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Part 1 of 4

Part 1 of 4. Program Editors . Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA. Jaime A. Davidson, MD President, Worldwide Initiative

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Part 1 of 4

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  1. Part 1 of 4

  2. Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA Jaime A. Davidson, MD President, Worldwide Initiative for Diabetes Education Clinical Professor of Internal Medicine Division of Endocrinology University of Texas Southwestern Medical School Dallas, Texas, USA

  3. Faculty Professor Rury Holman Professor of Diabetic Medicine Honorary Consultant Physician Diabetes Trials Unit University of Oxford Oxford, United Kingdom Professor Stefano Del Prato Professor of Endocrinology and Metabolism School of Medicine University of Pisa Pisa, Italy Professor Allan Vaag Chief Physician Steno Diabetes Center Gentofte, Denmark

  4. SGLT2 Inhibition A Novel Treatment Strategy for Type 2 Diabetes

  5. The Ominous Octet Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Neurotransmitter Dysfunction DecreasedIncretin Effect Increased Lipolysis Increased Glucose Reabsorption Increased HGP Decreased Glucose Uptake

  6. Renal Glucose Reabsorption in Type 2 Diabetes • Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule • Renal glucose reabsorption is increased in type 2 diabetes • Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Wright EM, et al. J Intern Med. 2007;261:32-43.

  7. Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 SGLT1 S3 90% 10% No Glucose

  8. Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes SGLT2 GLUT2 AMG Uptake P<0.05 2000 8 P<0.05 1500 6 Normalized Glucose Transporter Levels CPM 1000 4 P<0.05 500 2 0 0 NGT T2DM NGT T2DM NGT T2DM AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

  9. Normal Glucose Homeostasis Pancreas  Fat Liver 5 mmol/L Muscle FastingPlasma Glucose

  10. Pathophysiology of Type 2 Diabetes Impaired Insulin Secretion Insulin Resistance Increased HGP Islet b-cell 10 mmol/L 5 mmol/L FastingPlasma Glucose

  11. Rationale for SGLT2 Inhibitors • Inhibit glucose reabsorption in the renal proximal tubule • Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity • This therapy is simple and nonspecific • Even patients with refractory type 2 diabetes are likely to respond

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