Abstract
Monogenic Diabetes (MODY) results from mutations or changes in a single gene, and currently account for about 1 to 4% of all cases of diabetes (1). Our group has previously published on the successful use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in three consecutive generations of a family with an HNF1A mutation (MODY-3) (2). Although GLP-1 RA therapy has been studied in patients with HNF1A mutations (MODY-3) (3), it has not been studied in patients with HNF4A mutations (MODY-1). In this father-son cohort, we demonstrate successful use of GLP-1 RA therapy in two patients with c.790:1 bp deletion of G; codon:264 mutations of HNF4A. The son first presented with neonatal hypoglycemia, then later developed diabetes and presented to our clinic at age 20, when genetic testing was performed and confirmatory for an HNF4A mutation. He was prescribed glimepiride and titrated to 4 mg twice daily, and two years later, his hemoglobin A1c (HbA1c) rose to 8.7%. He was switched to semaglutide 0.25 mg once weekly and was titrated to a maximum dose of 1 mg weekly over 8 weeks. The patient reports improvement in his post-prandial blood glucose values at this time, but HbA1c has not yet been repeated. The father had been diagnosed with monogenic diabetes in his early 20s and had been on sulfonylurea therapy until age 40, at which time he was transitioned to a regimen of long- and short-acting insulin therapy. Thereafter, he presented to our clinic in July, 2018 with a HbA1c of 9.6% and was transitioned to long-acting insulin once daily and liraglutide 0.6 mg once daily which was subsequently titrated to 1.8 mg once daily over 3 weeks. The patient tolerated this well and has been off short acting insulin since December 2018, with notable improvement in his HbA1c to 5.9% and marked improvement in his post-prandial glycemic control. To our knowledge this is the first report demonstrating the benefits of GLP-1 RA therapy in patients with the HNF4A mutations (MODY-1). Based on this report, it appears that GLP-1 RA therapy could be an effective therapy in patients with MODY-1.
1). Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. The Journal of Clinical Endocrinology and Metabolism. 2013;98(10):4055–4062.
2). Maricor Docena, Charles Faiman, Christine Stanley, and Kevin Pantalone (2014) Mody-3: Novel HNF1A Mutation and the Utility of Glucagon-Like Peptide (GLP)-1 Receptor Agonist Therapy. Endocrine Practice: February 2014, Vol. 20, No. 2, pp. 107–111.
3). Ostoft SH, Bagger JI, Hansen T, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7):1797–17805.
Heterozygous RFX6 protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance
