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.

doi:10.1101/2021.05.17.444559

bioRxiv · 10.1101/2021.05.17.444559

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.

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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 {beta}-cells. We have previously shown that {beta}-cell specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in {beta}-cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycaemia in {beta}-cells. Here we show that islet miR-125b-5p expression is up-regulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human {beta}-cell line EndoC{beta}-H1 shortened mitochondria and enhanced GSIS, whilst mice overexpressing miR-125b-5p selectively in {beta}-cells (MIR125B-Tg) were hyperglycaemic and glucose intolerant. MIR125B-Tg {beta}-cells contained enlarged lysosomal structures and showed reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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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.. 2021-05-17. Glucose-dependent miR-125b is a negative regulator of β-cell function. https://doi.org/10.1101/2021.05.17.444559

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