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

Henrik Maagensen; Johanne S Jensen; Stine O Høyerup; Anne C B Thuesen; Jesper Krogh; Jens J Holst; Henrik Vestergaard; Peter Rossing; Torben Hansen; Filip K Knop; Sofie Hædersdal; Tina Vilsbøll

doi:10.2337/dc25-0737

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

Henrik Maagensen^*, Johanne S Jensen, Stine O Høyerup, Anne C B Thuesen, Jesper Krogh, Jens J Holst, Henrik Vestergaard, Peter Rossing, Torben Hansen, Filip K Knop, Sofie Hædersdal, Tina Vilsbøll^*

^*Corresponding author for this work

2 Citations (Scopus)

Abstract

OBJECTIVE: 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.

RESEARCH DESIGN AND METHODS: 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).

RESULTS: 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).

CONCLUSIONS: 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.

Original language	English
Journal	Diabetes Care
Volume	48
Issue number	9
Pages (from-to)	1536-1544
Number of pages	9
ISSN	1935-5548
DOIs	https://doi.org/10.2337/dc25-0737
Publication status	Published - 1 Sept 2025

Keywords

Adult
Benzhydryl Compounds/therapeutic use
Cross-Over Studies
Diabetes Mellitus, Type 2/drug therapy
Double-Blind Method
Female
Glucose Clamp Technique
Glucosides/therapeutic use
Glycosuria/drug therapy
Hepatocyte Nuclear Factor 1-alpha/genetics
Humans
Male
Middle Aged
Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Sodium-Glucose Transporter 2/metabolism

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@article{dfdcf7c0f893428b84b0c8c780b87aa0,

title = "Effect of SGLT2 Inhibition on Glucosuria During a Hyperglycemic Clamp in HNF1A-MODY (MODY3) and Type 2 Diabetes",

abstract = "OBJECTIVE: 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.RESEARCH DESIGN AND METHODS: 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).RESULTS: 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).CONCLUSIONS: 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.",

keywords = "Adult, Benzhydryl Compounds/therapeutic use, Cross-Over Studies, Diabetes Mellitus, Type 2/drug therapy, Double-Blind Method, Female, Glucose Clamp Technique, Glucosides/therapeutic use, Glycosuria/drug therapy, Hepatocyte Nuclear Factor 1-alpha/genetics, Humans, Male, Middle Aged, Sodium-Glucose Transporter 2 Inhibitors/therapeutic use, Sodium-Glucose Transporter 2/metabolism",

author = "Henrik Maagensen and Jensen, \{Johanne S\} and H{\o}yerup, \{Stine O\} and Thuesen, \{Anne C B\} and Jesper Krogh and Holst, \{Jens J\} and Henrik Vestergaard and Peter Rossing and Torben Hansen and Knop, \{Filip K\} and Sofie H{\ae}dersdal and Tina Vilsb{\o}ll",

note = "{\textcopyright} 2025 by the American Diabetes Association.",

year = "2025",

month = sep,

day = "1",

doi = "10.2337/dc25-0737",

language = "English",

volume = "48",

pages = "1536--1544",

journal = "Diabetes Care",

issn = "1935-5548",

publisher = "American Diabetes Association",

number = "9",

}

TY - JOUR

T1 - Effect of SGLT2 Inhibition on Glucosuria During a Hyperglycemic Clamp in HNF1A-MODY (MODY3) and Type 2 Diabetes

AU - Maagensen, Henrik

AU - Jensen, Johanne S

AU - Høyerup, Stine O

AU - Thuesen, Anne C B

AU - Krogh, Jesper

AU - Holst, Jens J

AU - Vestergaard, Henrik

AU - Rossing, Peter

AU - Hansen, Torben

AU - Knop, Filip K

AU - Hædersdal, Sofie

AU - Vilsbøll, Tina

PY - 2025/9/1

Y1 - 2025/9/1

N2 - OBJECTIVE: 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.RESEARCH DESIGN AND METHODS: 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).RESULTS: 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).CONCLUSIONS: 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.

AB - OBJECTIVE: 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.RESEARCH DESIGN AND METHODS: 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).RESULTS: 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).CONCLUSIONS: 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.

KW - Adult

KW - Benzhydryl Compounds/therapeutic use

KW - Cross-Over Studies

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Double-Blind Method

KW - Female

KW - Glucose Clamp Technique

KW - Glucosides/therapeutic use

KW - Glycosuria/drug therapy

KW - Hepatocyte Nuclear Factor 1-alpha/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use

KW - Sodium-Glucose Transporter 2/metabolism

UR - https://www.scopus.com/pages/publications/105013857066

U2 - 10.2337/dc25-0737

DO - 10.2337/dc25-0737

M3 - Journal article

C2 - 40608360

SN - 1935-5548

VL - 48

SP - 1536

EP - 1544

JO - Diabetes Care

JF - Diabetes Care

IS - 9

ER -

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

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Keywords

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