Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Manuel Blandino-Rosano, Rebecca Barbaresso, Margarita Jimenez-Palomares, Nadejda Bozadjieva, Joao Pedro Werneck- de-Castro, Masayuki Hatanaka, Raghavendra G. Mirmira, Nahum Sonenberg, Ming Liu, Markus A. Rüegg, Michael N. Hall and Ernesto Bernal-Mizrachi ()
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Manuel Blandino-Rosano: Diabetes and Metabolism, University of Miami, Miller School of Medicine
Rebecca Barbaresso: Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center
Margarita Jimenez-Palomares: Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center
Nadejda Bozadjieva: Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center
Joao Pedro Werneck- de-Castro: Diabetes and Metabolism, University of Miami, Miller School of Medicine
Masayuki Hatanaka: Indiana University School of Medicine
Raghavendra G. Mirmira: Indiana University School of Medicine
Nahum Sonenberg: McGill University
Ming Liu: Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center
Markus A. Rüegg: Biozentrum, University of Basel
Michael N. Hall: Biozentrum, University of Basel
Ernesto Bernal-Mizrachi: Diabetes and Metabolism, University of Miami, Miller School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKOf/f) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation. Restoration of both pathways partially recovers β-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in β-cells and identify downstream pathways driving β-cell mass, function and insulin processing.

Date: 2017
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DOI: 10.1038/ncomms16014

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