SUN-629 Hyperproinsulinemia due to a rare variant in the INS gene complicating the diagnosis of post gastric bypass hypoglycemia

Abstract Disclosure: S.K. Majumdar: None. M. Shapiro: None. L. Bernacet: None. R. Macleod: None. J. Farrell: None. R. Xicola: None. A 25 y.o. woman with a history of Roux en Y gastric bypass (RYGB) presented with recurrent postprandial hypoglycemia beginning about six months after surgery. She became pregnant 17 months after surgery and due to uncontrolled hypoglycemia and malnutrition a gastric tube was placed into her bypassed stomach for continuous tube feeding which reduced hypoglycemic episodes. Hospitalization at 8 weeks gestation did not reveal fasting hypoglycemia, but postprandial episodes were documented by home continuous glucose monitoring. PMH: Obesity, Asthma, PCOS, IBS, and a retinal epithelial pigment abnormality. Family history: Diabetes in her mother. Medications: acarbose, vitamins and famotidine. Exam at 20 weeks gestation: BP 129/79, Pulse 76, Wt 68.9 kg, BMI 26.06 kg/m². Well appearing with unremarkable findings. Prior hospital data: Capillary glucose 85 mg/dL, insulin 21pM (15.6-149.4 pM), C-peptide 596 pM (364-1457 pM), and proinsulin 82.8 pM (< 18.8 pM), with normal renal and liver function. Tube feeding was discontinued after delivery of a healthy girl so provocative testing could be done. Methods: Two supervised meal tests, one home capillary glucose test. Test 1: Sausage and eggs via oral route and test 2: ensure clear (74 gm carbohydrate, 16 gm protein, no fat) via gastric tube into her bypassed stomach. Test 3 was capillary glucose only using ensure by oral route. Result times are T0 = baseline, and Tmin after meal completion. Reference fasting values shown. Results: Test 1(sausage and eggs): T0, T30, T60, T90; Glucose (mg/dL) 80, 173, 71, 58; Insulin (18 - 75 pM) 10.2, 399.6, 57.6, 11.4; C-peptide (364-1457 pM) 433.3, 4500, 2267, 1100, and proinsulin (< 18.8 pM) 73, T30 missing, 462, 170. Test 2 (ensure clear): T0, T30, T60; Glucose 100, 125, 122; Insulin 31, 202, 242; C-peptide 833, 3067, 3300, and proinsulin 150, 872, 812, no hypoglycemia occurred over 4 hours. Test 3 (ensure clear): Glucose 84, 197, 74, 49, 78. Fasting insulin to proinsulin ratios (Tests 1,2): 0.14 and 0.21 (normal ≥ 20). Imaging: CT abdomen, MRI pancreas, Endoscopic ultrasound, and Dotatate PET scan were unrevealing. Hypoglycemia occurred with intake through the bypass route, not gastric route, and was dissociated from proinsulin. RYGB was reversed and genetic testing was done revealing a heterozygous variant in the insulin gene: INS:NM_000207:exon2:c.G164A:p.R55H (hg19: 11:2182038). This variant results in an Arginine to Histidine substitution adjacent to a trypsin cleavage site of proinsulin. Conclusion: We report a case of gastric bypass associated hypoglycemia where initial concerns included a proinsulin secreting tumor, yet meal testing dissociated hypoglycemia from proinsulin values, leading us to pursue bypass reversal and find a rare variant in the INS gene associated with hyperproinsulinemia likely due to impaired proinsulin cleavage. Presentation: Sunday, July 13, 2025