An ABCC8 R1420H Loss-ofFunction Variant Affects Insulin Secretory Function and Microvascular Disease in American Indians

The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. An R1420H loss-of-function variant in ABCC8 was previously detected in ~3% of people in an American Indian Community with a high prevalence of type 2 diabetes (T2D); heterozygous carriers had a doubling in T2D risk and developed this disease at younger ages and lower BMIs. To further examine the phenotype of this variant, we analyzed the relationship between insulin secretion (2-h post-load corrected insulin response) and insulin sensitivity index [104/(fasting insulin*glucose)] in 5701 members of this population without diabetes aged ≥5 years using standard major axis regression, which adjusts insulin secretion for sensitivity. We used hierarchical logistic regression models in up to 7672 individuals to study cross-sectional associations with diabetes complications including increased albuminuria [albumin to creatinine ratio (ACR) ≥30 mg/g], severe albuminuria (ACR ≥ 300 mg/g), reduced eGFR (eGFR<60 mL/min/1.73m2), and retinopathy assessed by fundoscopic examination. Variant carriers had worse beta-cell function than non-carriers both in children and adults (p=0.0003) with no difference in insulin sensitivity (p=0.50). This variant did not associate significantly with increased albuminuria, severe albuminuria or reduced eGFR after adjustment for age, sex, and presence and duration of diabetes. By contrast, carriers had significantly higher odds of retinopathy (OR=1.74, 95% CI: 1.19, 2.53). Increased odds of retinopathy were also observed among individuals with and without diabetes, and when adjusted for fasting plasma glucose (FPG) [carriers had higher FPG (b=6.1 mg/dl, 95% CI: 3.0, 9.2) adjusted for age, sex, and presence and duration of diabetes]. In sum, carriers of the R1420H ABCC8 variant have a higher risk of retinopathy but not of abnormal ACR or eGFR; this may be partially explained by higher glycemia levels and worse beta-cell function. Disclosure E.Vazquez arreola: None. W.C.Knowler: None. L.Baier: None. R.L.Hanson: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases