Table 1.
Overview of type 2 diabetes genetic clusters
| Cluster | Expected physiological impact | Key top-weighted traits | Key top-weighted loci | Suspected mechanism | Note |
|---|---|---|---|---|---|
| Beta cell 1 (63) | Insulin deficiency | CIR (−), DI (−) | MTNR1B, CDKAL1, HHEX, C2CD4A, ANK1, ST6GAL1, SLC35C1, SLC30A8 | Beta cell function, glucose homeostasis | Beta Cell cluster from Udler et al 2018 [5] divided into 2 clusters |
| Beta cell 2 (28) | Insulin deficiency | Fasting proinsulin adj. fasting insulin (+), HOMA-B (−), fasting insulin (−) | TCF7L2, SLC30A8, ADCY5, GCK, DGKB, MTNR1B, C2CD4A | Beta cell function, insulin processing | Beta Cell cluster from Udler et al 2018 [5] divided into 2 clusters |
| Proinsulin (18) | Insulin deficiency | Fasting proinsulin adj. fasting insulin (−), HOMA-B (−) | ARAP1, STARD10 | Insulin synthesis | Recaptures Proinsulin cluster from Udler et al 2018 [5] |
| Lipoprotein A (1) | Insulin deficiency | Lp(a) (+) | SLC22A3/LPA | Lp(a) metabolism | New cluster in this study |
| Obesity (35) | Insulin resistance | BMI (+), waistC (+), % body fat (+), CRP (+) | FTO, MC4R | Obesity-mediated insulin resistance | Recaptures Obesity cluster from Udler et al 2018 [5] |
| Lipodystrophy (54) | Insulin resistance | Adiponectin (−), ISI (−), HDL (−) | IRS, PPARG, KLF14 | Fat distribution-mediated insulin resistance | Recaptures Lipodystrophy cluster from Udler et al 2018 [5] |
| Liver/Lipid (11) | Insulin resistance | CRP (−), TG (−), GGT (−) | GCKR, HNF1A, PPP1R3B, TOMM40, PNPLA3 | Liver/lipid metabolism | Recaptures Liver/Lipid cluster from Udler et al 2018 [5] |
| ALP negative (4) | Insulin resistance | ALP (−) | ABO | ALP activity levels | New cluster in this study |
| Hyper Insulin Secretion (32) | Insulin resistance | DI (+), CIR (+) | PPP1R3B, CNTN2, DTNB, TNF, SREBF1 | Insulin secretion, inflammation | New cluster in this study |
| SHBG (1) | Unclear | SHBG (−) | SHBG | SHBG metabolism | New cluster in this study |
The numbers in parentheses next to cluster names indicate the numbers of top-weighted variants in each of the clusters
Decrease and increase are indicated by (−) and (+), respectively adj., adjusted; GGT, γ-glutamyl transferase; waistC, waist circumference