1. Type 2 diabetes Derek LeRoith

2. Insulin Resistance: A Core Defect of The Metabolic Syndrome Insulin Resistance Dyslipidemia Obesity Hypertension Dysfibrinolysis Hyperglycemia Endothelial Dysfunction Macrovascular Disease Glucose Intolerance Adapted from McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718; Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G.

3. Chris Rhodes Ph.D. PNRI, Seattle, WA. 0 10 20 Fasting Glucose (mM/L) 0 200 400 Fasting Insulin (pmol/L) 0 500 1000 Plasma FFA ( µmol/L) 50 100 150 ß-Cell Mass (% change) 0 2.5 5 Amyloid Deposit (% Pancreatic Area) INCREASING AGE AND/0R DEGREE OF OBESITY (increasing peripheral insulin resistance) Fasting Plasma Glucose Fasting Serum Insulin Circulating FFA Pancreatic ß-Cell Mass Islet Amyloid Deposit NormalAdaptation Glucose Intolerant Type-2 Diabetes The Pathogenesis of Obesity-linked Type-2 Diabetes [TIMM (2002) 8: 375-384]

4. Chris Rhodes Ph.D. PNRI, Seattle, WA. Type-2 Diabetes - A Question of Balance PERIPHERAL INSULIN RESISTANCE ß-CELL MASS & FUNCTION Non-Diabetic State PERIPHERAL INSULIN RESISTANCE ß-CELL MASS & FUNCTION Diabetic State

5. Regulation of Islet  -Cell Mass and Function

6. Mechanisms of  cell failure in T2D Christopher J. Nolan

7. Mechanisms of  cell compensation for insulin resistance Christopher J. Nolan

8.  Cell Compensation: Christopher J. Nolan 1.Expansion of  cell mass 2.Enhanced insulin biosynthesis 3.Increased responsiveness of nutrient-secretion coupling

9. Christopher J. Nolan Expansion of  Cell Mass GlucoseFFAGLP-1

10. Enhanced Insulin Biosynthesis

11. Increased Responsiveness

14. Biphasic Insulin Secretion

15. Glucose Ins/IGF Acetylcholine Kristina M. Utzschneider

16. Christopher J. Nolan Susceptible  Cells Genetic and acquired defects: Glucolipo-detoxification Mitochondrial function Anaplerosis/cataplerosis AMPK/Mal-CoA TG/FFA cycling Insulin biosynthesis Coupling mechanisms Exocytosis Intrauterine factors

17. I. E.T. van den Berg Diacylglycerol Triglycerides Fatty Acids Acylated Proteins K ATP -independent Insulin Secretion carnitine palmitoyltransferase-1 (CPT 1)

18. AMPK/Malonyl-CoA Signaling Network

19. TG/FFA Cycling in Beta Cells

20. IntraUterine Growth Retardation (IUGR) REBECCA A. SIMMONS IUGR

21. Christopher J. Nolan  Cells dysfunction IGT and early T2D T2D: initiation roles Gluolipotoxicity Lipotoxicity Oxidative stress/ROS Dysregulated TG/FFA cycling Altered AMPK/Mal-CoA  Cell exhaustion ER stress

22. Lipotoxicity

23. Glucolipotoxicity in Beta Cells Marc Prentki

24. F.M. Ashcroft Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress

25. Christopher J. Nolan  Cell failure Overt and late T2D T2D: progression roles Gluolipotoxicity Glucotoxicity Oxidative stress/ROS Islet inflammation Protein O-glycosylation AGEs Dedifferentiation Amyloid deposition Apoptosis

26. Michael Brownlee Four Pathways of Hyperglycaemic Damage

27. Michael Brownlee Aldose Reductase and The Polyol Pathway Decreased levels of GSHIncreased oxidative stress

28. Michael Brownlee Production of Advanced Glycation End- Product (AGE) Precursors

29. Michael Brownlee Consequences of Hyperglycaemia-Induced Activation of Protein Kinase C (PKC)

30. Michael Brownlee The Hexosamine Pathway