Novel Approach for Treating Diabetes in a Patient With the Heterozygous Pathogenic Variant R46Q in the Insulin Gene

• Published in: JCEM case reports Vol. 2; no. 7; p. luae134
• Main Authors: Laugesen, Kristina, Gregersen, Søren, Støy, Julie
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2024
• Subjects: Case Report; insulin gene mutation; monogenetic diabetes; metformin; sodium-glucose cotransporter 2 inhibitor; MODY; maturity-onset diabetes of the young
• ISSN: 2755-1520; 2755-1520
• DOI: 10.1210/jcemcr/luae134

Maturity-onset diabetes of the young (MODY) is a monogenic disorder of glucose homeostasis with several subtypes, each defined by a distinct genetic etiology. Heterozygous pathogenic variants in the insulin gene are rare causes of MODY, and optimal treatment strategies remain uncertain. Herein we describe a patient with diabetes caused by the heterozygous pathogenic variant R46Q in the insulin gene and the glycemic response to selected antidiabetic treatment regimens. The R46Q pathogenic variant leads to secretion of both mutant and wild-type insulin. In vitro, the mutant insulin is associated with a lower insulin-receptor affinity compared with wild-type insulin and a decline in wild-type insulin secretion. In our patient, treatment with a combination of long- and short-acting insulin led to a decline in hemoglobin A1C (HbA1c), although not to the recommended target. A shift to metformin and subsequent add-on of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) resulted in HbA1c levels of less than 7% (53 mmol/mol) and durable glycemic control. Continuous glucose monitoring and oral glucose tolerance tests confirmed that treatment with metformin and SGLT2i was superior to treatment with insulin. In conclusion, diabetes caused by the pathogenic variant R46Q in the insulin gene may be effectively treated with noninsulin.