Gene Variants in the Novel Type 2 Diabetes Loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B Affect Different Aspects of Pancreatic β-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 Hart6
- 1Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands;
- 2EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands;
- 3Department of Internal Medicine, Utrecht University Medical Center, Utrecht, the Netherlands;
- 4Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands;
- 5Department of Biological Psychology, VU University, Amsterdam, the Netherlands;
- 6Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands;
- 7Eli Lilly & Company, Indianapolis, Indiana.
- Corresponding author: Leen M. 't Hart, l.m.t_hart{at}lumc.nl.
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 β-cell function.
RESEARCH DESIGN AND METHODS For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (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 β-cell response to GLP-1 and arginine (both P < 1.6 × 10−3), suggesting lower β-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward 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 β-cell function.
CONCLUSIONS Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of β-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic β-cells.
Footnotes
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- Received July 17, 2009.
- Accepted October 7, 2009.
- © 2010 American Diabetes Association
