Yau Belinda, Ghislain Julien, Kebede Melkam A, Hughes Jing, Poitout Vincent
Charles Perkins Centre, University of Sydney, Camperdown, NSW, Australia.
School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
Diabetologia. 2025 Aug 6. doi: 10.1007/s00125-025-06499-z.
Recent advances in genome-wide approaches, the availability of isolated human islets for research and the evaluation of novel incretin mimetics in large clinical trials have brought about remarkable progress in our understanding of the role of the pancreatic beta cell in type 2 diabetes. Here, we review key developments in type 2 diabetes initiation, progression and remission, focusing mostly on human studies published in the last 5 years. Progress in multi-omics technologies has enabled researchers to identify links between type 2 diabetes risk variants and gene regulatory networks in islet endocrine cells that control beta cell development, function and stress resilience. These studies support the notion that early abnormalities in insulin secretion, rather than a reduction in beta cell mass, play a fundamental and primary role in early type 2 diabetes pathogenesis. Contributing to these intrinsic beta cell defects are various pathogenic signals from other (endocrine and non-endocrine) islet cells, the exocrine pancreas, the gut and insulin-sensitive tissues. It has also become apparent that beta cells comprise a heterogeneous population that responds differently to stress situations and that sex-related differences in beta cell responses should not be underestimated. Finally, human clinical trials have clearly demonstrated that diabetes remission can be achieved using glucose-lowering therapies and particularly strategies focused on weight loss, including bariatric surgery and, more recently, the use of highly efficient new drugs targeting the incretin system. While progress in the last 5 years has been significant, much remains to be uncovered to bring these advances to the clinic and thereby alleviate the dramatic consequences of type 2 diabetes complications for the hundreds of millions of people who live with this disease.
全基因组研究方法的最新进展、可用于研究的分离人胰岛以及新型肠促胰岛素类似物在大型临床试验中的评估，使我们对胰腺β细胞在2型糖尿病中的作用有了显著进展。在此，我们回顾2型糖尿病起始、进展和缓解方面的关键进展，主要关注过去5年发表的人体研究。多组学技术的进步使研究人员能够识别2型糖尿病风险变异与胰岛内分泌细胞中控制β细胞发育、功能和应激恢复力的基因调控网络之间的联系。这些研究支持这样一种观点，即胰岛素分泌的早期异常而非β细胞数量的减少，在早期2型糖尿病发病机制中起根本和主要作用。来自其他（内分泌和非内分泌）胰岛细胞、外分泌胰腺、肠道和胰岛素敏感组织的各种致病信号导致了这些内在的β细胞缺陷。同样明显的是，β细胞构成了一个异质性群体，对应激情况有不同反应，且不应低估β细胞反应中的性别差异。最后，人体临床试验清楚地表明，使用降糖疗法，特别是专注于减肥的策略，包括减肥手术以及最近使用针对肠促胰岛素系统的高效新药，可以实现糖尿病缓解。虽然过去5年取得了重大进展，但仍有许多有待揭示，以便将这些进展应用于临床，从而减轻2型糖尿病并发症对数亿患者造成的严重后果。
