B623 - Examination of the relationship between SNPs in genes encoding insulin signalling proteins and insulin resistance - 03/03/2008

B number: 
Principal applicant name: 
Prof Jeremy M Tavare (Not used 0, Not used 0)
Prof Ian Day (Not used 0, Not used 0), Prof Debbie A Lawlor (Not used 0, Not used 0), George Davey-Smith (Not used 0, Not used 0)
Title of project: 
Examination of the relationship between SNPs in genes encoding insulin signalling proteins and insulin resistance
Proposal summary: 

Insulin-dependent (type I) and non-insulin-dependent (type II) diabetes remain diseases of significant unmet medical need. The long-term aim of the PI's work is to define the molecular basis by which insulin brings about its metabolic effects on cells, with a specific interest in the stimulation of glucose transport. Understanding insulin action at the molecular level in health and disease, is essential to identifying novel therapeutic regimens for treating both forms of diabetes.

Insulin action on glucose uptake involves the translocation of the insulin responsive glucose transporter, GLUT4, from intracellular storage sites to the plasma membrane and while many of the potential signalling and vesicle trafficking components have been identified, precisely how they contribute to the regulated translocation phenomenon is not yet fully understood.

The translocation of GLUT4 to the plasma membrane in response to insulin requires the activation of a complex array of signalling events. Centrally involved are the activation of phosphoinositide 3-kinase (PI3-kinase), the subsequent generation of the phosphoinositide lipid PI(3,4,5)P3 (PIP3) in the plasma membrane, and the consequent recruitment and activation of protein kinase B (PKB/Akt) via its phosphorylation on Thr308 by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser473 by TORC2.

There is now a considerable body of evidence to suggest that PKB plays a central role in insulin-stimulated glucose uptake. Much of our most recent work, therefore, has focussed on examining the role of PKB substrates in insulin-stimulated glucose uptake. This includes the proteins PIKfyve and AS160. AS160 is actually derived from two related proteins expressed from the Tbc1d1 and Tbc1d4 genes. These two proteins play a critical role in insulin action on glucose uptake.

Recent advances in genome sequencing and the analysis of single nucleotide polymorphisms (SNPs) are providing significant new opportunities to uncover the genetic basis of disease, particularly for those which are polygenic in nature such as type II diabetes. In collaboration with Profs George Davey Smith, Debbie Lawlor and Ian Day, genetic epidemiologists in the MRC Centre for Causal Analyses in Translational Epidemiology in Bristol, we have undertaken an initial examination of the Wellcome Trust Case Controlled Consortium data for associations between type II diabetes and the frequency of SNPs in genes encoding proteins that form part of the PI3-kinase signalling pathway alluded to above. This involved analysing comparative plots of data from eight major disease genome-wide association scans and noting the presence of a prominent cluster of significantly associated SNPs specific for type 2 diabetes, but not other diseases. Using this method, non-coding SNPs in both the Tbc1d1 (Chr 4) and Tbc1d4 (Chr 13) isoforms of AS160 show an association with type II diabetes at the 1/300 to 1/1000 significance levels. While lower than the significance level expected in a genome-wide scan, the conjunction of such signals in two genes within one signalling pathway strengthens the case to follow up the finding in more depth. The significance of the observation is also enhanced because an association between a coding variant in Tbc1d1 and obesity risk in females has been previously reported.

Date proposal received: 
Monday, 3 March, 2008
Date proposal approved: 
Monday, 3 March, 2008
Primary keyword: