Retired Research Associate Professor, Boston University Goldman School of Dental Medicine, Boston, MA 02118, USA.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Cells. 2024 Nov 7;13(22):1842. doi: 10.3390/cells13221842.
Recent clinical trials using synthetic incretin hormones, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have demonstrated that these treatments ameliorated many complications related to obesity, emphasizing the significant impact of body weight on overall health. Incretins are enteroendocrine hormones secreted by gut endothelial cells triggered by nutrient ingestion. The phenomenon that oral ingestion of glucose elicits a much higher insulin secretion than intra-venous injection of equimolar glucose is known as the incretin effect. This also alludes to the thesis that food intake is the root cause of insulin resistance. Synthetic GLP-1 and GIP agonists have demonstrated unprecedented glucoregulation and body weight reduction. Also, randomized trials have shown their ability to prevent complications of obesity, including development of diabetes from prediabetes, reducing cardiovascular disease risks and renal complications in diabetic patients. Moreover, the benefits of these agonists persist among the patients who are already on metformin or insulin. The ultimate question is "Are these benefits of incretin agonism sustainable?" Chronic agonism of pancreatic β-cells may decrease the number of receptors and cause β-cell exhaustion, leading to β-cell failure. Unfortunately, the long-term effects of these drugs are unknown at the present because the longest duration in randomized trials is 3 years. Additionally, manipulation of the neurohormonal axis to control satiety and food intake may hinder the long-term sustainability of these treatments. In this review, we will discuss the incretins' mechanism of action, challenges, and future directions. We will briefly review other molecules involved in glucose homeostasis such as amylin and glucagon. Amylin is co-expressed with insulin from the pancreas β-cells but does not have insulinotropic function. Amylin suppresses glucagon secretion, slowing gastric emptying and suppressing the reward center in the central nervous system, leading to weight loss. However, amylin can self-aggregate and cause serious cytotoxicity and may cause β-cell apoptosis. Glucagon is secreted by pancreatic α-cells and participates in glucose homeostasis in a glucose-dependent manner. In hypoglycemia, glucagon increases the blood glucose level by glycogenolysis and gluconeogenesis and inhibits glycogenesis in the liver. Several triple agonists, in combination with dual incretins and glucagon, are being developed.
最近的临床试验使用合成肠促胰岛素激素、胰高血糖素样肽 1（GLP-1）和葡萄糖依赖性胰岛素促分泌多肽（GIP）受体激动剂表明，这些治疗方法改善了许多与肥胖相关的并发症，强调了体重对整体健康的重大影响。肠促胰岛素是肠道内皮细胞受到营养摄入刺激分泌的肠内分泌激素。口服葡萄糖引起的胰岛素分泌比等摩尔静脉注射葡萄糖高得多的现象称为肠促胰岛素效应。这也暗示了进食是胰岛素抵抗的根源。合成 GLP-1 和 GIP 激动剂已证明具有前所未有的血糖调节和体重减轻作用。此外，随机试验表明它们能够预防肥胖的并发症，包括从糖尿病前期发展为糖尿病，降低糖尿病患者的心血管疾病风险和肾脏并发症。而且，这些激动剂在已经使用二甲双胍或胰岛素的患者中仍然有效。最终的问题是“肠促胰岛素激动剂的这些益处是否可持续？”胰腺β细胞的慢性激动可能会减少受体数量并导致β细胞衰竭，从而导致β细胞衰竭。不幸的是，由于随机试验的最长持续时间为 3 年，目前尚不清楚这些药物的长期效果。此外，操纵神经激素轴来控制饱腹感和食物摄入可能会阻碍这些治疗的长期可持续性。在这篇综述中，我们将讨论肠促胰岛素的作用机制、挑战和未来方向。我们将简要回顾其他参与葡萄糖稳态的分子，如胰淀素和胰高血糖素。胰淀素与胰岛素一起从胰腺β细胞表达，但没有胰岛素促分泌作用。胰淀素抑制胰高血糖素的分泌，减缓胃排空并抑制中枢神经系统的奖励中心，从而导致体重减轻。然而，胰淀素可以自聚集并引起严重的细胞毒性，并可能导致β细胞凋亡。胰高血糖素由胰腺α细胞分泌，以葡萄糖依赖的方式参与葡萄糖稳态。在低血糖时，胰高血糖素通过糖原分解和糖异生增加血糖水平，并抑制肝脏的糖生成。几种三重激动剂与双重肠促胰岛素和胰高血糖素结合正在开发中。
