RESUMEN
Objectives: To determine the causal correlations of lifestyle behaviours and body fat distribution on diabetic microvascular complications through a Mendelian Randomization (MR). Methods: Genetic variants significantly associated with lifestyle behaviours, abdominal obesity, generalized obesity and diabetic microvascular complications were extracted from the UK Biobank (UKB) and FinnGen. The inverse variance weighted (IVW) method was regarded as the primary method. The main results were presented in odds ratio (OR) per standard deviation (SD) increase, and a series of sensitivity analyses were also conducted to validate the stability of the results. Results: There was a positive causal correlation between smoking and the development of diabetic retinopathy (OR = 1.16; 95%CI: 1.04-1.30; p = 0.01). All of the indicators representing abdominal obesity had a statistically significant causal association with diabetic microvascular complications. Concerning generalized obesity, there were significant causal associations of body mass index (BMI) on diabetic nephropathy (OR = 1.92; 95%CI: 1.58-2.33; p < 0.001), diabetic retinopathy (OR = 1.27; 95%CI: 1.15-1.40; p < 0.001), and diabetic neuropathy (OR = 2.60; 95%CI: 1.95-3.45; p < 0.001). Other indicators including leg fat mass (left), and arm fat mass (left) also had a significant positive causality with diabetic microvascular complications. Conclusion: Our findings suggested that smoking has a genetically causal association with the development of diabetic retinopathy rather than diabetic nephropathy and diabetic neuropathy. In addition, both abdominal obesity and generalized obesity are risk factors for diabetic microvascular complications. To note, abdominal obesity represented by waist circumference (WC) is the most significant risk factor.
RESUMEN
Diabetes mellitus (DM) is a disease syndrome characterized by chronic hyperglycaemia. A long-term high-glucose environment leads to reactive oxygen species (ROS) production and nuclear DNA damage. Human umbilical cord mesenchymal stem cell (HUcMSC) infusion induces significant antidiabetic effects in type 2 diabetes mellitus (T2DM) rats. Insulin-like growth factor 1 (IGF1) receptor (IGF1R) is important in promoting glucose metabolism in diabetes; however, the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear. In this study, a DM rat model was induced with high-fat diet feeding and streptozotocin (STZ) administration and rats were infused four times with HUcMSC. Blood glucose, interleukin-6 (IL-6), IL-10, glomerular basement membrane, and renal function were examined. Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays. The expression of IGF1R, phosphorylated checkpoint kinase 2 (p-CHK2), and phosphorylated protein 53 (p-p53) was examined using immunohistochemistry (IHC) and western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry experiments were used to detect the surface markers of HUcMSC. The identification of the morphology and phenotype of HUcMSC was performed by way of oil red "O" staining and Alizarin red staining. DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane, increased the expression of IGF1 and IGF1R. IGF1R interacted with CHK2, and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown cells. When cisplatin was used to induce DNA damage, the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin treatment. HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats. The expression of IGF1, IGF1R, p-CHK2, and p-p53, and the level of 8-OHdG in the DM group increased significantly compared with those in the control group, and decreased after HUcMSC treatment. Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage. HUcMSC infusion protected against kidney injury in DM rats. The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.
