A molecular link between diabetes, obesity, and cellular aging

Obese people and type-2 diabetes patients have high levels of LMNA, a protein associated with cellular aging

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RCSB PDB of PDB 1IVT / Krimm et al., Structure vol.10, issue 6 June 2002

Obesity and type-2 diabetes are known to increase the risk of cardiovascular disease, a leading cause of death. Some experts believe that inflammation triggered by premature ageing of immune cells might be the primary mechanism driving obesity and type-2 diabetes. However, the molecular mechanisms underlying this relationship remain poorly understood.

To investigate this question, Mohammed Al Dubayee and his co-workers at KAIMRC, King Saud bin Abdulaziz University for Health Sciences, and Alfaisal University in Riyadh obtained blood samples from 110 people, including lean individuals, obese individuals, and diabetes patients, whether newly diagnosed or on Metformin, and then quantified the expression of several proteins associated with premature aging of peripheral blood mononuclear cells. They found that the LMNA protein was highly expressed in obese people and type-2 diabetes patients but not in lean individuals. The result suggests that LMNA might be a key mediator in the inflammatory processes underlying obesity and type-2 diabetes, as well as a promising biomarker for these metabolic diseases.

Earlier studies have already demonstrated that proteins associated with cellular aging can be useful biomarkers for metabolic diseases. For example, the tumour suppressor protein p53 and cyclin-dependent kinase inhibitors p16INK4a and p21CIP1/WAF1 have been shown to be upregulated in atherosclerosis patients. In the current study, the researchers found that p53, p16INK4a, p21CIP1/WAF1 and LMNC (a transcriptional variant of LMNA) were all downregulated in type-2 diabetes patients. In contrast, LMNA was highly upregulated in obese individuals and type-2 diabetes patients.

The researchers found that LMNA, LMNC, p53, p16INK4a and p21CIP1/WAF1 were expressed normally in type-2 diabetes patients who were taking the anti-diabetic drug metformin. The researchers hypothesize that metformin works by modulating LMNA transcription. 

LMNA is best known for its role Hutchinson-Gilford Progeria Syndrome, a genetic condition characterized by the dramatic, rapid appearance of ageing in children. Studies have shown that defects in LMNA could result in growth retardation, shortened lifespan, and plaques building up in blood vessels in young patients. A better understanding of the role of LMNA in obesity and type 2 diabetes might yield new insights on cellular ageing and other diseases.

References

  1.  Al Dubayee, M. et al. Metformin alters peripheral blood mononuclear cells (PBMC) senescence biomarkers gene expression in type 2 diabetic patients. Journal of Diabetes and Its Complications 35, 107758 (2021). | article

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