End-organ damage in diabetes
Diabetes mellitus (DM) affects the function of blood vessels and various organs, eventually leading to life-threatening DM complications. The prediction of diabetic end-organ damage and exploring novel treatment strategies herein was the topic of this thesis. We first showed that intra-renal small artery function at pre-diabetes predicted an individual’s susceptibility to diabetic nephropathy. DM also increases the risk of brain damage and Alzheimer's disease via derailment of protein homeostasis. We showed that NaHS - a donor of H2S - is a powerful antioxidant compound which attenuates brain protein aggregation DM-rats. The results highlight the role of CBS system – which produces H2S in the brain – and the potential use of NaHS as a novel strategy against protein aggregation in diabetic brain. Anti-diabetic drugs may also exert beneficial effects independent of blood glucose control. Employing an animal model of hypertension, we found that metformin and vildagliptin both reduced blood pressure and improved vascular function. However, when hypertension was combined with insulin-dependent DM the beneficial effects remained after metformin, but not vildagliptin. The results suggest superior vascular pleiotropic effects of metformin compared to vildagliptin in DM. The immunosuppressant drug and sphingosine 1-phosphate (S1P) analog fingolimod – used in the treatment of multiple sclerosis - also exerts pleiotropic effects on vascular function but the mechanisms involved are relative unknown. Our present findings in normal rats now suggest a dual action of fingolimod treatment both on vascular smooth muscle and endothelial cell S1P-receptors; how this translates in DM conditions remains to be determined. This research may help to identify individuals at higher risk of diabetic end-organ damage and provide fuel for novel treatment strategies in DM.