Title: Extreme Phenotypes relevant to Diabetic Complications in Type 1 Diabetes
Funder: Juvenile Diabetes Research Foundation

Abstract: This project aims to understand why some people are very susceptible to, and some people very resistant, to diabetic nephropathy and retinopathy. We aim to discover both pathogenic mechanisms underlying this difference in risk and also better markers of future risk. We will do this by identifying those who are at the extremes of risk in three cohorts of people with type 1 diabetes and examining whether there are differences in certain novel blood markers in those susceptible versus those resistant. For some studies we want to choose those who have an unexpectedly high or low risk given their known risk factor levels. Thus we first need to consider what risk would be expected given a given risk factor profile by conducting detailed statistical analyses of the rate of disease and the impact of risk factors on these rates (i.e. predictive modelling). We will therefore construct predictive models of nephropathy and retinopathy in three cohorts; a cohort of those in Scotland with type 1 diabetes (n>25000) from whom we have recently created a large database of risk factor, treatment and health outcomes data that is held anonymously, the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) (n=996) and the Pittsburgh Epidemiology of Diabetes Complications (n=660) cohorts. The next part of the project will be to apply these models to identify the best sub-groups of peoples samples to study from the WESDR the EDC and a new Scottish cohort comprising 8000 people with type 1diabetes that is currently being recruited (3550 already recruited). We will then compare the N-glycan profile in 1320 samples from those susceptible and those resistant to complications. The N-glycan profile characterizes the range of sugar entities on certain proteins in the blood that are secreted from cells termed glycoproteins. This modification of secreted proteins with sugar residues is known to determine many aspects of protein function. We hypothesize that it is disrupted in diabetes and is associated with complications. We already know that the main intracellular pathway that is the upstream source of these sugar residues is altered in diabetes and is related to some intracellular abnormalities. At the end we expect to have i) a highly informative bioresource in Scotland for further biomarker discovery and replication studies ii) constructed predictive models of disease for efficient sampling of those at the extremes of risk iii) a collaborative framework with these other investigators facilitating future work iv) we hope to have established that N-glycan profiling is informative for complications risk. Understanding pathogenic mechanisms can help to lead to development of new therapies. Identifying measurable markers of future risk allows targeting of intensive therapy to those most in need and can accelerate the development of therapies as they can be used to select those most at risk into clinical trials, thereby increasing power and reducing trial duration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE