Considering a strong association between HNF4A deregulation and increased risk of T2DM, our findings suggest that HNF4α may act as a critical converging point linking hyperprocoagulant condition to VEGF resistance in diabetic ECs, and repression of FLK1 expression by thrombin-induced HNF4α mediates, at least partially, the vascular dysfunction caused by T2DM.
Mean C-peptide at diagnosis was higher for HNF4A-MODY than for T1D (1.8 vs 0.9 ng/mL; P < 0.01); 36.4% of patients with HNF4A-MODY and 65.7% of patients with HNF1B-MODY were treated with insulin, whereas 20.5% and 8.6% received oral antidiabetics only (P < 0.05 and P < 0.01 vs T2D).
Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.
We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population.
In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (p <sub>discovery</sub> < 6.45 × 10<sup>-7</sup>).
The T2DM association in FITM2-R3HDML-HNF4A (rs3212183; P = .0002; OR = 1.19 [1.09-1.30]) was independent from the East Asian lead SNP (rs6017317), which did not associate with T2DM in American Indians.