The central role of the β-cell in diabetes: from monogenic forms to type 1, type 2, and gestational diabetes

Diabetes encompasses a heterogeneous group of metabolic disorders characterized by hyperglycemia resulting from inadequate insulin secretion and/or impaired insulin action. A central, common feature across all major forms of diabetes is the loss of functional pancreatic β-cell mass. Recent advancements have significantly highlighted the critical role of pancreatic β-cell in diabetes, primarily driven by advances in genome-wide and multi-omics approaches, the availability of isolated human islets, and the data from large clinical trials. This review synthesizes current evidence on the pathogenesis of different diabetes types including monogenic diabetes (MD), type 1 diabetes (T1D), type 2 diabetes (T2D), and gestational diabetes (GD), from the perspective of the pancreatic β-cell, emphasizing its contribution to disease heterogeneity and progression. In MD, single-gene defects directly impair β-cell function, highlighting the genetic basis of insulin secretion and offering insights into personalized treatment. In T1D, β-cells are not merely passive targets of autoimmunity but may actively participate in initiating immune responses through stress-induced changes. T2D is characterized by β-cell failure in the context of insulin resistance (IR), with genetic and functional studies underscoring the key role of β-cell decline in disease development. GD results from an inadequate β-cell compensatory response to pregnancy-related IR, revealing the intrinsic metabolic defect. Overall, a β-cell-centered framework helps elucidate the diverse mechanisms underlying different types of diabetes, provides a mechanistic foundation for improved disease subclassification.