Dapagliflozin Lowers Plasma Glucose Concentration and Improves β-Cell Function

• Published in: The journal of clinical endocrinology and metabolism Vol. 100; no. 5; pp. 1927 - 1932
• Main Authors: Merovci, Aurora, Mari, Andrea, Solis, Carolina, Xiong, Juan, Daniele, Giuseppe, Chavez-Velazquez, Alberto, Tripathy, Devjit, Urban McCarthy, Scheherezada, Abdul-Ghani, Muhammad, DeFronzo, Ralph A.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.05.2015; Copyright by The Endocrine Society; Endocrine Society
• Subjects: Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Beta cells; Blood Glucose - drug effects; C-Peptide - blood; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Glucose; Glucose tolerance; Glucose Tolerance Test; Glucosides - pharmacology; Glucosides - therapeutic use; Humans; Hyperglycemia; Hyperglycemia - blood; Hyperglycemia - drug therapy; Hyperglycemia - physiopathology; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin - blood; Insulin resistance; Insulin-Secreting Cells - drug effects; Male; Middle Aged; Original; Peptides; Placebos; Plasma; Treatment Outcome
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2014-3472

Background: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.Research Design and Methods: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.Results: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.Conclusion: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.