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Diabetes. 2020 Jan 31. pii: db190377. doi: 10.2337/db19-0377. [Epub ahead of print]

Lamin C Counteracts Glucose Intolerance in Aging, Obesity and Diabetes Through β-Cell Adaptation.

Author information

1
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France marion.detoledo@igmm.cnrs.fr carine.chavey@igmm.cnrs.fr jamal.tazi@igmm.cnrs.fr.
2
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
3
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
4
MGX, Biocampus Montpellier, CNRS, INSERM, University of Montpellier, Montpellier, France.
5
Univ. Lille, CNRS, CHU Lille, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France.

Abstract

Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity and diabetes remain unclear. Lamin A, lamin C and progerin, products of the Lmna gene, have antagonistic functions on energy metabolism and lifespan. Lamin C, albeit promoting obesity, increases lifespan suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Since β-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to β-cell function in physiopathological conditions. We demonstrate that aged lamin C-only expressing mice (Lmna LCS/LCS ) become obese but remain glucose tolerant, due to adaptive mechanisms including increased β-cell mass and insulin secretion. Triggering diabetes in young mice revealed that Lmna LCS/LCS animals normalize their fasting glycemia by both increasing insulin secretion and regenerating β-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in Lmna LCS/LCS islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time, that the sole expression of lamin C protects from glucose intolerance through a β-cell adaptive transcriptional program during metabolic stresses highlighting Lmna gene processing as a new therapeutic target for diabetes treatment.

PMID:
32005707
DOI:
10.2337/db19-0377

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