Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A and MTNR1B affect different aspects of pancreatic beta cell function.
- Annemarie M. Simonis-Bik1,
- Giel Nijpels2,
- Timon W. van Haeften3,
- Jeanine J. Houwing-Duistermaat4,
- Dorret I. Boomsma5,
- Erwin Reiling6,
- Els C van Hove6,
- Michaela Diamant1,
- Mark H.H. Kramer1,
- Robert J. Heine1,2,7,
- J. Antonie Maassen1,6,
- P. Eline Slagboom4,
- Gonneke Willemsen5,
- Jacqueline M. Dekker2,
- Elisabeth M. Eekhoff1,
- Eco J. de Geus5 and
- Leen M. 't Hart (l.m.t_Hart{at}lumc.nl)6
- 1 Diabetes center, VU University Medical Center, Amsterdam, The Netherlands
- 2 EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
- 3 Department of Internal Medicine, Utrecht University Medical Center, Utrecht, The Netherlands
- 4 Department of Medical statistics, Leiden University Medical Center, Leiden, The Netherlands
- 5 Department of Biological Psychology, VU University, Amsterdam, The Netherlands
- 6 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
- 7 Eli Lilly & Company, Indianapolis, In, USA
Abstract
Objective - Recently results from a meta-analysis of genome wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of beta cell function.
Research design and methods- 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a two hour hyperglycemic clamp. In a subset we also assessed the response to GLP-1 and arginine during an extended clamp (n=123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1 and MTNR1B.
Results - Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A and MTNR1B affected various aspects of the insulin response to glucose (all p<6.9*10−3). The THADA gene variant was associated with lower beta cell response to GLP-1 and arginine (both p<1.6*10−3) suggesting lower beta cell mass as a possible pathogenic mechanism. Remarkably we also noted a trend towards an increased insulin response to GLP-1 in carriers of MTNR1B (p=0.03) which may offer new therapeutic possibilities. The other seven loci were not detectably associated with beta cell function.
Conclusions - Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A and MTNR1B are associated with various specific aspects of beta cell function. These findings point to a clear diversity in the impact that these different gene variants may have on (dys-)function of pancreatic beta cells.
Footnotes
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- Received July 17, 2009.
- Accepted October 7, 2009.
- Copyright © American Diabetes Association
