title: Dapagliflozin lowers plasma glucose concentration and improves β-cell function.
abstract: β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-cell function in T2DM individuals.
  
  
  
  Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (OGTT) and insulin clamp were performed before and after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured during the OGTT.
  
  
  
  Dapagliflozin significantly lowered both the fasting and 2-hour plasma glucose concentrations and the incremental area under the plasma glucose concentration curve (ΔG0-120) during OGTT by -33 ± 5 mg/dL, -73 ± 9 mg/dL, and -60 ± 12 mg/dL · min, respectively, compared to -13 ± 9, -33 ± 13, and -18 ± 9 reductions in placebo-treated subjects (both P < .01). The incremental area under the plasma C-peptide concentration curve tended to increase in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects. Thus, ΔC-Pep0-120/ΔG0-120 increased significantly in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects (0.019 ± 0.005 vs 0.002 ± 0.006; P < .01). Dapagliflozin significantly improved whole-body insulin sensitivity (insulin clamp). Thus, β-cell function, measured as ΔC-Pep0-120/ ΔG0-120 ÷ insulin resistance, increased by 2-fold (P < .01) in dapagliflozin-treated vs placebo-treated subjects.
  
  
  
  Lowering the plasma glucose concentration with dapagliflozin markedly improves β-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on β-cell function.
authors.affiliation: Division of Diabetes (A.Me., C.S., G.D., A.C.-V., D.T., S.U.M., M.A.-G., R.A.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; and Consiglio Nazionale delle Ricerche Institute of Biomedical Engineering (A.Ma.), 35127 Padova, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Merovci
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Carolina
authors.initials: C
authors.lastname: Solis-Herrera
authors.forename: Juan
authors.initials: J
authors.lastname: Xiong
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.forename: Alberto
authors.initials: A
authors.lastname: Chavez-Velazquez
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.forename: Scheherezada
authors.initials: S
authors.lastname: Urban McCarthy
authors.forename: Muhammad
authors.initials: M
authors.lastname: Abdul-Ghani
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects*; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D002096:C-Peptide; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; C529054:dapagliflozin