Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes

Giuseppe Daniele, Juan Xiong, Carolina Solis-Herrera, Aurora Merovci, Roy Eldor, Devjit Tripathy, Ralph A Defronzo, Luke Norton, Muhammad A Abdul-ghani

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

OBJECTIVE Insulin resistance is associatedwithmitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DMto dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg · min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg · min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.

Original languageEnglish (US)
Pages (from-to)2036-2041
Number of pages6
JournalDiabetes Care
Volume39
Issue number11
DOIs
StatePublished - Nov 1 2016

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Ketones
Type 2 Diabetes Mellitus
Fats
Glucose
Sodium-Glucose Transporter 2
Insulin Resistance
Adenosine Triphosphate
Insulin
Glucagon
Fasting
Lipids
Indirect Calorimetry
Ketosis
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Glycogen
Placebos
Biopsy
Muscles

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

Cite this

Daniele, G., Xiong, J., Solis-Herrera, C., Merovci, A., Eldor, R., Tripathy, D., ... Abdul-ghani, M. A. (2016). Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care, 39(11), 2036-2041. https://doi.org/10.2337/dc15-2688

Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. / Daniele, Giuseppe; Xiong, Juan; Solis-Herrera, Carolina; Merovci, Aurora; Eldor, Roy; Tripathy, Devjit; Defronzo, Ralph A; Norton, Luke; Abdul-ghani, Muhammad A.

In: Diabetes Care, Vol. 39, No. 11, 01.11.2016, p. 2036-2041.

Research output: Contribution to journalArticle

Daniele, G, Xiong, J, Solis-Herrera, C, Merovci, A, Eldor, R, Tripathy, D, Defronzo, RA, Norton, L & Abdul-ghani, MA 2016, 'Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes', Diabetes Care, vol. 39, no. 11, pp. 2036-2041. https://doi.org/10.2337/dc15-2688
Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care. 2016 Nov 1;39(11):2036-2041. https://doi.org/10.2337/dc15-2688
Daniele, Giuseppe ; Xiong, Juan ; Solis-Herrera, Carolina ; Merovci, Aurora ; Eldor, Roy ; Tripathy, Devjit ; Defronzo, Ralph A ; Norton, Luke ; Abdul-ghani, Muhammad A. / Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. In: Diabetes Care. 2016 ; Vol. 39, No. 11. pp. 2036-2041.
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AB - OBJECTIVE Insulin resistance is associatedwithmitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DMto dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg · min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg · min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.

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