Effect of SGLT2 inhibition on Glucosuria During a Hyperglycemic Clamp in HNF1A-MODY (MODY3) and Type 2 Diabetes

Résumé fourni par la source

Objective: Pathogenic variants of HNF1A cause maturity-onset diabetes of the young type 3 (HNF1A-MODY). Individuals with HNF1A-MODY are primarily treated with sulfonylureas, while little is known about the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in HNF1A-MODY. Interestingly, HNF1A-MODY is associated with increased glucosuria that has been attributed to lower expression of SGLT2 as observed in HNF1A knockout mice. Here, we investigated the impact of acute SGLT2 inhibition on glucosuria in individuals with HNF1A-MODY and type 2 diabetes, respectively. Research Design and Methods: In a randomized, double-blind, crossover study, individuals with HNF1A-MODY and type 2 diabetes underwent two three-step hyperglycemic clamps targeted at one-hour periods of 10, 14, and 18 mM glucose with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo administrated 2 hours before clamp procedures). Results: Eleven individuals with HNF1A-MODY (age [mean ± SD]: 49 ± 15 years, GFR: 113 ± 18 mL/min) and ten individuals with type 2 diabetes (age: 63 ± 7 years, GFR: 103 ± 27 mL/min) were included. During the 3-hour hyperglycemic clamp, SGLT2 inhibition increased urinary glucose excretion in both groups (HNF1A-MODY: 24.5 g [95% CI 20.6; 28.3], type 2 diabetes: 23.5 g [95% CI 20.4; 26.5]). The effect of SGLT2 inhibition was not significantly different between the groups (1.0 g [95% CI -3.5; 5.6], P = 0.6). Conclusions: The robust effect of SGLT2 inhibition on urinary glucose excretion in individuals with HNF1A-MODY observed here point to SGLT2 inhibition as a relevant glucose-lowering treatment strategy in people with HNF1A-MODY.

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