Highlights
- •SGLT2i treatment results in beneficial metabolic adaptations in non-diabetic, insulin resistant individuals
- •SGLT2i treatment led to lower 24-h glucose levels and higher free fatty acid and ß-hydroxybutyrate levels
- •SGLT2i treatment improved skeletal muscle mitochondrial oxidative capacity
- •SGLT2i treatment did not significantly affect hepatic glycogen levels, but seemed to affect muscle glycogen levels
Abstract
Aims/hypothesis
Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus
patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic
adaptations. It is so far unknown if SGLT2i exerts beneficial metabolic effects in
prediabetic insulin resistant individuals, yet this is of interest since SGLT2is also
reduce the risk for progression of heart failure and chronic kidney disease in patients
without diabetes.
Methods
Fourteen prediabetic insulin resistant individuals (BMI: 30.3 ± 2.1 kg/m2; age: 66.3 ± 6.2 years) underwent 2-weeks of treatment with dapagliflozin (10 mg/day)
or placebo in a randomized, placebo-controlled, cross-over design. Outcome parameters
include 24-hour and nocturnal substrate oxidation, and twenty-four-hour blood substrate
and insulin levels. Hepatic glycogen and lipid content/composition were measured by
MRS. Muscle biopsies were taken to measure mitochondrial oxidative capacity and glycogen
and lipid content.
Results
Dapagliflozin treatment resulted in a urinary glucose excretion of 36 g/24-h, leading
to a negative energy and fat balance. Dapagliflozin treatment resulted in a higher
24-hour and nocturnal fat oxidation (p = 0.043 and p = 0.039, respectively), and a
lower 24-hour carbohydrate oxidation (p = 0.048). Twenty-four-hour plasma glucose
levels were lower (AUC; p = 0.016), while 24-hour free fatty acids and nocturnal β-hydroxybutyrate
levels were higher (AUC; p = 0.002 and p = 0.012, respectively) after dapagliflozin
compared to placebo. Maximal mitochondrial oxidative capacity was higher after dapagliflozin
treatment (dapagliflozin: 87.6 ± 5.4, placebo: 78.1 ± 5.5 pmol/mg/s, p = 0.007). Hepatic
glycogen and lipid content were not significantly changed by dapagliflozin compared
to placebo. However, muscle glycogen levels were numerically higher in the afternoon
in individuals on placebo (morning: 332.9 ± 27.9, afternoon: 368.8 ± 13.1 nmol/mg),
while numerically lower in the afternoon on dapagliflozin treatment (morning: 371.7 ± 22.8,
afternoon: 340.5 ± 24.3 nmol/mg).
Conclusions/interpretation
Dapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted
in significant metabolic adaptations in whole-body and skeletal muscle substrate metabolism
despite being weight neutral. Dapagliflozin improved fat oxidation and ex vivo skeletal
muscle mitochondrial oxidative capacity, mimicking the effects of calorie restriction.
Trial registration
ClinicalTrials.gov NCT03721874.
Keywords
Abbreviations:
AU (arbitrary units), AUC (area under the curve), EGP (endogenous glucose production), ESM (electronic supplementary material), MRS (magnetic resonance spectroscopy), MTPRT (Macronutrient and Taste Preference Ranking Task), MUFA (monounsaturated fatty acids), NAFLD (non-alcoholic fatty liver disease), OGIS (oral glucose insulin sensitivity), PUFA (polyunsaturated fatty acids), RER (respiratory exchange ratio), SFA (saturated fatty acids), SGLT2 (sodium-glucose cotransporter 2), SGLT2i (sodium-glucose cotransporter 2 inhibitor), T2DM (type 2 diabetes mellitus)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 30, 2022
Accepted:
December 26,
2022
Received:
November 1,
2022
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