Exosomal miR-375-3p as a mediator of pancreas-liver crosstalk in impaired hepatic glycogenesis

Abstract

Type 2 diabetes mellitus is a complex metabolic disorder characterized by impaired insulin secretion, insulin resistance, and dysregulated inter-organ communication. Beyond classical endocrine signaling, exosomes have recently emerged as critical mediators of crosstalk between pancreatic β cells and peripheral metabolic tissue. In a recent study, Xu et al demonstrated that hepatocytes can receive exosomal miR-375-3p derived from pancreatic β-cells, which suppresses the Rbpj region and consequently impairing hepatic glycogenesis. These findings provide novel mechanistic insights into how glucotoxic β cells influence hepatic glucose metabolism independently of insulin secretion. Notably, this study highlights exosomal miR-375-3p as a potential biomarker and therapeutic target for metabolic diseases. However, clinical validation in human cohorts and assessment of long-term metabolic outcomes are still required. A deeper understanding of exosome-mediated communication between the pancreas and liver may ultimately pave the way for new strategies to restore metabolic homeostasis and mitigate disease-related complications.

Keywords: Type 2 diabetes mellitus; Hepatic glycogenesis; Pancreas-liver crosstalk; Exosome; miR-375-3p; Pancreatic β cells; Hepatocytes

Core Tip: Xu et al revealed that pancreatic β-cell-derived exosomal miR-375-3p inhibits Rbpj expression in hepatocytes, leading to the suppression of the AKT/GSK signaling pathway and impaired hepatic glycogenesis. Their study identified a novel exosome-mediated pancreas-liver communication axis in the progression of diabetes, underscoring the promising role of exosomal microRNAs as both diagnostic biomarkers and therapeutic targets.