Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University, Tübingen, Germany.
Diabetes Obes Metab. 2012 Oct;14 Suppl 3:85-90. doi: 10.1111/j.1463-1326.2012.01648.x.
One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.
2 型糖尿病的一个主要风险因素是葡萄糖诱导的胰岛素分泌受损，这是由个体遗传背景和环境因素介导的。除了葡萄糖诱导的胰岛素分泌受损外，研究还发现，糖尿病和糖耐量受损患者存在胰高血糖素样肽 (GLP)1 诱导的胰岛素分泌受损，但对其基本机制知之甚少。GLP1 抵抗状态可能是解释 2 型糖尿病中观察到的肠促胰岛素效应降低的重要机制。在这篇综述中，我们介绍了可用于测量人类对 GLP1 反应的胰岛素分泌的方法，以及研究表明，特定的糖尿病风险基因与 β 细胞对 GLP1 给药的分泌功能的抵抗有关。此外，我们还讨论了其他与 GLP1 诱导的胰岛素分泌受损相关的因素，例如胰岛素抵抗。最后，我们提供了证据表明，高血糖本身、遗传背景及其相互作用导致 β 细胞对 GLP1 的抵抗。我们推测，对 GLP1 类似物和/或二肽基肽酶-4 (DPP-IV) 抑制剂治疗的反应或无反应，取决于 GLP1 抵抗的程度。
