Defining the Molecular and Physiological Mechanisms of Pancreatic Islet Cell Dysfunction Which Lead to Type 2 Diabetes (DIabetes VAriants)

Introduction:

Working with collaborators as part of ongoing genetic studies, the investigators have identified several genetic variations (DNA changes) associated with the production of and processing of insulin and are trying to understand how these genetic variations cause differences in people's ability to produce or process insulin. Their findings will lead to an improved understanding of how the pancreas produces and processes insulin after a meal and will help to improve understanding of why some people develop diabetes and some people do not, despite similar levels of obesity. This question is of great public health significance because it is unlikely that the prevalence of obesity will fall dramatically in the foreseeable future.

The investigators would like to test the hypothesis that individuals carrying different genetic variations have different abilities to produce or process insulin. They will test the consequences of these genetic variations when the pancreas has to produce insulin in response to a meal or components of a meal, such as sugar or amino acids.

Study design:

This is a prospective "recruit by genotype" cohort study that will test the role of several genetic variants (or combinations of variants) over a 4 year period (late 2014 to late 2018). The genetic variants will be chosen if there is strong evidence that they have a role in the pancreas and on insulin secretion. Each genetic variant will involve a different set of research volunteers and a slightly different set of tests. Participants will be blinded to their genetic variant status. Some genetic variants will be identified during the next 4 years so it is not possible to define at the outset a detailed methodology for all cohorts to be studied. This protocol has therefore been written to describe a core protocol relevant to the whole study, with appendices to describe specific cohorts within the study. Since the general management and ethical issues are overarching, as new genetic variants are identified over the 4 year study period, cohort-specific appendices will be added as major amendments, rather than submitting each cohort as a separate ethics application. The procedure for recruitment and testing of each set of research volunteers will be the same except for a component that will be outlined in cohort-specific appendices.