Lamin C Counteracts Glucose Intolerance in Aging, Obesity, and Diabetes Through β-Cell Adaptation
- 31 January 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (4), 647-660
- https://doi.org/10.2337/db19-0377
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 life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because 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 (LmnaLCS/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 LmnaLCS/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 LmnaLCS/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.Keywords
This publication has 29 references indexed in Scilit:
- Pancreas regenerationNature, 2018
- Lamin A/C Maintains Exocrine Pancreas Homeostasis by Regulating Stability of RB and Activity of E2FGastroenterology, 2018
- Pancreatic β Cell Regeneration as a Possible Therapy for DiabetesCell Metabolism, 2017
- The molecular architecture of lamins in somatic cellsNature, 2017
- Lamins and metabolismClinical Science, 2016
- Loss of lamin A function increases chromatin dynamics in the nuclear interiorNature Communications, 2015
- Antagonistic functions of
LMNA
isoforms in energy expenditure and lifespanEMBO Reports, 2014
- Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiationNature Communications, 2012
- Splicing-Directed Therapy in a New Mouse Model of Human Accelerated AgingScience Translational Medicine, 2011
- Mobility and immobility of chromatin in transcription and genome stabilityCurrent Opinion in Genetics & Development, 2007