SUN-548 - Dual GIP/GLP-1 Receptor Agonist Use in PDX1-MODY: A Case Report

Maturity-Onset Diabetes of the Young (MODY) due to a mutation in the PDX1 gene is rare, and the genetic and clinical features of patients with diabetes from the Michigan-Kentucky pedigree were originally described with homozygosity for the IPF1 mutation Pro63fsx60 (1). It had been described that patients with a c.188del(p.P63Rfs*60) mutation have pancreatic agenesis on computed tomography (CT) and low fecal elastase (2). However, there have been few reports of differing phenotypes of heterozygous patients without pancreatic agenesis or exocrine pancreatic insufficiency, and no reports on the use of dual glucose insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (dual GIP/GLP-1 RA) treatment. In this report, we describe the use of tirzepatide in a patient with a PDX1-MODY c.188del.p(P63Rfs*60) mutation who did not have exocrine pancreatic insufficiency or pancreatic agenesis. A 44-year-old non-Hispanic White woman was initially diagnosed with diabetes at age 13 when she presented with frequent headaches, excessive thirst and urination, urinary tract infections, delayed wound healing, and glucose levels >300 mg/dl. She did not have DKA, and was overweight (BMI 27.4 kg/m2, 95.7th percentile) at diagnosis. Autoantibodies to GAD65 and IA-2 were negative. She was treated by an endocrinologist for 17 years with an insulin pump titrated to 80-100 units per day. She gained 60 lbs. (weight of 235 lbs.) but eventually was treated with (GIP/)GLP-1 RA (semaglutide, then tirzepatide) and her HbA1c was 7.4%. Upon presentation to us, she was taking tirzepatide 10 mg once weekly, insulin glargine 20 units daily, and her weight was 200 lbs. (BMI 29.5 kg/m2). C-peptide was at 2.1 ng/mL with a glucose of 174 mg/dL, HbA1c was 7.1%, and antibody testing (GAD65, IA-2, ZnT8) was negative. She underwent genetic testing that revealed a heterozygous pathogenic variant c.188del(p.P63Rfs*60) in exon 1 of the PDX1 gene (NM_000209.3) confirming PDX1-MODY. Her fecal elastase was >500 mcg/g (>200 mcg/g considered normal) with no evidence of pancreatic agenesis on CT. Tirzepatide was increased to 12.5 mg once weekly, insulin was discontinued, and glipizide extended release (ER) was initiated and titrated to 7.5 mg once daily. She lost an additional 39 lbs. in 8 months (weight 161 lbs.), BMI of 24.5 kg/m2), and her HbA1c improved to 6.0%. This report demonstrates that tirzepatide is potentially effective in patients with a heterozygous PDX1-MODY c.188del(p.P63Rfs*60) mutation without pancreatic agenesis.

References:
1). Fajans SS, Bell GI, Paz VP, et al. Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Trans Res. 2010;156(1):7-14. PMID: 20621032.
2). Caetano LA, Santana LS, Costa-Riquetto AD, et al. PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease. Clin Genet. 2018;93(2):382-386. PMID: 28436541.

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