Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study.
BACKGROUND
A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity.


RESULTS
Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2(nd) phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits.


CONCLUSIONS
The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.
Steno Diabetes Center and Hagedorn Research Institute, Copenhagen, Denmark. tweb@steno.dk
Trine Welløv
TW
Boesgaard
Anette Prior
AP
Gjesing
Niels
N
Grarup
Jarno
J
Rutanen
Per-Anders
PA
Jansson
Marta Letizia
ML
Hribal
Giorgio
G
Sesti
Andreas
A
Fritsche
Norbert
N
Stefan
Harald
H
Staiger
Hans
H
Häring
Ulf
U
Smith
Markku
M
Laakso
Oluf
O
Pedersen
Torben
T
Hansen
D051722:ADAM Proteins / Q000235:genetics*; D000071119:ADAMTS9 Protein; D000328:Adult; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012680:Sensitivity and Specificity
D007328:Insulin; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human