Yvo J M Op den Kamp1, Marlies de Ligt1, Bas Dautzenberg1, Esther Kornips1, Russell Esterline2, Matthijs K C Hesselink1, Joris Hoeks1, Vera B Schrauwen-Hinderling1,3, Bas Havekes4, Jan Oscarsson5, Esther Phielix1, Patrick Schrauwen6. 1. Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands. 2. BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD. 3. Radiology and Nuclear Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands. 4. Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands. 5. BioPharmaceuticals R&D, Late-Stage Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden. 6. Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands p.schrauwen@maastrichtuniversity.nl.
Abstract
OBJECTIVE: SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments. RESULTS: Evaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m2, and HbA1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, P < 0.0001). Insulin-induced suppression of EGP (-1.71 [-2.75, -0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (-21.93% [-39.31, -4.54], P = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (-0.11 [-0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (-0.010 [-0.017, -0.002], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (-20.51 [-27.90, -13.12] g/day). CONCLUSIONS: Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism.
OBJECTIVE: SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments. RESULTS: Evaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m2, and HbA1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, P < 0.0001). Insulin-induced suppression of EGP (-1.71 [-2.75, -0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (-21.93% [-39.31, -4.54], P = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (-0.11 [-0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (-0.010 [-0.017, -0.002], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (-20.51 [-27.90, -13.12] g/day). CONCLUSIONS: Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism.
Authors: Aino Latva-Rasku; Miikka-Juhani Honka; Joel Kullberg; Nina Mononen; Terho Lehtimäki; Juha Saltevo; Anna K Kirjavainen; Virva Saunavaara; Patricia Iozzo; Lars Johansson; Jan Oscarsson; Jarna C Hannukainen; Pirjo Nuutila Journal: Diabetes Care Date: 2019-03-18 Impact factor: 19.112
Authors: Per Lundkvist; Maria J Pereira; Prasad G Kamble; Petros Katsogiannos; Anna Maria Langkilde; Russell Esterline; Eva Johnsson; Jan W Eriksson Journal: J Clin Endocrinol Metab Date: 2019-01-01 Impact factor: 5.958
Authors: Jakob Wefers; Niels J Connell; Ciarán E Fealy; Charlotte Andriessen; Vera de Wit; Dirk van Moorsel; Esther Moonen-Kornips; Johanna A Jörgensen; Matthijs K C Hesselink; Bas Havekes; Joris Hoeks; Patrick Schrauwen Journal: Mol Metab Date: 2020-07-11 Impact factor: 7.422
Authors: Kristina Wallenius; Tobias Kroon; Therese Hagstedt; Lars Löfgren; Maria Sörhede-Winzell; Jeremie Boucher; Daniel Lindén; Nicholas D Oakes Journal: J Lipid Res Date: 2022-02-02 Impact factor: 5.922
Authors: Jack A Sargeant; James A King; Thomas Yates; Emma L Redman; Danielle H Bodicoat; Sudesna Chatterjee; Charlotte L Edwardson; Laura J Gray; Benoit Poulin; Ghazala Waheed; Helen L Waller; David R Webb; Scott A Willis; John P H Wilding; Kamlesh Khunti; David J Stensel; Melanie J Davies Journal: Diabetes Obes Metab Date: 2022-05-13 Impact factor: 6.408