1. Part 7

2. GLUT2 AMG Uptake NGTT2DMNGTT2DM AMG=methyl-  -D-[U 14 C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54:3427-3434. SGLT2 NGTT2DM 0 2 6 8 0 500 1000 1500 2000 Normalized Glucose Transporter Levels CPM Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes P<0.05 4

3. The Ominous Octet Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect

4. Lower Posterior Hypothalamus Magnitude of Inhibitory Response (%) 0 4 8 ObeseLean P<0.01 Time to Max Inhibitory Response (min) 0 4 8 Obese Lean P<0.01 12 Matsuda M, et al. Diabetes. 1999;48:1801-1806. Altered Hypothalamic Function in Response to Glucose Ingestion in Obese Humans

5. 1.Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA 1c 2.Will require multiple drugs in combination to correct multiple pathophysiologic defects 3.Must be started early in the natural history of T2DM, if progressive  -cell dysfunction is to be prevented Treatment of Type 2 Diabetes

6. DPP-4 Inhibitors Sulfonylureas/ Meglitinides  Treatment of Type 2 Diabetes: A Sound Approach Based Upon Its Pathophysiology Metformin TZDs Metformin  GLP-1 analogues Islet  -cell Impaired Insulin Secretion IncreasedLipolysis Decreased Glucose Uptake IncreasedHGP DPP-4=dipeptidyl peptidase-4.

7. Years 8 7 6 0 9 036 9 1215 UKPDS Group. Lancet. 1998;352:854-865. Median HbA 1c (%) UKPDS: Effect of Glibenclamide and Metformin Therapy on HbA 1c IDF Treatment Goal: <6.5% ConventionalGlibenclamideMetformin

8. Kahn SE, et al. N Engl J Med. 2006;355:2427-2443. ADOPT: Effect of Glyburide, Metformin, and Rosiglitazone on HbA 1c HbA 1c (%) Years IDF Treatment Goal: <6.5% 7.6 7.2 6.8 6.4 0 012345 -0.13% (P=0.002) -0.42% (P<0.001) GlyburideMetforminRosiglitazone

9. Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia Unmet Needs in Diabetes Care CVD Risk (Lipid and Hypertension Control)

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

11. 5 mmol/L Fasting Plasma Glucose Muscle  Normal Glucose Homeostasis Fat Liver Pancreas

12. Fasting Plasma Glucose Pathophysiology of Type 2 Diabetes 10 mmol/L Islet  -cell Impaired Insulin Secretion Insulin Resistance Increased HGP 5 mmol/L