Table 4. Multiple mediation models of β-cell function and insulin resistance in the associations between sphingolipids and incident T2D.
| Sphingolipid or module | SP on mediator (X→M) |
P value | Direct effect (X→Y, adjusted M) |
P value | Indirect effect (X→M→Y) |
P value | Proportion mediated (%) |
|---|---|---|---|---|---|---|---|
| HOMA-B | |||||||
| Cer(d18:1/18:1) | −0.096 (−0.139, −0.054) | <0.001 | 0.159 (0.051, 0.267) | 0.004 | 0.030 (0.015, 0.050) | <0.001 | 15.87 |
| Cer(d18:1/20:0) | −0.132 (−0.174, −0.090) | <0.001 | 0.146 (0.038, 0.253) | 0.008 | 0.040 (0.023, 0.064) | <0.001 | 21.51 |
| Cer(d18:1/20:1) | −0.174 (−0.216, −0.132) | <0.001 | 0.183 (0.075, 0.292) | <0.001 | 0.051 (0.030, 0.077) | <0.001 | 21.79 |
| Cer(d18:1/22:1) | −0.210 (−0.257, −0.162) | <0.001 | 0.156 (0.034, 0.279) | 0.01 | 0.062 (0.039, 0.092) | <0.001 | 28.44 |
| SM C34:0 | −0.281 (−0.328, −0.235) | <0.001 | 0.114 (−0.011, 0.238) | 0.07 | 0.084 (0.049, 0.123) | <0.001 | 42.42 |
| SM C36:0 | 0.011 (−0.033, 0.054) | 0.64 | 0.223 (0.111, 0.334) | <0.001 | −0.004 (−0.020, 0.011) | 0.64 | 0.00 |
| SM C38:0 | −0.181 (−0.225, −0.136) | <0.001 | 0.196 (0.086, 0.307) | <0.001 | 0.053 (0.032, 0.079) | <0.001 | 21.29 |
| SM C40:0 | −0.101 (−0.145, −0.056) | <0.001 | 0.165 (0.056, 0.274) | 0.003 | 0.031 (0.016, 0.048) | <0.001 | 15.82 |
| SM C34:1 | −0.277 (−0.324, −0.229) | <0.001 | 0.167 (0.044, 0.290) | 0.008 | 0.079 (0.048, 0.115) | <0.001 | 32.11 |
| SM C36:1 | −0.193 (−0.236, −0.149) | <0.001 | 0.165 (0.050, 0.280) | 0.005 | 0.057 (0.034, 0.087) | <0.001 | 25.68 |
| SM C42:3 | −0.101 (−0.148, −0.053) | <0.001 | 0.169 (0.051, 0.287) | 0.005 | 0.031 (0.015, 0.052) | 0.001 | 15.50 |
| SM (2OH) C34:1 | −0.098 (−0.142, −0.054) | <0.001 | 0.238 (0.124, 0.352) | <0.001 | 0.030 (0.014, 0.050) | <0.001 | 11.19 |
| SM (OH) C38:3 | −0.194 (−0.243, −0.144) | <0.001 | 0.189 (0.062, 0.317) | 0.004 | 0.057 (0.035, 0.083) | <0.001 | 23.17 |
| HexCer(d18:1/20:1) | −0.228 (−0.270, −0.186) | <0.001 | 0.156 (0.046, 0.266) | 0.005 | 0.065 (0.038, 0.094) | <0.001 | 29.41 |
| Module yellow | −0.082 (−0.108, −0.055) | <0.001 | 0.172 (0.058, 0.286) | 0.003 | 0.043 (0.025, 0.068) | <0.001 | 20.00 |
| Module turquoise | −0.131 (−0.156, −0.107) | <0.001 | 0.165 (0.049, 0.282) | 0.005 | 0.067 (0.040, 0.098) | <0.001 | 28.88 |
| Module green | −0.090 (−0.120, −0.061) | <0.001 | 0.150 (0.018, 0.282) | 0.03 | 0.049 (0.027, 0.078) | <0.001 | 24.62 |
| Module brown | −0.118 (−0.143, −0.094) | <0.001 | 0.108 (−0.005, 0.221) | 0.06 | 0.063 (0.039, 0.092) | <0.001 | 36.84 |
| HOMA-IR | |||||||
| Cer(d18:1/18:1) | 0.066 (0.025, 0.108) | 0.002 | 0.175 (0.068, 0.282) | 0.001 | 0.010 (0.002, 0.026) | 0.05 | 5.41 |
