Introduction & Objective: Pathogenic variants in HNF1A cause maturity-onset diabetes of the young type 3 (HNF1A-MODY, MODY3) which is associated with relative hyper-glucosuria that has been attributed to lower expression of sodium-glucose cotransporter 2 (SGLT2) in HNF1A knockout mice; questioning SGLT2 as a relevant treatment target in these individuals.

Methods: In a randomized, double-blind, crossover study, persons with MODY3 and type 2 diabetes (T2D) underwent two three-step hyperglycemic clamps targeted at 10, 14, and 18 mmol/L (1h each) with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo 2h before clamp).

Results: Participants characteristics: MODY3 (N = 11, 5 men; age (mean, SD) 49 ± 15 years; BMI 24.5 ± 3.9 kg/m2; HbA1c 6.7 ± 0.7%; eGFR 109 ± 14 mL/min/1.73 m2); T2D (n = 10, 8 men; age 63 ± 7 years; BMI 26.4 ± 3.5 kg/m2; HbA1c 6.7 ± 0.6%; eGFR 93 ± 12 mL/min/1.73 m2). In both groups, SGLT2 inhibition had robust effects on urinary glucose excretion, urine volume, infused glucose, and plasma glucose AUC (data in table). No significant differences between groups in the effects of SGLT2 inhibition were observed.

Conclusion: The similar effects of SGLT2 inhibition in persons with MODY3 and T2D observed here, point to SGLT2 inhibition as a relevant glucose-lowering treatment strategy in persons with MODY3 despite the potentially lower SGLT2 expression.

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Disclosure

H. Maagensen: None. J.S. Jensen: None. S. Offersgaard Høyerup: None. A.B. Thuesen: None. J. Krogh: None. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. T. Hansen: None. F.K. Knop: Advisory Panel; AstraZeneca. Consultant; AstraZeneca. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Advisory Panel; Novo Nordisk A/S. Consultant; Novo Nordisk A/S. Employee; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. Advisory Panel; Sanofi. Speaker's Bureau; Lundbeck. Advisory Panel; Zealand Pharma A/S. Consultant; Zealand Pharma A/S. Research Support; Zealand Pharma A/S. Speaker's Bureau; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. S. Haedersdal: None. T. Vilsbøll: Consultant; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Mundipharma. Advisory Panel; Novo Nordisk, Lilly Diabetes, Sanofi. Speaker's Bureau; Bayer Inc., Gilead Sciences, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. Research Support; Lilly Diabetes.

© 2024 by the American Diabetes Association
2024
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