title: Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes.
abstract: Insulin resistance is associated with mitochondrial 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.
  
  
  
  The study randomized 18 individuals with T2DM to 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.
  
  
  
  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.
  
  
  
  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.
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Giuseppe
authors: G
authors: Daniele
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Juan
authors: J
authors: Xiong
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Carolina
authors: C
authors: Solis-Herrera
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Aurora
authors: A
authors: Merovci
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Roy
authors: R
authors: Eldor
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Devjit
authors: D
authors: Tripathy
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Ralph A
authors: RA
authors: DeFronzo
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors: Luke
authors: L
authors: Norton
authors: Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX abdulghani@uthscsa.edu.
authors: Muhammad
authors: M
authors: Abdul-Ghani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007659:Ketones / Q000097:blood*; D050356:Lipid Metabolism / Q000187:drug effects*; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005960:Glucosides; D007328:Insulin; D007659:Ketones; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D005934:Glucagon; D003404:Creatinine