| Cer(d18:1/20:0) | 0.025 (−0.017, 0.066) | 0.25 | 0.180 (0.073, 0.286) | 0.001 | 0.004 (−0.003, 0.016) | 0.31 | 2.17 |
| Cer(d18:1/20:1) | 0.047 (0.005, 0.089) | 0.03 | 0.226 (0.119, 0.332) | <0.001 | 0.007 (0.0004, 0.024) | 0.10 | 3.00 |
| Cer(d18:1/22:1) | 0.099 (0.052, 0.147) | <0.001 | 0.203 (0.082, 0.324) | 0.001 | 0.015 (0.004, 0.035) | 0.03 | 6.88 |
| SM C34:0 | 0.072 (0.025, 0.120) | 0.003 | 0.190 (0.070, 0.311) | 0.002 | 0.011 (0.002, 0.028) | 0.05 | 5.47 |
| SM C36:0 | 0.101 (0.058, 0.144) | <0.001 | 0.201 (0.090, 0.313) | <0.001 | 0.015 (0.002, 0.032) | 0.03 | 6.94 |
| SM C38:0 | 0.144 (0.100, 0.188) | <0.001 | 0.226 (0.116, 0.335) | <0.001 | 0.020 (0.004, 0.041) | 0.03 | 8.13 |
| SM C40:0 | 0.168 (0.124, 0.212) | <0.001 | 0.171 (0.061, 0.281) | 0.002 | 0.024 (0.004, 0.049) | 0.03 | 12.31 |
| SM C34:1 | 0.133 (0.086, 0.181) | <0.001 | 0.226 (0.107, 0.346) | <0.001 | 0.019 (0.002, 0.040) | 0.03 | 7.76 |
| SM C36:1 | 0.052 (0.009, 0.095) | 0.02 | 0.213 (0.101, 0.326) | <0.001 | 0.008 (0.0004, 0.022) | 0.09 | 3.62 |
| SM C42:3 | 0.134 (0.087, 0.180) | <0.001 | 0.177 (0.058, 0.295) | 0.003 | 0.020 (0.003, 0.040) | 0.04 | 10.15 |
| SM (2OH) C34:1 | 0.073 (0.030, 0.116) | 0.001 | 0.256 (0.142, 0.370) | <0.001 | 0.011 (0.002, 0.026) | 0.05 | 4.12 |
| SM (OH) C38:3 | 0.164 (0.115, 0.213) | <0.001 | 0.226 (0.099, 0.352) | <0.001 | 0.023 (0.004, 0.050) | 0.03 | 9.24 |
| HexCer(d18:1/20:1) | 0.060 (0.018, 0.103) | 0.005 | 0.211 (0.104, 0.318) | <0.001 | 0.009 (0.001, 0.024) | 0.06 | 4.09 |
| Module yellow | 0.090 (0.066, 0.114) | <0.001 | 0.189 (0.075, 0.303) | 0.001 | 0.024 (0.003, 0.05) | 0.03 | 11.27 |
| Module turquoise | 0.037 (0.013, 0.060) | 0.002 | 0.221 (0.107, 0.335) | <0.001 | 0.011 (0.002, 0.024) | 0.05 | 4.74 |
| Module green | 0.066 (0.039, 0.093) | <0.001 | 0.179 (0.047, 0.311) | 0.008 | 0.019 (0.005, 0.040) | 0.02 | 9.60 |
| Module brown | 0.023 (0.000, 0.046) | 0.05 | 0.165 (0.054, 0.276) | 0.004 | 0.007 (0.001, 0.020) | 0.12 | 4.07 |
Model was adjusted for age, sex, region (Beijing or Shanghai), residence (urban or rural), educational attainment (0–6 years, 7–9 years, or ≥10 years), current smoking (yes or no), current alcohol drinking (yes or no), physical activity (low, moderate, or high), family history of diabetes (yes or no), and BMI. In the model, X denotes the sphingolipid, M denotes the mediator, and Y denotes incident T2D.
Cer, ceramide; HexCer, hexosylceramide; HOMA-B, homeostatic model assessment of β-cell function; HOMA-IR, homeostatic model assessment of insulin resistance; SM, sphingomyelin; SM (OH), hydroxyl-sphingomyelin with 1 additional hydroxyl; SM (2OH), hydroxyl-sphingomyelin with 2 additional hydroxyls; SP, sphingolipid; T2D, type 2 diabetes.