TABLE 1

Associations of 19 SNPs previously associated with fasting glucose, fasting insulin, and/or 2-h glucose on detailed physiologic measures of insulin processing, secretion, and sensitivity

SNPNearest geneAlleles (effect*/ other)Insulin processing, secretion and/or β-cell functionInsulin secretionInsulin sensitivity
ProinsulinInsulinogenic indexInsulin sensitivity intravenous measuresStumvoll§Matsuda§Belfiore§Gutt§
n17,40215,3993,19515,78915,55415,80215,999
Loci implicated in abnormal insulin processing
    rs7944584MADDA/TBeta (SE)0.10 (0.0059)0.0072 (0.01)−0.024 (0.028)−0.011 (0.005)−0.02 (0.0078)−0.0085 (0.0038)−0.0076 (0.0048)
Page + sex2.07 × 10−710.470.380.0330.00970.0240.11
    rs17271305VPS13CG/ABeta (SE)−0.018 (0.007)0.019 (0.013)−0.022 (0.039)0.0041 (0.0055)−0.0034 (0.0097)−0.0011 (0.0047)−0.0012 (0.0078)
Page + sex0.0160.130.580.460.720.810.88
Loci associated with higher proinsulin and lower insulin secretion
    rs7903146TCF7L2T/CBeta (SE)0.045 (0.0066)−0.057 (0.011)−0.01 (0.026)0.011 (0.0052)0.022 (0.0084)0.011 (0.004)−0.0052 (0.0057)
Page + sex4.08 × 10−122.00 × 10−70.700.0410.00820.00530.36
    rs13266634SLC30A8C/TBeta (SE)0.031 (0.0067)−0.035 (0.011)−0.04 (0.027)0.0047 (0.0049)0.013 (0.0083)0.0072 (0.0038)−0.003 (0.0057)
Page + sex2.74 × 10−60.00120.140.340.120.0550.6
    rs10423928GIPRA/TBeta (SE)0.031 (0.0062)−0.079 (0.011)0.033 (0.032)0.016 (0.0055)0.029 (0.0085)0.025 (0.0044)−0.0099 (0.0051)
Page + sex6.23 × 10−72.10 × 10−130.300.00290.000771.00 × 10−80.053
    rs11071657C2CD4BA/GBeta (SE)0.017 (0.0059)−0.019 (0.01)0.016 (0.028)−0.0033 (0.0058)0.0026 (0.0081)0.0017 (0.0043)−0.0001 (0.0049)
Page + sex0.00370.0630.560.560.740.700.99
Loci associated with abnormalities in early insulin secretion
    rs10830963MTNR1BG/CBeta (SE)0.0074 (0.0054)−0.081 (0.009)0.046 (0.024)−0.0079 (0.0045)−0.0091 (0.0071)0.0021 (0.0034)−0.012 (0.0043)
Page + sex0.172.30 × 10−190.0570.0770.200.550.0064
    rs4607517GCKA/GBeta (SE)0.0026 (0.0072)−0.048 (0.013)0.0015 (0.033)−0.0079 (0.0065)−0.0053 (0.0099)0.0029 (0.0048)−0.023 (0.0058)
Page + sex0.722.22 × 10−40.960.220.590.548.13 × 10−5
    rs174550FADS1T/CBeta (SE)−0.0005 (0.0051)−0.028 (0.0086)0.011 (0.023)0.0078 (0.0043)0.005 (0.0067)0.0048 (0.0033)−0.0013 (0.0042)
Page + sex0.930.00130.650.0690.460.150.77
    rs2191349DGKBT/GBeta (SE)0.0057 (0.0049)−0.023 (0.0083)0.0046 (0.029)0.005 (0.0041)0.014 (0.0064)0.0038 (0.0032)0.0021 (0.0041)
Page + sex0.250.0060.870.220.0310.230.61
    rs340874PROX1C/TBeta (SE)0.0069 (0.0051)−0.02 (0.0083)0.0062 (0.023)−0.0042 (0.0042)−0.0002 (0.0064)0.0013 (0.0032)−0.0031 (0.0041)
Page + sex0.180.0150.780.310.980.680.44
    rs560887G6PC2C/TBeta (SE)−0.0017 (0.0073)0.052 (0.013)−0.045 (0.025)0.0044 (0.0068)−0.011 (0.0098)−0.009 (0.0045)−0.0052 (0.0059)
Page + sex0.814.98 × 10−50.0690.520.260.0440.38
Loci associated with reduced insulin sensitivity
    rs780094GCKRC/TBeta (SE)0.003 (0.0054)0.015 (0.0094)−0.034 (0.023)−0.017 (0.0051)−0.032 (0.0075)−0.011 (0.0036)0.00 (0.0045)
Page + sex0.570.120.140.00112.89 × 10−50.00330.99
    rs35767IGF1G/ABeta (SE)0.0002 (0.0067)−0.0061 (0.011)−0.02 (0.03)0.0016 (0.0054)−0.022 (0.0084)−0.0095 (0.0041)−0.016 (0.0052)
Page + sex0.980.570.500.770.0100.0200.0021
No obvious effects on insulin processing, secretion, or sensitivity
    rs11708067ADCY5A/GBeta (SE)0.016 (0.0063)−0.014 (0.011)−0.0095 (0.027)0.0051 (0.0054)−0.0009 (0.0082)−0.0031 (0.004)−0.016 (0.0049)
Page + sex0.0130.200.730.340.910.440.0012
    rs10885122ADRA2AG/TBeta (SE)−0.017 (0.0076)−0.018 (0.013)−0.005 (0.033)−0.0095 (0.0062)−0.0077 (0.0098)−0.0011 (0.0047)−0.0051 (0.006)
Page + sex0.0290.150.880.130.430.810.40
    rs11605924CRY2A/CBeta (SE)−0.0053 (0.0049)−0.014 (0.0083)−0.013 (0.022)−0.0076 (0.0041)−0.0079 (0.0065)−0.0027 (0.0031)−0.0098 (0.004)
Page + sex0.280.0980.550.0670.230.380.015
    rs11920090SLC2A2T/ABeta (SE)−0.0112 (0.0073)0.028 (0.012)−0.021 (0.033)0.0009 (0.0061)−0.0007 (0.0096)−0.0031 (0.0046)−0.0095 (0.006)
Page + sex0.130.0220.540.880.940.500.11
    rs7034200GLIS3A/CBeta (SE)0.018 (0.0063)0.0008 (0.011)0.0027 (0.028)−0.0015 (0.0048)0.0006 (0.0079)−0.0043 (0.0037)−0.0036 (0.005)
Page + sex0.00500.940.920.750.940.240.48
  • *Per-allele betas (SEs) are shown at the upper lines; P values from age- and sex-adjusted analyses are shown at the lower lines. Effect allele was defined as the 2-h glucose–raising alleles for GIPR rs10423928 and VPS13C rs17271305; the fasting insulin–raising allele for IGF1 rs35767; and the fasting glucose–raising allele for all other SNPs.

  • †We used naturally log-transformed trait values for proinsulin, insulinogenic index, and the insulin sensitivity indices.

  • ‡Insulin sensitivity measured with standard intravenous methods (M/I derived from euglycemic-hyperinsulinemic clamp [13]; SI from FSIGT [14]; and SSPG from the insulin suppression test [15]) and combined after Z-score transformation.

  • §The insulin sensitivity indices are defined in supplementary Table 3.