Abstract
Although there is increasing evidence showing that cell senescence is increased in circulating PBMC in type 2 diabetes mellitus (T2DM), the data are contradictory. This study examined several senescence biomarkers, including LMNA/C transcript variants, p16INK4a, p53, and p21Cip1/WAF, in PBMC of T2DM patients and the effect of Metformin on these senescence markers.
Blood samples were obtained from 30 lean, 30 obese, 20 newly diagnosed type 2 diabetes mellitus (T2DM), and 30 T2DM on Metformin. PBMC were isolated and mRNA expression of the senescence biomarkers were quantified by RT-qPCR. The effect of ectopic expression of LMNA and LMNC in human monocytic cells lines (THP-1 and U937) on several inflammatory mediators were also examined.
LMNA expression was significantly higher in PBMC of obese and T2DM patients. LMNC expression was significantly inhibited in T2DM patients. LMNAΔ10 and Progerin mRNA expression was not detected in PBMC of all groups. Expression of p16INK4a, p21Cip1/WAF and p53 were inhibited significantly in T2DM. Metformin treatment reverted LMNA, LMNC, and p53 expression levels to normal levels. Upregulation of LMNA in monocytic THP-1 and U937 cell lines induced CD68, TNFα, CCL2, IL-6 and NOS2.
These data support the notion that LMNA may mediate senescence in PBMCs of T2DM by upregulating inflammatory pathways. Metformin may exert its anti-inflammatory property by modulation of senescence mediator LMNA.
•This study examined the differential expression of several senescence biomarkers in peripheral blood mononuclear cells (PBMC) from normal weight, obese, T2DM and T2DM on Metformin.•PBMC of T2DM subjects had higher levels of LMNA expression while LMNC, p16INK4a, p53 and p21CIP1/WAF1 expression levels were significantly lower. Metformin treatment reverted LMNA and LMNC expression to levels comparable to the lean subjects.•There were increased expression levels of CD68, IL-6, TNFα, CCL2 and NOS2 in T2DM and ectopic expression of LMNA in THP-1 or U937 upregulated the expression of these genes.•LMNA transcript variant may mediate senescence in accelerated atherosclerosis associated with T2DM by upregulating inflammatory pathways.•Metformin modulates the senescence mediator LMNA.