Introduction and Objective: Post-bariatric hypoglycemia (PBH) is an increasingly recognized complication of bariatric surgery. Preoperative symptoms of hypoglycemia are associated with risk and suggest that genetic variants affecting beta-cell function and glucose sensing could contribute to dysregulated insulin secretion in PBH. Methods: Four groups of participants were studied: (1) hypoglycemia after surgery (PBH, n=17), (2) asymptomatic post-RYGB (RYGB non-hypo, n=27), (3) hypoglycemia without surgery (Hypo non-surg, n=16), and (4) obese non-surgical controls (CON, n=13). Next-generation sequencing was performed to identify variants in 29 known genes for monogenic diabetes. Non-synonymous variants with minor allele frequency (MAF) ≥5% were selected to examine common variants with potential population-level relevance. The MAF for each SNP was compared between groups using Fisher’s exact test. Results: Among 202 identified variants, two SNPs had frequencies that differed between PBH and RYGB non-hypo. SNP rs5400, in the SLC2A2 gene (p.Thr110Ile) coding for glucose transporter GLUT2, was less frequent in PBH vs RYGB non-hypo (MAF PBH = 0.06, MAF RYGB non-hypo = 0.27; OR=0.17, 95% CI 0.02-0.74; nominal p=0.009). This SLC2A2 variant had MAF=0.19 in Hypo non-surg and 0.27 in CON groups. SNP rs734312, in the WFS1 gene (p. H611R) coding for the ER protein wolframin (mutated in Wolfram Syndrome), was less frequent in PBH vs RYGB non-hypo (MAF PBH = 0.35, MAF RYGB non-hypo = 0.59; OR=0.38, 95% CI 0.14-1.00; nominal p=0.047). This variant had MAF of 0.31 in Hypo non-surg and 0.62 in CON groups. These associations did not reach statistical significance after FDR correction for multiple comparisons. Conclusion: Missense variants in SLC2A2 rs5400 and WFS1 rs734312 showed differential frequencies between PBH and RYGB non-hypo groups, suggesting potential protective associations. These exploratory findings provide preliminary evidence for gene variants involved in PBH susceptibility and support further investigation in larger, prospectively enrolled cohorts. Disclosure E. Arevalo-Rios: None. H. Saeed: None. C. Mendonca: None. A. Doria: Research Support; Current; Lexicon Pharmaceuticals, Inc., Abbott Diabetes, Dexcom, Inc. Advisory Panel; Current; Nephris. M.E. Patti: Other - My institution receives research funding for clinical trial.; Current; Recordati S.p.A, Amylyx. Other - Data Safety Monitoring Board; Current; Fractyl Health, Inc. Funding National Institutes of Health (R01-DK121995)
Arevalo-Rios et al. (Fri,) studied this question.