Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study

Trine Welløv Boesgaard; Anette Prior Gjesing; Niels Grarup; Jarno Rutanen; Per-Anders Jansson; Marta Letizia Hribal; Giorgio Sesti; Andreas Fritsche; Norbert Stefan; Harald Staiger; Hans Häring; Ulf Smith; Markku Laakso; Oluf Pedersen; Torben Hansen; EUGENE2 Consortium

doi:10.1371/journal.pone.0007236

Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study

Trine Welløv Boesgaard, Anette Prior Gjesing, Niels Grarup, Jarno Rutanen, Per-Anders Jansson, Marta Letizia Hribal, Giorgio Sesti, Andreas Fritsche, Norbert Stefan, Harald Staiger, Hans Häring, Ulf Smith, Markku Laakso, Oluf Pedersen, Torben Hansen, EUGENE2 Consortium

Department of Biomedical Sciences

41 Citations (Scopus)

Abstract

BACKROUND: 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. METHODOLOGY/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. CONCLUSION: 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.

Original language	English
Journal	PLoS ONE
Volume	4
Issue number	9
Pages (from-to)	e7236
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0007236
Publication status	Published - 2009

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Boesgaard, T. W., Gjesing, A. P., Grarup, N., Rutanen, J., Jansson, P-A., Hribal, M. L., Sesti, G., Fritsche, A., Stefan, N., Staiger, H., Häring, H., Smith, U., Laakso, M., Pedersen, O., Hansen, T., & EUGENE2 Consortium (2009). Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study. PLoS ONE, 4(9), e7236. https://doi.org/10.1371/journal.pone.0007236

Boesgaard, TW, Gjesing, AP, Grarup, N, Rutanen, J, Jansson, P-A, Hribal, ML, Sesti, G, Fritsche, A, Stefan, N, Staiger, H, Häring, H, Smith, U, Laakso, M, Pedersen, O, Hansen, T & EUGENE2 Consortium 2009, 'Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study', PLoS ONE, vol. 4, no. 9, pp. e7236. https://doi.org/10.1371/journal.pone.0007236

@article{1da1b4d035af11df8ed1000ea68e967b,

title = "Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study",

abstract = "BACKROUND: 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. METHODOLOGY/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. CONCLUSION: 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.",

author = "Boesgaard, {Trine Well{\o}v} and Gjesing, {Anette Prior} and Niels Grarup and Jarno Rutanen and Per-Anders Jansson and Hribal, {Marta Letizia} and Giorgio Sesti and Andreas Fritsche and Norbert Stefan and Harald Staiger and Hans H{\"a}ring and Ulf Smith and Markku Laakso and Oluf Pedersen and Torben Hansen and {EUGENE2 Consortium}",

note = "Keywords: ADAM Proteins; Adult; Alleles; Diabetes Mellitus, Type 2; Female; Genetic Variation; Genome-Wide Association Study; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Sensitivity and Specificity",

year = "2009",

doi = "10.1371/journal.pone.0007236",

language = "English",

volume = "4",

pages = "e7236",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

}

TY - JOUR

T1 - Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study

AU - Boesgaard, Trine Welløv

AU - Gjesing, Anette Prior

AU - Grarup, Niels

AU - Rutanen, Jarno

AU - Jansson, Per-Anders

AU - Hribal, Marta Letizia

AU - Sesti, Giorgio

AU - Fritsche, Andreas

AU - Stefan, Norbert

AU - Staiger, Harald

AU - Häring, Hans

AU - Smith, Ulf

AU - Laakso, Markku

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - EUGENE2 Consortium

N1 - Keywords: ADAM Proteins; Adult; Alleles; Diabetes Mellitus, Type 2; Female; Genetic Variation; Genome-Wide Association Study; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Sensitivity and Specificity

PY - 2009

Y1 - 2009

N2 - BACKROUND: 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. METHODOLOGY/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. CONCLUSION: 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.

AB - BACKROUND: 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. METHODOLOGY/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. CONCLUSION: 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.

U2 - 10.1371/journal.pone.0007236

DO - 10.1371/journal.pone.0007236

M3 - Journal article

C2 - 19789630

SN - 1932-6203

VL - 4

SP - e7236

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 9

ER -

Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study

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