Introduction and Objective: East (EAS) and South (SAS) Asians are at increased risk of developing T2DM relative to Europeans (EUR). We hypothesized that a reduced insulin secretion rate (ISR) may mediate this excess risk. Methods: We analyzed 184 subjects (146 EUR, 23 EAS, 15 SAS) who underwent an insulin suppression test (IST) and a graded glucose infusion study. ISRAUC was regressed separately on T2DM-derived partitioned polygenic scores (pPS) and on 1365 plasma proteins (Olink), adjusting for age, sex, and steady-state plasma glucose. We then repeated our analysis with 485 participants (357 EUR, 59 EAS, 69 SAS) that had fasting C-peptide data, a measure that was highly correlated with ISRAUC (r=0.83, p0.001). A false discovery rate of 0.05 was considered significant. Results: We found no significant differences in ISRAUC among the three groups (p=0.49). However, C-peptide levels were lower in EAS than in EUR (p=0.04). In SAS, among 9 pPS tested, only the beta-cell minus proinsulin pPS was positively associated with ISRAUC (FDR = 0.04), whereas the bodyfat pPS was negatively associated with C-peptide (FDR = 0.01). A total of 79 proteins were significantly associated with ISRAUC. Only one (CD207) was unique to EAS. For C-peptide, 420 proteins were significant, with 22 being unique to EAS or SAS (Figure 1D). Conclusion: These findings suggest the presence of ancestry-specific genetic and proteomic correlates of insulin secretion, warranting validation in larger studies. Disclosure S. Ali: None. D.J. Panyard: None. P. Kho: Employee; Current; Alnylam Pharmaceuticals, Inc. L. Palaniappan: None. A. Gloyn: Speaker's Bureau; Ended; Novo Nordisk. Other - Spouse is an employee and holds stock options in Roche; Current; Genentech, Inc. F. Abbasi: None. J. Knowles: Consultant; Current; Wave Biosciences, Mammoth. T. Assimes: None.
Ali et al. (Fri,) studied this question.