Published on Sat Jul 03 2021

Glucose-dependent miR-125b is a negative regulator of β-cell function

Cheung, R. W. S., Pizza, G., Chabosseau, P., Rolando, D., Tomas, A., Burgoyne, T., Salowka, A., Macklin, A., Cao, Y., Nguyen-Tu, M.-S., Marchetti, P., Shapiro, J., Piemonti, L., de Koning, E. J. P., Leclerc, I., Sakamoto, K., Smith, D. M., Rutter, G. A., Martinez-sanchez, A.

Impaired pancreatic {beta}-cell function and insulin secretion are hallmarks of type 2 diabetes. MiR-125b expression in human islets correlates with body mass index (BMI) of the donors and is regulated by glucose.

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Abstract

Impaired pancreatic {beta}-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding RNAs that silence gene expression, vital for the development and function of endocrine cells. MiR-125b is a highly conserved miRNA abundant in {beta}-cells, though its role in these cells remains unclear. Here, we show that miR-125b expression in human islets correlates with body mass index (BMI) of the donors and is regulated by glucose in an AMP-activated protein kinase-dependent manner in both mice and humans. Using and unbiased high-throughput approach, we identify dozens of direct gene targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Whereas inactivation of miR-125b in human {beta}-cells led to shorter mitochondria and improved glucose stimulated insulin secretion, mice over-expressing mir-125b selectively in {beta}-cells displayed defective insulin secretion and marked glucose intolerance. Moreover, the {beta}-cells of these transgenic animals showed strongly reduced insulin content and secretion and contained enlarged lysosomal structures. Thus, miR125b provides a glucose-controlled regulator of organelle dynamics that negatively regulates insulin secretion in {beta}-cells.