Effect of Common Genetic Variants Associated with Type 2 Diabetes and Glycemic Traits on α- and β-cell Function and Insulin Action in Man

  1. Valeriya Lyssenko1,7
  1. 1Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden, Lund University Diabetes Centre, Malmö, Sweden
  2. 2Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical and Sciences, University of Copenhagen, Copenhagen, Denmark
  3. 3Folkhälsan Research Centre, Helsinki, Finland
  4. 4Department of Social Services and Health Care, Jakobstad, Finland
  5. 5Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
  6. 6Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland
  7. 7Steno Diabetes Center A/S, Gentofte, Denmark
  1. Corresponding author: Anna Jonsson, jonsson{at}sund.ku.dk

Abstract

Although meta-analyses of genome-wide association studies have identified more than 60 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes and/or glycemic traits, there is little information whether these variants also affect α-cell function. The aim of the present study was to evaluate the effects of glycemia-associated genetic loci on islet function in vivo and in vitro. We studied 43 SNPs in 4,654 normoglycemic participants from the Finnish population-based PPP-Botnia study. Islet function was assessed, in vivo, by measuring insulin and glucagon concentrations during OGTT, and, in vitro, by measuring glucose stimulated insulin and glucagon secretion from human pancreatic islets. Carriers of risk variants in BCL11A, HHEX, ZBED3, HNF1A, IGF1 and NOTCH2 showed elevated, while those in CRY2, IGF2BP2, TSPAN8 and KCNJ11 decreased fasting and/or 2hr glucagon concentrations in vivo. Variants in BCL11A, TSPAN8, and NOTCH2 affected glucagon secretion both in vivo and in vitro. The MTNR1B variant was a clear outlier in the relationship analysis between insulin secretion and action, as well as between insulin, glucose and glucagon. Many of the genetic variants shown to be associated with type 2 diabetes or glycemic traits also exert pleiotropic in vivo and in vitro effects on islet function.

  • Received November 27, 2012.
  • Accepted March 28, 2013.

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