MicroRNA-Driven Regulation of β-Cell Function in Type 2 Diabetes: Molecular Mechanisms, Network Insights, and...

MicroRNAs (miRNAs) have emerged as central regulators of pancreatic islet biology, influencing β-cell development, proliferation, and function. In type 2 diabetes (T2D), both adaptive and maladaptive miRNA responses shape β-cell compensation and progressive secretory dysfunction. Here, we review current insights into the regulation of insulin secretion, with a focus on exocytosis and the autocrine and paracrine regulation of β-cells, and discuss the involvement of miRNAs in these processes. We describe miRNA biogenesis and the regulation of miRNAs in β-cells, focusing on glucose- and cAMP-responsive miRNAs and epigenetic control. We summarize mechanistic evidence linking individual miRNAs to the regulation of β-cell function during T2D development, including effects on metabolic signaling and the exocytotic machinery, and compare results from humans, rodents, and cell lines, while emphasizing both the need for and difficulties of performing these investigations in β-cells from human donors. Moreover, recent network-level analyses reveal that T2D is characterized not by isolated miRNA changes but by coordinated changes in miRNA-mRNA regulatory pathways that converge on reduced and/or compensatory insulin secretion. Beyond cell-intrinsic actions, we discuss how circulating miRNAs transported via extracellular vesicles (EVs) mediate crosstalk between β-cells and peripheral tissues, influencing insulin resistance, β-cell function, and systemic glucose homeostasis. Finally, we highlight the potential of circulating miRNAs as diagnostic and predictive biomarkers, as well as the use of EVs and miRNAs for therapeutic applications, while underscoring the technical challenges that currently limit clinical translation. Nevertheless, advances in technical, network, and inter-organ analyses position miRNAs as promising biomarkers and therapeutic targets in T2D.