Introduction TCF7L2 1 PPARγ 2 KCNJ11 3 1 TCF7L2 TCF7L2 4 12 13 TCF7L2 6 7 9 10 TCF7L2 TCF7L2 TCF7L2 WNT GCG 14 WNT TCF7L2 TCF7L2 TCF7L2 15 Methods Participants 1 2 TCF7L2 Table 1 Anthropometric and metabolic data from all 1,110 participants who underwent an OGTT   rs7903146 p p Genotype C/C C/T T/T   n 546 474 90   NGT/IGT 461/85 386/88 63/27 0.007 0.03 Sex (female/male) 346/200 315/159 50/40 0.13 0.64 Age (years) 39 ± 1 40 ± 1 41 ± 1 0.39 0.67 2 29.5 ± 0.4 28.9 ± 0.4 28.2 ± 1.0 0.51 0.24 Plasma glucose (mmol/l)  Fasting  5.1 ± 0.02 5.1 ± 0.02 5.2 ± 0.07 0.25 0.39  2 h  6.1 ± 0.07 6.2 ± 0.07 6.7 ± 0.2 0.06 0.17 Plasma insulin (pmol/l)  Fasting 62.0 ± 2.1 53.4 ± 1.7 49.8 ± 3.1 0.004 0.001  2 h 442 ± 19 356 ± 17 372 ± 34 0.12 0.04 OGTT 16.8 ± 0.5 18.2 ± 0.5 17.8 ± 1.2 a a OGTT 319 ± 5 301 ± 5 292 ± 10 b b Insulin/glucose ratio (pmol/mmol) 143 ± 5 127 ± 5 124 ± 13 b b Data are means ± SEM p χ 2 p p p a p b p Table 2 Anthropometric and metabolic data of the subgroup of 155 participants with additional measurements of GLP-1   rs7903146 p p Genotype C/C C/T T/T   n 73 67 15   NGT/IGT 64/9 48/19 10/5 0.03 0.009 Sex (female/male) 50/23 42/25 8/7 0.50 0.33 Age (years) 46 ± 1 47 ± 1 47 ± 3 0.99 0.96 2 29.8 ± 0.7 30.3 ± 0.7 27.1 ± 1.1 0.15 0.88 Plasma glucose (mmol/l)  Fasting 5.2 ± 0.05 5.3 ± 0.07 5.6 ± 0.2 0.17 0.21  2 h 6.5 ± 0.1 7.0 ± 0.2 7.2 ± 0.5 0.22 0.10 OGTT 12.8 ± 0.7 13.6 ± 1.0 15.7 ± 2.6 a a OGTT 304 ± 12 287 ± 13 235 ± 19 b b GLP-1 (pmol/l)  0 min  16.1 ± 0.9 17.3 ± 1.3 17.3 ± 2.0 0.91 0.88  30 min 34.1 ± 2.1 38.8 ± 4.0 38.1 ± 3.5 0.45 0.36  120 min 28.9 ± 1.5 29.0 ± 1.7 28.9 ± 2.4 0.87 0.88  Fold increase 0–30 min 2.5 ± 0.2 2.7 ± 0.3 2.4 ± 0.4 0.77 0.84 Data are means ± SEM p χ 2 p p a p b p 16 3 Table 3 Anthropometric and metabolic data of 210 participants who underwent a combined IVGTT and hyperinsulinaemic–euglycaemic clamp   rs7903146 p Genotype C/C X/T  n 97 113  NGT/IGT 80/17 81/32 0.06 Sex (female/male) 59/38 64/49 0.58 Age (years) 44 ± 1 45 ± 1 0.29 2 29.0 ± 0.5 28.8 ± 0.5 0.82 clamp −1 −1 −1 0.07 ± 0.01 0.07 ± 0.01 0.77 a     IVGTT C-peptide secretion (pmol/l) 7,904 ± 306 7,679 ± 323 0.40  IVGTT insulin secretion (pmol/l) 2,059 ± 131 1,924 ± 129 0.25  OGTT insulin secretion (pmol/mmol) 314 ± 8 292 ± 8 0.04 Data are means ± SEM p χ 2 t p a 17 4 17 19 n 15 20 22 Table 4 Anthropometric and metabolic data of 233 participants who underwent a hyperglycaemic clamp and of 73 participants who underwent a modified hyperglycaemic clamp with additional GLP-1 and arginine