Dissecting mechanisms involved in the aetiological overlap between Type 2 diabetes and Cancer

Lead Research Organisation: University of Oxford
Department Name: RDM OCDEM

Abstract

Recent advances in genetics have provided valuable new insights into mechanisms involved in the development of Type 2 diabetes. One of the more interesting observations is that several of the genes which influence individual risk of diabetes also play a role in the development of certain cancers.

The research which I will perform, if awarded this fellowship, aims to understand some of the mechanisms involved in this cancer-diabetes overlap: I will focus on two genes where the evidence for shared effects is greatest. In one set of studies, I will look at families who harbour rare mutations in these genes which place them at particularly high risk of cancer, and establish whether these same individuals display metabolic changes which indicate they are also at altered risk of diabetes. In complementary laboratory-based studies, I will use human tissue samples (pancreas, muscle and fat) to explore the molecular events which account for these effects.

This work will help us understand some of the fundamental processes involved in both diabetes and cancer. It may also contribute to development of improved clinical care, not least by aiding appreciation of the potential side-effects of manipulating some of these disease processes.

Technical Summary

There is accumulating evidence of overlap in the molecular mechanisms involved in the development of Type 2 diabetes (T2D) and certain common cancers. Understanding the processes involved not only addresses questions of fundamental biological importance but has clear translational impact, not least with respect to the potential for adverse oncogenic events related to manipulation of these pathways to treat diabetes.
This research proposal seeks to explore the relationships between T2D pathogenesis and cancer predisposition with a specific focus on clinical and functional studies involving mutations in the CDKN2A/B and PTEN loci. The overarching hypothesis that I will aim to substantiate is that genetic variation at these loci has divergent effects on cancer predisposition and the development of Type 2 diabetes and related metabolic phenotypes. The research has the following aims:
To establish whether individuals segregating cancer-predisposing mutations in the CDKN2A gene region also display abnormalities of pancreatic beta-cell function and glucose tolerance. I will obtain standardised measures of these metabolic parameters (75g-0GTT, HOMA%B, 30‘?G/?I, IVGTT) in approximately 25 mutation carriers and a similar number of appropriate controls (aim 1);
To examine the relationships between ANRIL and CDKN2A/B through examination of transcriptional patterns at these loci (RNA and/or protein; both levels and alternative transcript forms) within human islets. In addition, I will examine the effects of modulating levels of ANRIL expression on patterns of CDKN2A/B transcript expression and islet function; and the relationship between T2D-risk variants in CDKN2A/B and islet mass in human pancreas samples (aim 2);
To extend the pilot study of patients with mutations in the cancer-predisposing PTEN gene to establish the effect of PTEN haploinsufficiency on glucose tolerance, beta-cell function and insulin action in humans; and to undertake functional studies to examinehe consequence of PTEN disruption on insulin action in human fat and muscle (aim 3).
These studies, addressing functional and clinical aspects of the overlap between cancer and T2D will provide important clues to the mechanisms involved, and will underpin future efforts to manipulate the systems involved for clinical benefit. From a personal point of view, exposure to the wide range of approaches contained in this proposal represents an opportunity for superb research training in a leading international centre.

Publications

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Description Babraham Institute Cambridge for PI3K-AKT pathway analysis 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution We established the research project investigating mechanism underlying increased insulin sensitivity in PTEN mutation carriers
Collaborator Contribution Michael Wakelam and colleagues at the Babraham institute were able to demonstrate enhanced signalling through the PI3K-AKT pathway in adipose and muscle tissue samples that we had obtained from research subjects in Oxford
Impact NEJM publication
Start Year 2011