Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion
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Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion. / Müssig, Karsten; Staiger, Harald; Machicao, Fausto; Kirchhoff, Kerstin; Guthoff, Martina; Schäfer, Silke A; Kantartzis, Konstantinos; Silbernagel, Günther; Stefan, Norbert; Holst, Jens J; Gallwitz, Baptist; Häring, Hans-Ulrich; Fritsche, Andreas.
In: Diabetes, Vol. 58, No. 7, 2009, p. 1715-20.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion
AU - Müssig, Karsten
AU - Staiger, Harald
AU - Machicao, Fausto
AU - Kirchhoff, Kerstin
AU - Guthoff, Martina
AU - Schäfer, Silke A
AU - Kantartzis, Konstantinos
AU - Silbernagel, Günther
AU - Stefan, Norbert
AU - Holst, Jens J
AU - Gallwitz, Baptist
AU - Häring, Hans-Ulrich
AU - Fritsche, Andreas
N1 - Keywords: Adult; Chromosome Mapping; Chromosomes, Human, Pair 11; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Exons; Female; Genetic Variation; Germany; Glucose Tolerance Test; Humans; Incretins; Insulin; KCNQ1 Potassium Channel; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Protein Subunits
PY - 2009
Y1 - 2009
N2 - OBJECTIVE: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered beta-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli. RESEARCH DESIGN AND METHODS: We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic-euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli. RESULTS: rs151290 was nominally associated with 30-min C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P < or = 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P < 0.05). No SNPs were associated with beta-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide and GLP-1 increase after adjustment in the dominant model (P = 0.0042 and P = 0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all P > or = 0.05). CONCLUSIONS: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.
AB - OBJECTIVE: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered beta-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli. RESEARCH DESIGN AND METHODS: We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic-euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli. RESULTS: rs151290 was nominally associated with 30-min C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P < or = 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P < 0.05). No SNPs were associated with beta-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide and GLP-1 increase after adjustment in the dominant model (P = 0.0042 and P = 0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all P > or = 0.05). CONCLUSIONS: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.
U2 - 10.2337/db08-1589
DO - 10.2337/db08-1589
M3 - Journal article
C2 - 19366866
VL - 58
SP - 1715
EP - 1720
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 7
ER -
ID: 18700754