Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes caused by a mutation in a single gene. The frequency of mutation carriers for HNF4A-MODY has been reported to be 1.2% (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-MODY (2). Although GLP-1 RA therapy has been studied in patients with HNF1A-MODY (3), it has not been studied in patients with HNF4A-MODY. 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-MODY. He was prescribed glimepiride and titrated to 4 mg twice daily, and 2 years later his hemoglobin A1c (HbA1c) rose to 8.7%. He was switched to semaglutide 0.25 mg once weekly, which was titrated to a maximum dose of 1 mg weekly over 8 weeks. The patient’s HbA1c improved to 6.2% after 6 months of GLP-1 RA therapy and he reported fewer hypoglycemic events. 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 with an HbA1c of 9.6% and was transitioned to once-daily long-acting insulin in combination with once-daily liraglutide, initiated at 0.6 mg and subsequently titrated to 1.8 mg over 3 weeks. The patient tolerated this therapy well and has been off short-acting insulin for more than 1 year, with notable improvement in his HbA1c to 5.9% and fewer hypoglycemic events.
To our knowledge, this is the first report demonstrating the benefits of GLP-1 RA therapy in patients with the HNF4A-MODY. GLP-1 receptor activation on β-cells results in stimulation of adenylate cyclase and subsequent elevation of cAMP. Both cAMP and activated protein kinase A may influence secretory events distal to the generation of ATP by glucose metabolism (4,5). Our hypothesis is similar to that proposed by Østoft et al. (3), in which a GLP-1 RA is likely capable of bypassing the decreased concentrations of ATP associated with HNF1A-MODY and HNF4A-MODY and thereby stimulates the secretion of insulin and reduces postprandial glucose values. Based on this report, it appears that GLP-1 RA therapy could be an effective therapy to consider in patients with HNF4A-MODY.
Duality of Interest. K.M.P. receives consulting fees from Bayer, Inc., Novo Nordisk, Merck, and Sanofi and speaker fees from AstraZeneca, Novo Nordisk, and Merck. K.M.P. is a research investigator for Novo Nordisk and receives research support from Merck. A.E.M. receives speaker fees from Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. D.T.B. wrote the manuscript. Z.T., K.M.P., and A.E.M. edited and revised the manuscript. D.T.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. An abstract on this study, which had been accepted for presentation at ENDO 2020, was published in the April-May 2020 supplemental issue of the Journal of the Endocrine Society.