Human Type 2 diabetes and glycaemic traits
The Gloyn group is based jointly at the Oxford Centre for Diabetes, Endocrinology & Metabolism (OCDEM) and the Wellcome Trust Centre for Human Genetics (WTCHG). Our work is funded by the Wellcome Trust, Medical Research Council (MRC) and the National Institute of Health Research (NIHR). Working very closely with the team of Professor Mark McCarthy, we aim to understand the genetic basis of diabetes and related metabolic conditions and to translate this understanding into improved clinical care.
We have a long-standing interest in forms of diabetes caused by variants in single genes, from gene discovery through to the cellular and molecular characterisation of identified genetic variants. We are especially interested in mutations in the glucokinase (GCK) gene, which cause a spectrum of disorders related to the control of blood sugar, and those in hepatocyte nuclear factor 1 alpha (HNF1A) which also affect pancreatic beta-cell function and are a common cause maturity onset diabetes of the young (MODY). We aim to interpret the consequence of protein-altering variants as they are uncovered by medical re-sequencing efforts such as the NHS 100,000 Genomes Project in genes such as HNF1A that are potentially susceptible to medical intervention.
Our interests extend to the molecular characterisation of type 2 diabetes (T2D) risk variants identified through genome-wide associations studies (GWAS) and more recently through exome and whole genome re-sequencing approaches. We have developed pipelines to understand the functional consequences of some of the small number of coding variants that have been identified, including variants in GCKR, KCNJ11/ABCC8 and G6PC2. However, the vast majority of T2D risk variants map to non-coding regions of the genome, presumed to play a regulatory role. Of the 100 or so loci involved in T2D risk we know from their impact on physiology in non-diabetic carriers that most work through pancreatic islet dysfunction. To unlock the biology at these GWAS loci we are integrating genetic data with expression profiles from human islets to match causal variants for T2D risk with their associated effector transcripts.
We have also recently been funded to investigate the impact of T2D risk variants on pancreatic beta-cell function in vivo. The DIVA consortium is recruiting individuals with specific genotypes for detailed physiological characterisation. The aim of this work is to understand the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes.
Selected recent publications
Mahajan A , Sim X, Ng HJ, Manning A, Rivas M, Highland H et al Identification and functional characterization of G6PC2 coding variants Influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus. PLoS Genetics 2015 Jan 27;11(1):e1004876. doi: 10.1371/journal.pgen.1004876. eCollection 2015
Raimondo A, Chakera A, Thomsen SK, Colclough K, Barrett A, De Franco E, Chatelas A, Demirbilek H, Akcay T, Alawneh H, The International NDM Consortium, Flanagan SE, van de Bunt M, Hattersley AT, Gloyn AL, Ellard S Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Human Molecular Genetics. 2014 Jul 11. pii: ddu360.
Thomsen SK, Gloyn AL 2014 The pancreatic beta cell: recent insights from human genetics. Trends in Endocrinology and Metabolism: TEM.doi:10.1016/j.tem.2014.05.001
Rees MG, Raimondo A, Wang J, Ban MR, Davis MI, Barrett A, Ranft J, Jagdhuhn D, Waterstradt R, Baltrusch S, Simeonov A, Collins FS, Hegele RA, Gloyn AL. 2014 Inheritance of Rare Functional GCKR Variants and Their Contribution to Triglyceride Levels in Families. Human Molecular Genetics. 2014 May 30. pii: ddu269
McCarthy MI, Rorsman P, Gloyn AL TCF7L2 and Diabetes: A Tale of Two Tissues, and of Two Species. Cell Metabolism 17:157-159 2013
Travers ME, Mackay DJ, Dekker Nitert M, Morris AP, Lindgren CM, Berry A, Johnson PR, Hanley N, Groop LC, McCarthy MI, Gloyn AL Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets. Diabetes 62:987-992;2013
van de Bunt M, Gaulton KJ, Parts L, Moran I, Johnson PR, Lindgren CM, Ferrer J, Gloyn AL, McCarthy MI The miRNA Profile of Human Pancreatic Islets and Beta-Cells and Relationship to Type 2 Diabetes Pathogenesis. PLoS one 8:e55272; 2013
Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, Cooper NS, Linden H, Levy JC, Wakelam MJ, Walker L, Karpe F, Gloyn AL PTEN mutations as a cause of constitutive insulin sensitivity and obesity. The New England Journal of Medicine 367:1002-1011;2012