Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes

Jens Hohwü Voigt; Katrine M Lauritsen; Steen Bønløkke Pedersen; Troels K Hansen; Niels Møller; Niels Jessen; Marcello C Laurenti; Chiara Dalla Man; Adrian Vella; Lars C Gormsen; Esben Søndergaard

doi:10.1111/bcpt.13991

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes

Jens Hohwü Voigt, Katrine M Lauritsen, Steen Bønløkke Pedersen, Troels K Hansen, Niels Møller, Niels Jessen, Marcello C Laurenti, Chiara Dalla Man, Adrian Vella, Lars C Gormsen, Esben Søndergaard

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

3 Citations (Scopus)

Abstract

Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [ ¹⁸F]FDG positron emission tomography/computed tomography (PET/CT) and [ ¹¹C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10 ⁻⁹ min ⁻¹, p < 0.01) and glucose effectiveness (2.6 × 10 ⁻² ± 0.3 × 10 ⁻² vs. 2.4 × 10 ⁻² ± 0.3 × 10 ⁻², dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.

Original language	English
Journal	Basic & Clinical Pharmacology & Toxicology
Volume	134
Issue	5
Pages (from-to)	643-656
Number of pages	14
ISSN	1742-7835
DOIs	https://doi.org/10.1111/bcpt.13991
Publication status	Published - May 2024

Keywords

SGLT2 inhibition
beta-cell function
glucose tolerance
glucose uptake
lipid uptake
type 2 diabetes
Benzhydryl Compounds
Humans
Insulin Resistance
Positron Emission Tomography Computed Tomography
Diabetes Mellitus, Type 2/drug therapy
Fatty Acids, Nonesterified
Insulin/metabolism
Sodium-Glucose Transporter 2/metabolism
Glucose/metabolism
Muscle, Skeletal
Glucosides

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10.1111/bcpt.13991Licence: CC BY-NC-ND

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Voigt, J. H., Lauritsen, K. M., Pedersen, S. B., Hansen, T. K., Møller, N., Jessen, N., Laurenti, M. C., Dalla Man, C., Vella, A., Gormsen, L. C., & Søndergaard, E. (2024). Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes. Basic & Clinical Pharmacology & Toxicology, 134(5), 643-656. https://doi.org/10.1111/bcpt.13991

@article{1df657b407c5496c9e4303a83b65c5bf,

title = "Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes",

abstract = "Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [ 18F]FDG positron emission tomography/computed tomography (PET/CT) and [ 11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10 −9 min −1, p < 0.01) and glucose effectiveness (2.6 × 10 −2 ± 0.3 × 10 −2 vs. 2.4 × 10 −2 ± 0.3 × 10 −2, dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.",

keywords = "SGLT2 inhibition, beta-cell function, glucose tolerance, glucose uptake, lipid uptake, type 2 diabetes, Benzhydryl Compounds, Humans, Insulin Resistance, Positron Emission Tomography Computed Tomography, Diabetes Mellitus, Type 2/drug therapy, Fatty Acids, Nonesterified, Insulin/metabolism, Sodium-Glucose Transporter 2/metabolism, Glucose/metabolism, Muscle, Skeletal, Glucosides",

author = "Voigt, {Jens Hohw{\"u}} and Lauritsen, {Katrine M} and Pedersen, {Steen B{\o}nl{\o}kke} and Hansen, {Troels K} and Niels M{\o}ller and Niels Jessen and Laurenti, {Marcello C} and {Dalla Man}, Chiara and Adrian Vella and Gormsen, {Lars C} and Esben S{\o}ndergaard",

note = "{\textcopyright} 2024 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).",

year = "2024",

month = may,

doi = "10.1111/bcpt.13991",

language = "English",

volume = "134",

pages = "643--656",

journal = "Basic & Clinical Pharmacology & Toxicology",

issn = "1742-7835",

publisher = "Wiley-Blackwell Publishing Ltd.",

number = "5",

}

Voigt, JH, Lauritsen, KM, Pedersen, SB , Hansen, TK , Møller, N , Jessen, N, Laurenti, MC, Dalla Man, C, Vella, A, Gormsen, LC & Søndergaard, E 2024, 'Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes', Basic & Clinical Pharmacology & Toxicology, vol. 134, no. 5, pp. 643-656. https://doi.org/10.1111/bcpt.13991

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes. / Voigt, Jens Hohwü; Lauritsen, Katrine M; Pedersen, Steen Bønløkke et al.
In: Basic & Clinical Pharmacology & Toxicology, Vol. 134, No. 5, 05.2024, p. 643-656.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes

AU - Voigt, Jens Hohwü

AU - Lauritsen, Katrine M

AU - Pedersen, Steen Bønløkke

AU - Hansen, Troels K

AU - Møller, Niels

AU - Jessen, Niels

AU - Laurenti, Marcello C

AU - Dalla Man, Chiara

AU - Vella, Adrian

AU - Gormsen, Lars C

AU - Søndergaard, Esben

N1 - © 2024 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2024/5

Y1 - 2024/5

N2 - Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [ 18F]FDG positron emission tomography/computed tomography (PET/CT) and [ 11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10 −9 min −1, p < 0.01) and glucose effectiveness (2.6 × 10 −2 ± 0.3 × 10 −2 vs. 2.4 × 10 −2 ± 0.3 × 10 −2, dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.

AB - Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [ 18F]FDG positron emission tomography/computed tomography (PET/CT) and [ 11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10 −9 min −1, p < 0.01) and glucose effectiveness (2.6 × 10 −2 ± 0.3 × 10 −2 vs. 2.4 × 10 −2 ± 0.3 × 10 −2, dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.

KW - SGLT2 inhibition

KW - beta-cell function

KW - glucose tolerance

KW - glucose uptake

KW - lipid uptake

KW - type 2 diabetes

KW - Benzhydryl Compounds

KW - Humans

KW - Insulin Resistance

KW - Positron Emission Tomography Computed Tomography

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Fatty Acids, Nonesterified

KW - Insulin/metabolism

KW - Sodium-Glucose Transporter 2/metabolism

KW - Glucose/metabolism

KW - Muscle, Skeletal

KW - Glucosides

U2 - 10.1111/bcpt.13991

DO - 10.1111/bcpt.13991

M3 - Journal article

C2 - 38409617

SN - 1742-7835

VL - 134

SP - 643

EP - 656

JO - Basic & Clinical Pharmacology & Toxicology

JF - Basic & Clinical Pharmacology & Toxicology

IS - 5

ER -

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes

Abstract

Keywords

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