We propose that control of capillary flow is lost in diabetes due to endothelial/glycocalyx damage, loss of pericytes, thickening of capillary basement membranes, and elevated blood viscosity. We have shown that the resulting disturbance of capillary flow patterns causes “physiological shunting” of oxygen and glucose through tissue and propose that this capillary dysfunction contributes to endoneurial hypoxia, oxidative stress, metabolic changes, and, eventually, nerve damage in diabetic neuropathy. Hyperglycaemia is associated with damage to the capillary lining and pericyte apoptosis, and we expect the resulting loss of capillary flow control to be a dominating source of capillary dysfunction in type 1 diabetes. In type 2 diabetes, obesity, hypertension, and hyperlipidemia cause systemic inflammation and oxidative stress that expose endoneurial capillaries to activated blood cells and oxidized lipoproteins. Unlike what is seen in type 1 diabetes, hyperglycaemia may therefore be only one of several sources of nerve damage in type 2 diabetes.  

We will study capillary flow disturbances in sciatic nerves of diabetic mice, using both type 1 and type 2 models for diabetic neuropathy. With these methods we can test the hypothesis that elevated capillary transit time heterogeneity and reduced oxygen tension are early features of diabetic neuropathy in mice.

We will determine capillary flow in the peripheral nerves and tissues of both type 1 and type 2 diabetes patients. Cross-sectional studies will allow us to demonstrate both microvascular and metabolic changes in the DD2 cohort, and in prospective studies, we will study the development and initial signs of capillary dysfunction and nerve damage in type 2 diabetes from the DD2 database in Denmark. The experimental data in murine models can be complemented by targeted metabolomics in mice to allow a cross-species comparison of clinical findings and metabolomics data in both patients and murine models of type 1 and type 2 diabetic neuropathy. This reciprocal cross-species approach can discover relevant metabolite profiles in diabetic neuropathy to identify candidate pathways and molecules whose regulation alters disease progression. Targeted therapy in murine models, if successful, could then lead to new therapies for man.