Recently, we have shown that serotonin (5-HT) regulates the insulin secretion of pancreatic beta-cells. As a consequence, mice lacking 5-HT in peripheral tissues (Tph1-/-) have an impaired insulin secretion and are diabetic. Diabetes mellitus, if left untreated, significantly curtails life expectancy, because chronic hyperglycaemia damages blood vessels and shortens energy supply of organs. Therefore we expected a curtailed life span of the diabetic Tph1-/- mice. Unexpectedly, these mice showed none of the typical diabetes-associated complications like retinopathy, nephropathy, or neuropathy and lived as long as their wild type littermates. We have previously demonstrated that Tph1-/- mice are less prone to succumb to vessel occlusion in experimental thromboembolism and thrombosis due to a reduced primary haemostatic response. Combining these findings, therapeutic peripheral 5-HT reduction specifically in thrombocytes, together with blood glucose management, might ameliorate vascular disease and its complications in diabetic patients.

To verify this hypothesis, we are generating an inducible animal model for type 1 diabetes, as most of the currently applied models have some major drawbacks concerning reproducibility, disease incidence and time of onset. Our model bases on the b-cell specific expression of the innoxious E. coli nitroreductase (NTR) which is able to convert the inactive protoxin 5-aziridin-1-yl-2,4-dinitrobenzamide (CB1954) to a potent cytotoxin. Targeted cells are thus specifically killed upon CB1954 administration. Instead of the wild type gene we used a version with several silent mutations (ntro) to adapt the prokaryotic gene to the codon usage in mammalian cells, which largely enhances protoxin sensitivity. The reduction of 5-HT levels in the ntro-mice should clarify its impact on healthiness in diabetes.