Insulin resistance is associated with increased DNA-damage, senescence associated secretory phenotype and decreased kidney function in pre-diabetes and type 2 diabetes.

Question Increased DNA-damage and senescence are associated with progression of diabetic complications. The underlying mechanisms are yet unclear. Aim of this study is to investigate the relation of DNA-damage and senescence-associated-secretory-phenotype (SASP) with insulin resistance and beta-cell function in type 2 diabetes and pre-diabetes.

Method Participants with pre-diabetes (n=33) and type 2 diabetes (T2DM, n=152) were screened for markers of SASP (IL-6, TGF-b1; sUPAR, hs-CRP), DNA-damage and integrity (Comet-tail-length and γH2Ax) in white blood cells with markers for insulin resistance (HOMA-IR, Quicki) and beta-cell function (HOMA-beta). Clinical parameters for glucose control, kidney function and neuropathy were evaluated at baseline. One-way-ANOVA, Spearman rho and regression analyses were performed to investigate associations between DNA-damage, SASP with insulin resistance, beta-cell function and clinical parameters. Results Beta-cell function was 35% higher in participants with pre-diabetes as compared to T2DM (p<0.05). Markers of DNA-damage and SASP were 2-3-fold higher in T2DM compared to PreDM (p<0.05). Increased DNA-damage (Comet-tail-length) related positively to insulin resistance (r=0.49, p<0.05), but not to HOMA-beta. DNA-integrity was not related to insulin resistance or beta-cell function. Additionally, markers of SASP were 80% higher in participants with pronounced insulin resistance (p<0.01). Participants with pronounced DNA-damage and SASP also showed decreased kidney function (p<0.01) but no increased incidence of neuropathy.

Conclusion Increased markers for DNA-damage and SASP are significantly associated with increased insulin resistance and decreased kidney function and might be a target for prevention.

Publication History

Article published online:
02 May 2023