply constraints to the alpha-cell in type 2 diabetes.