ß-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes (LamineA-C_RRBS)

Lamin A, lamin C and progerin, produced by alternative RNA processing of LMNA gene, are intermediate filaments involved in nuclear and chromatin architecture. We investigate the ability of LMNALCS/LCS mice to adapt insulin level to physiological and physiopathologic conditions. The metabolic status of young vs old mice shows that old LMNALCS/LCS mice are obese but glucose tolerant due to an increased ß cell mass and insulin secretion. By combining RNAseq and RRBS analysis, we observed a transcriptional disregulation of genes related to translation and mitochondria, confirmed by functionnal analysis, suggesting that LMNALCS/LCS mice set up a transcriptional program to adapt ß cell mass and function to insulin demand. To investigate this point, we challenged young mice by inducing T1DM and T2DM. In these contexts, we show that LMNALCS/LCS mice are able to normalize their fasting glycemia by both increasing insulin secretion and regenerating ß cells. Overall design: islets of Langherans isolated from wt and lmna LCS mice are analysed as 2 replicates. Each replicate is made a pool of islets from 3 different mice