The Obesity-Risk Variant in CREBRF (R457Q) Protects against Diabetes by Enhancing First-Phase Insulin Secretion and ß-Cell Compensation

Introduction and Objective: Obesity and diabetes are globally prevalent and closely linked. We previously identified a missense variant in CREBRF (rs373863828; p.R457Q) that paradoxically increases BMI yet protects against diabetes. The mechanism underlying this protection is not known. We hypothesized that the variant enhances first-phase insulin secretion and β-cell compensation. Methods: Anthropometric data and 75-g OGTTs were collected from 521 adults from American Samoa carrying 0, 1, or 2 risk alleles (Soifua Manuia study). Individuals without diabetes (N=306; 158 M, 148 F) underwent further characterization of glucose homeostasis and insulin action using sex-stratified linear mixed models adjusted for age and BMI. Results: As expected, the variant was associated with higher BMI. After adjustment, fasting glucose, insulin, NEFA, HOMA2-IR, and HOMA2-%B did not differ by genotype. During the OGTT, carriers displayed lower glucose excursions (significant in females; trend in males), higher first-phase insulin secretion in both sexes, and higher log-transformed disposition index, indicating superior β-cell compensation. Measures of whole-body and tissue-specific insulin sensitivity did not differ consistently by genotype. Females exhibited more favorable glycemic responses overall. Conclusion: This largest study of CREBRF R457Q carriers demonstrates enhanced first-phase insulin secretion and β-cell compensation in both males and females. These findings support a model in which the variant reduces diabetes risk despite higher BMI by enabling β cells to scale early insulin secretion to increased metabolic demand, offering insights that may inform future therapeutic strategies for type 2 diabetes. Disclosure: M.G. Rossillo: None. J. Carlson: None. A. Pomer: None. S.L. Manna: None. R.L. Duckham: None. T.K. Naseri: None. R. Minster: None. D.E. Weeks: None. S.T. McGarvey: None. N. Hawley: None. E.E. Kershaw: Consultant; Ended; Novo Nordisk. Consultant; Current; NodThera, Sparrow Pharmaceuticals. Research Support; Current; Pfizer Inc., Arrowhead Pharmaceuticals, Inc. Funding: National Institutes of Health (R01HL093093)