Maagensen Henrik, Jensen Johanne S, Høyerup Stine O, Thuesen Anne C B, Krogh Jesper, Holst Jens J, Vestergaard Henrik, Rossing Peter, Hansen Torben, Knop Filip K, Hædersdal Sofie, Vilsbøll Tina
Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetes Care. 2025 Sep 1;48(9):1536-1544. doi: 10.2337/dc25-0737.
Pathogenic variants of HNF1A cause maturity-onset diabetes of the young type 3 (HNF1A-MODY; also known as MODY3). Individuals with HNF1A-MODY are primarily treated with sulfonylureas; however, little is known about the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in HNF1A-MODY. Interestingly, HNF1A-MODY is associated with increased glucosuria, which has been attributed to lower expression of SGLT2 as observed in HNF1A-knockout mice. We investigated the impact of acute SGLT2 inhibition on glucosuria in individuals with HNF1A-MODY or type 2 diabetes.
In a randomized, double-blind, crossover study, individuals with HNF1A-MODY or type 2 diabetes underwent two three-step hyperglycemic clamps targeted at 1-h periods of 10, 14, and 18 mmol/L glucose with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo administrated 2 h before clamp procedures).
Eleven individuals with HNF1A-MODY (age [mean ± SD] 49 ± 15 years; glomerular filtration rate [GFR; mean ± SD] 113 ± 18 mL/min) and 10 individuals with type 2 diabetes (age 63 ± 7 years; GFR 103 ± 27 mL/min) were included. During the 3-h 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).
The robust effect of SGLT2 inhibition on urinary glucose excretion in participants with HNF1A-MODY points to SGLT2 inhibition as a relevant glucose-lowering treatment strategy in individuals with HNF1A-MODY.
肝细胞核因子1α（HNF1A）的致病变异会导致青年发病型3型糖尿病（HNF1A-MODY，也称为MODY3）。HNF1A-MODY患者主要接受磺脲类药物治疗；然而，关于钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂对HNF1A-MODY的影响知之甚少。有趣的是，HNF1A-MODY与糖尿增加有关，这在HNF1A基因敲除小鼠中表现为SGLT2表达降低。我们研究了急性抑制SGLT2对HNF1A-MODY患者或2型糖尿病患者糖尿的影响。
在一项随机、双盲、交叉研究中，HNF1A-MODY患者或2型糖尿病患者接受了两次三步高血糖钳夹试验，目标血糖浓度在1小时内分别维持在10、14和18 mmol/L，试验过程中有无急性SGLT2抑制（在钳夹操作前2小时给予25 mg恩格列净或安慰剂）。
纳入了11例HNF1A-MODY患者（年龄[均值±标准差]49±15岁；肾小球滤过率[GFR；均值±标准差]113±18 mL/min）和10例2型糖尿病患者（年龄63±7岁；GFR 103±27 mL/min）。在3小时的高血糖钳夹试验中，抑制SGLT2使两组患者的尿糖排泄均增加（HNF1A-MODY组：24.5 g[95%置信区间20.6，28.3]；2型糖尿病组：23.5 g[95%置信区间20.4，26.5]）。两组间SGLT2抑制的效果无显著差异（1.0 g[95%置信区间-3.5，5.6]；P = 0.6）。
SGLT2抑制对HNF1A-MODY参与者尿糖排泄有显著作用，这表明SGLT2抑制是HNF1A-MODY患者一种有效的降糖治疗策略。
