Inhibition of Renal Glucose Reabsorption: A Novel Strategy for Achieving Glucose Control in Type 2 Diabetes Mellitus |
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| Institution: | 1. Department of surgical, medical, molecular and critical area pathology, university of Pisa, Via Roma 67, 56126 Pisa, Italy;2. Department of medicine, surgery and neuroscience, university of Siena and Fondazione Umberto di Mario-Toscana life science, Viale Bracci 18, 53100 Siena, Italy;3. Department of clinical and experimental medicine, university of Pisa, Pisa, Italy;1. Department of Internal Medicine, Ota&Jinemed Hospital, Istanbul, Turkey;2. Department of Biochemistry, Private Practice, Istanbul, Turkey;1. The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia;2. School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia;3. Department of Preventive Medicine and Public Health, Fukuoka University, Fukuoka, Japan;4. Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada;5. Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK;6. The George Institute for Global Health, University of Oxford, Oxford, UK;7. Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA;8. Phoenix VA Health Care System, Phoenix, AZ, USA;9. Ann Arbor VA Health Care System, Ann Arbor, MI, USA;10. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA;1. Cardiovascular Division, Department of Medicine Brigham and Women''s Hospital, Boston, MA, United States;2. Kidney and Hypertension Section, Joslin Diabetes Center, Boston, MA, United States;3. Danielle Alberti Memorial Centre for Diabetes Complications, Baker Heart Research Institute, Melbourne, Australia;4. Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, United States;1. Department of Internal Medicine IV (Nephrology and Hypertension), Medical University, Innsbruck, Austria;2. Division of Nephrology, Würzburg University Clinic, Würzburg, Germany;3. Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA;4. Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut, USA;5. Boehringer Ingelheim International GmbH, Ingelheim, Germany;6. Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia;7. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada;8. Department of Medicine and Department of Physiology, Division of Nephrology, University Health Network, University of Toronto, Canada;1. TIMI Study Group, Cardiovascular Division, Brigham and Women''s Hospital, Boston, MA, USA;2. The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine, Jerusalem, Israel;3. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan;4. Li Ka Shing Knowledge Institute, St Michael''s Hospital, University of Toronto, Toronto, ON, Canada;5. Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA;6. Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK |
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| Abstract: | ObjectiveTo review the renal handling of glucose and the role of inhibition of a sodium-glucose transporter (SGLT2) in the treatment of type 2 diabetes mellitus (T2DM).MethodsWe review the published data about (1) the filtration and reabsorption of glucose by the kidneys in normal subjects and patients with diabetes; (2) the deleterious effects of long-term elevation of plasma glucose levels on muscle and hepatic insulin sensitivity and beta cell function (that is, glucotoxicity); (3) the effect of inhibiting the SGLT2 transporter on the induction of glycosuria, glycemic control, insulin resistance, and beta cell dysfunction in animals and humans with diabetes; and (4) the safety of SGLT2 inhibition as a therapeutic modality to treat human T2DM.ResultsStudies in animal models of diabetes document the efficacy of the SGLT2 inhibitors in inducing glycosuria, decreasing both fasting and postprandial glucose levels, augmenting beta cell function, and enhancing hepatic and muscle insulin sensitivity. In human T2DM, short-term studies with dapagliflozin (12 weeks) and sergliflozin (2 weeks) have confirmed the efficacy of these agents in improving glycemic control. Excessive urinary electrolyte or water loss, plasma electrolyte disturbances, and hypoglycemia were not observed.ConclusionSGLT2 inhibitors represent a promising approach to the treatment of T2DM. They have the potential to be used as monotherapy, as well as in combination with all approved antidiabetic agents. Because their mechanism of action is independent of the severity of beta cell dysfunction or insulin resistance, efficacy should not decline with progressive beta cell failure or in the presence of severe insulin resistance. (Endocr Pract. 2008;14:782-790) |
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