Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function.
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.


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 x 10(-3)). The THADA gene variant was associated with lower beta-cell response to GLP-1 and arginine (both P < 1.6 x 10(-3)), suggesting lower beta-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 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 various gene variants may have on (dys)function of pancreatic beta-cells.
Simonis-Bik
Annemarie M
AM
Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
Nijpels
Giel
G
van Haeften
Timon W
TW
Houwing-Duistermaat
Jeanine J
JJ
Boomsma
Dorret I
DI
Reiling
Erwin
E
van Hove
Els C
EC
Diamant
Michaela
M
Kramer
Mark H H
MH
Heine
Robert J
RJ
Maassen
J Antonie
JA
Slagboom
P Eline
PE
Willemsen
Gonneke
G
Dekker
Jacqueline M
JM
Eekhoff
Elisabeth M
EM
de Geus
Eco J
EJ
't Hart
Leen M
LM
D051722:ADAM Proteins / Q000235:genetics*; D000071119:ADAMTS9 Protein; D000328:Adult; D000368:Aged; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002353:Carrier State; D018797:Cell Cycle Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins; D018570:Risk Assessment
C486563:BCL11A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C477698:THADA protein, human; C098828:CDC123 protein, human; C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human