Abstract
Disclosure: A. Abdulkader: None. S.B. Ten: None. MODY is suspected in nonobese subjects with hyperglycemia, negative islet cell antibodies, and a family history of diabetes. Children with morbid obesity and diabetes can still have MODY and require different treatment. Case report The patient was born after a pregnancy complicated with gestational diabetes, treated with insulin, BW 9 (1/2) lbs. He had early onset obesity from 3 yrs. of age. At 8 yrs., he developed impaired glucose tolerance, elevated triglycerides, low HDL, and fatty liver. He developed diabetes at 11 yrs. and was treated with Insulin, but treatment was not effective, Hb A1c was 11.4%, and BMI was 51.8 kg/m(2). At 12 yrs., he was diagnosed with MODY on the base of normal C-peptide, negative islet cell AB, strong family history of diabetes: mother, uncle and MGM had diabetes. Insulin was discontinued. Glyburide and Metformin were started that improved his glucose level significantly. Hb A1c improved to 6.2%. Diet was changed, physical exercises were added, and he lost 25 lbs., BMI improved to 44.8 kg/m(2). His mother, 46 yrs. old, was diagnosed with diabetes type 1 at 18 yrs. and treated with Insulin. She also had morbid obesity with BMI 48 kg/m(2). She developed diabetic neuropathy, nephropathy, and had amputation of the left leg below the knee, eGFR 44 mL/min/1.73m(2), Hb A1c 10.5%. She was diagnosed with MODY on the base of normal C-peptide 3.21 ng/mL, negative islet cell AB, family history of diabetes: her mother, brother, son have diabetes. Glyburide and pioglitazone were started, Insulin total daily dose was decreased from 90 units to 15 units a day. Her Hb A1c improved to 6 %, insulin was discontinued. She underwent Roux-en-Y Gastric Bypass surgery, lost 30 lbs. BMI improved to 42 kg/m(2), Hb A1c became 5.3%. Her current glucose level is normal on Glyburide 2.5 mg and pioglitazone 7.5 mg daily. Results: Patient and his mother had heterozygous gene polymorphism in GLIS3, c.951G>T (p.Glu317Asp). This sequence replaces glutamic acid with aspartic acid at codon 317 of the GLIS3 protein (p.Glu317Asp). GLIS3 is a variant of MODY and is a transcriptional factor in beta cell differentiation and insulin production. Patient and mother had pathogenic heterozygous variant of KSR2 gene, c.1622del, resulting in a frameshift and premature protein termination (p.Lys541Serfs*27). Pathogenic variants in KSR2 are associated with obesity and insulin resistance. Patient was also heterozygous in the NTRK2 gene for a sequence variant c.500C>A, which is predicted to result in the amino acid substitution p.Ser167Tyr, also associated with obesity. Conclusion Genetic analysis of MODY is necessary even in cases of diabetes with morbid obesity, negative islet cell AB, positive family history of diabetes. Diagnosis of MODY helps provide individualized treatment and avoid complications secondary to unnecessary treatment with insulin. Presentation: Thursday, June 15, 2023