Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Type 2 diabetes is characterized by impaired pancreatic beta-cell function and insulin secretion.
• MicroRNAs (miRNAs) are crucial regulators of gene expression in beta-cell development and function.
• Previous studies linked AMP-activated protein kinase (AMPK) deletion in beta cells to increased miR-125b-5p levels.

Purpose of the Study:

• To investigate the role of miR-125b-5p in beta-cell function and its regulation by glucose.
• To determine if miR-125b-5p mediates detrimental effects of hyperglycemia in beta cells.

Main Methods:

• Glucose-induced upregulation of islet miR-125b-5p was assessed in an AMP-activated protein kinase (AMPK)-dependent manner.
• Glucose-stimulated insulin secretion (GSIS) was measured in mouse insulinoma MIN6 cells and human islets with altered miR-125b-5p levels.
• High-throughput screening identified miR-125b-5p targets, including M6pr and Mtfp1.
• Mitochondrial morphology and lysosomal structures were analyzed in human beta-cell lines and transgenic mice overexpressing miR-125b-5p.

Main Results:

• Glucose upregulated islet miR-125b-5p expression via AMPK.
• Overexpression of miR-125b-5p impaired GSIS in MIN6 cells and human islets.
• Inactivation of miR-125b-5p in human beta cells shortened mitochondria and enhanced GSIS.
• Mice overexpressing miR-125b-5p in beta cells exhibited hyperglycemia, glucose intolerance, enlarged lysosomes, and reduced insulin secretion.

Conclusions:

• miR-125b-5p is a glucose-controlled regulator of organelle dynamics in pancreatic beta cells.
• This miRNA modulates insulin secretion and plays a role in hyperglycemia associated with type 2 diabetes.