It is now well established by retrospective and animal model studies that metformin prevents development and growth of abdominal aortic aneurysms (AAA). In our recent study, we also observed that metformin caused upregulation at the gene expression level of GPNMB [1]. This gene encodes for a leukocyte associated glycoprotein, that has been previously associated with type 2 diabetes mellitus (DM) but not with AAA. It is reasonable to assume it can have an effect on AAA, as GPNMB stimulates the production of MMP2, MMP9 and M2 macrophage polarization and inhibits T-cell activation [2, 3]. Other hormones associated with DM, potentially regulated by metformin are irisin [4] and ghrelin [5]. These have comparable actions to adipokines such as leptin, adiponectin and resistin, previously studied in a context of DM and AAA [6]. This suggests that irisin and ghrelin can also be involved in AAA development. Our aim is to explore the association between GPNMB, irisin, ghrelin and metformin in a context of AAA and DM.

Evaluation of GPNMB, irisin and ghrelin's gene expression in control and AAA tissue. Evaluation of GPNMB, irisin and ghrelin's plasma concentration in samples from control patients (no AAA, no DM), AAA patients and patients with AAA and DM, without metformin treatment (AAA DM) or with metformin treatment (AAA DM+Met).

No differences were found in mRNA expression of GPNMB between AAA tissues and control (p=0.12). AAA tissue has a lower mRNA expression of irisin than control (p<0.05). AAA tissue samples have a 1.5-fold increase in ghrelin mRNA expression, compared with control tissue (p=0.08). Plasma concentration of GPNMB is increased in AAA DM (p<0.05) and AAA DM+Met (p<0.05) samples, compared with AAA samples. Plasma concentrations of irisin are increased in AAA (p<0.05) and AAA DM (p<0.05) samples, compared with control. AAA DM+Met samples have preliminary lower levels of plasma irisin, compared with AAA DM (p=0.06) samples. AAA DM+Met samples have a significant decrease in ghrelin's plasma concentration, compared with controls (p<0.05) and AAA samples (p<0.05).

These results suggest that, in patients with AAA and DM, irisin and ghrelin plasma levels are regulated by metformin. The implications of this association remain to be explored. The apparent discrepancy between gene expression and plasma concentrations in control and AAA samples suggests post-translational modifications or different regulations in local (aortic tissue) and systemic (plasma) effects of these proteins. This is the first report that suggests an interplay between GPNMB, irisin, ghrelin and metformin in a context of AAA and DM. Further studies are necessary to characterize these proteins in more detail in AAA. Functional studies in mice can be useful to understand GPNMB, irisin and ghrelin roles in the pathogenesis of AAA and potential treatment.

1. Kunath, A., et al., Inhibition of angiotensin-induced aortic aneurysm by metformin in apolipoprotein E-deficient mice. JVS: Vascular Science 2021. 2: p. 33-42. 2. Ghilardi, C., et al., Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC genomics 2008. 9.1: p. 1-18. 3. Saade, M., et al., The Role of GPNMB in Inflammation. Frontiers in Immunology, 2021. 12: p. 1687. 4. Leustean, L., et al., Role of Irisin in Endocrine and Metabolic Disorders—Possible New Therapeutic Agent? Applied Sciences, 2021. 11(12). 5. Doogue, M.P., et al., Metformin increases plasma ghrelin in Type 2 diabetes. Br J Clin Pharmacol, 2009. 68(6): p. 875-82. 6. Thanigaimani, S. and J. Golledge, Role of adipokines and perivascular adipose tissue in abdominal aortic aneurysm: A systematic review and meta-analysis of animal and human observational studies. Frontiers in Endocrinology 2021. 12.