administration   Germany The Netherlands (Utrecht) The Netherlands (Hoorn) rs7903146 p rs7903146 p rs7903146 p Genotype C/C X/T  C/C X/T  C/C X/T  Sex (female/male) 15/20 24/14 0.08 5/31 22/11 <0.01 17/11 30/33 0.27 NGT/IGT 30/5 27/11 0.13 31/5 26/7 0.53 0/28 0/66 – Age (years) 38 ± 2 40 ± 2 0.66 47 ± 1 47 ± 1 0.94 56 ± 1 58 ± 1 0.43 2 26.1 ± 0.9 25.1 ± 0.6 0.41 25.6 ± 0.7 26.2 ± 0.7 0.49 29.2 ± 0.8 27.9 ± 0.4 0.13 Plasma glucose (mmol/l)  Fasting 5.1 ± 0.1 5.0 ± 0.1 0.72 4.6 ± 0.1 4.8 ± 0.1 0.18 6.6 ± 0.1 6.6 ± 0.1 0.75  2 h glucose 5.9 ± 0.3 6.5 ± 0.3 0.21 5.7 ± 0.3 5.6 ± 0.3 0.74 9.5 ± 0.1 9.5 ± 0.1 0.84 −1 −1 −1 0.15 ± 0.02 0.15 ± 0.01 0.90 0.17 ± 0.02 0.18 ± 0.02 0.60 0.11 ± 0.01 0.14 ± 0.01 0.21 a  First phase (sum 0–10 min) 1,067 ± 158 815 ± 105 0.18 963 ± 75 891 ± 96 0.76 699 ± 70 679 ± 72 0.68  Second phase 308 ± 47 291 ± 41 0.80 389 ± 42 376 ± 47 0.71 304 ± 45 303 ± 38 0.18  First phase GLP-1 2,049 ± 258 1,466 ± 175 0.03 n.a. n.a.  n.a. n.a.   Second phase GLP-1 4,567 ± 568 2,881 ± 341 0.006 n.a. n.a.  n.a. n.a.   Arginine 2,680 ± 226 2,252 ± 181 0.40 n.a. n.a.  n.a. n.a.  Data are means±SE p χ 2 t p p p n.a. a Genotyping TCF7L2 1 23 OGTT Combined IVGTT and hyperinsulinaemic–euglycaemic clamp 2 Hyperglycaemic clamp 15 18 19 Combined hyperglycaemic clamp 15 20 22 −1 −1 1 Fig. 1 TCF7L2 Open circles closed circles AIR Arrow p Methods  Analytical procedures 14 17 20 21 24 125 Calculations CP Glc 25 21 Statistical analysis W p Results Genetic variants in the TCF7L2 gene 1 1 OGTT: glucose tolerance, insulin secretion, insulin sensitivity and GLP-1 levels p p p CP Glc p 1 25 TCF7L2 1 1 TCF7L2 2 Combined IVGTT and hyperinsulinaemic–euglycaemic clamp: glucose-induced insulin secretion and insulin sensitivity TCF7L2 3 3 p Hyperglycaemic clamp: glucose-, GLP-1- and arginine-induced insulin secretion and insulin sensitivity 4 TCF7L2 p p p p p 4 1 TCF7L2 4 Discussion TCF7L2 1 6 7 9 10 TCF7L2 TCF7L2 To address this issue we first measured basal GLP-1 concentrations and GLP-1 response during an OGTT. None of the tested variants that have been shown in the literature to exert a reproducible effect on type 2 diabetes were associated with basal GLP-1 levels or with GLP-1 response during the OGTT. TCF7L2 WNT 14 26 14 TCF7L2 TCF7L2 1 6 9 12 13 TCF7L2 27 TCF7L2 28 TCF7L2 TCF7L2 14 TCF7L2 15 20 TCF7L2 21 TCF7L2 25 TCF7L2 9 TCF7L2 TCF7L2 TCF7L2 Electronic supplementary material Below is the link to the electronic supplementary material.
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