1. How Can We Cure Diabetes? Clayton E. Mathews, Ph. D. Department of Pathology Diabetes Center of Excellence University of Florida College of Medicine

2. What do you need to cure diabetes? 1.What is diabetes? 2.People & More People 3.$ 4.Know how diabetes develops People $ 5.Good/Great Ideas! People $

3. What do you need to cure diabetes? 1.What is diabetes? 2.People & More People 3.$ 4.Know how diabetes develops People $ 5.Good/Great Ideas! People $

4. - + Glucose Production Glucose Absorption Blood Glucose Brain & Nervous System GUT Liver Glucose Uptake Fat Muscle Islet Pancreas Regulation of Blood Glucose

5. - + Glucose Production Glucose Absorption Brain & Nervous System GUT Liver Glucose Uptake Fat Muscle Islet Pancreas Regulation of Blood Glucose Blood Glucose

6. What is Diabetes? Type 1 diabetes –Accounts for 10-15% of all people with the disease Monogenic autoimmune diabetes (i.e. APS1*, XLAAD) Latent autoimmune diabetes of adults (LADA) –Adult onset T1D Type 2 diabetes –Affecting 85-90% of all people with the disease –Atypical or ketosis-prone type 2 diabetes* –Prediabetes: blood glucose levels are higher than normal Gestational diabetes mellitus (GDM) –Occurs in about 2%–10% of all pregnancies-improves after delivery –About 20%–50% of affected women develop type 2 diabetes later Maturity onset diabetes of the young (MODY) –Hereditary forms of diabetes: mutations in autosomal dominant genes Mitochondrial Diabetes (MIDD) Neonatal Diabetes –Congenital impairment in insulin secretion (GCK, KCNJ11, INS, ABCC8) Syndromes of Extreme Insulin Resistance CGL (congenital generalized lipodystrophy) –Severe Islet Amyloidosis Familial Partial Lipodystrophy, Dunnigan Variety (FPLD) –Adipose disorder (Laminin A) Type 2 GDM Type 1

7. American Diabetes Association. Diabetes Care January 2012 35:S1-S2 *Requires confirmation by repeat testing Symptoms of diabetesPolyuria, polydipsia, polyphagia, diabetic plusketoacidosis (DKA) Random plasma glucose  200 mg/dL* (11mmol/L) or A1c  6.5% or Fasting plasma glucose (FPG)  126 mg/dL* (7.0mmol/L) or Oral glucose tolerance test (OGTT) with 2-hour value  200 mg/dL* (11mmol/L) and confirmed by Presence of islet autoantibodiesGADA, ICA, IA-2A, IAA Making the Diagnosis of Type 1 Diabetes

8. Source: SEARCH for Diabetes in Youth Study NHW=non-Hispanic whites; NHB=non-Hispanic blacks; H=Hispanics/Latinos; API=Asian/Pacific Islander Americans; AI=American Indians Who does Type 1 diabetes strike? For the past few decades T1D incidence has been increasing at a rate of 3% per year: total population The incidence in the young (<5 years of age) has been increasing at a rate of 5.4% per year

9. TYPE 1 DIABETES 2012 STATUS QUO UNACCEPTABLE Epidemic worldwide Increasing burden to individual and society No recent improvement in early mortality No reduction in acute complications Potential benefits of improved glycemic control reaching a minority of patients Current ‘successful’ immune interventions of questionable translation

10. What do you need to cure diabetes? 1.What is diabetes? 2.People & More People 3.$ 4.Know how diabetes develops People $ 5.Good/Great Ideas! People Even more $

11. Clinical Staff & Physicians Building a Diabetes Research Team Clinical Trialists Clinical Investi- gators Basic Scientists

12. Building a Diabetes Research Team Clinical Staff & Physicians Clinical Trialists Clinical Investi- gators Basic Scientist s

13. What do you need to cure diabetes? 1.What is diabetes? 2.People & More People 3.$ 4.Know how diabetes develops People $ 5.Great Ideas! People Even more $

14. Pietropaolo M. et al. Diabetologia 45: 66-76, 2002 Cumulative risk of developing clinical Type 1 diabetes in relatives of T1DM probands using Ab markers alone (IAA, GAD65, IA-2, ICA) 1 Ab 2 Abs 3 Abs 4 Abs 0 Abs Log Rank P < 0.00001 Percent T1D-Free

16. β cells dendritic cells CD8 + T cells pLN Infiltrated islets INSULIN, CD8, CD4

17. Genetic Susceptibility No Disease Subclinical T1D Environmental Exposure Diet Viral Infections Maternal Environment Lack of Environmental Exposure Clinical T1D No Disease or Remission Protective Factors Promoting Factors Low Vitamin D Status Beta Cell Stress Natural History of Type 1 Diabetes

18. Inherited Susceptibility Loci

19. Stages in Human T1D Development Beta Cell Mass or Beta Cell Function

20. Holst JJ & Gromada J, Amer J Physiol 2004, 287, E199-E206 Insulin Secretion by Pancreatic  -cells

21. Loss of FPIR to glucose but not MMTT during T1D Progression Peak C-Peptide Time (years) Before T1D Diagnosis ivGTT MMTT OGTT P<0.0001

22. Metabolic / Endocrine Markers of T1D Risk

23. When, Where, How Beta Cell Mass or Beta Cell Function

24. What do you need to cure diabetes? 1.What is diabetes? 2.People & More People 3.$ 4.Know how diabetes develops People $ 5.Great Ideas! People Even more $ Modified from Bluestone et al : April 2010jdoi:10.1038/nature08933 with permission Potential Diabetes Therapeutic Targets

25. Genetic Risk “Pre”-Diabetes New- Onset Established Complications Antibodies OPPORTUNITIES FOR PREVENTION AND CURE PREVENTION INTERVENTION CURE WITHOUT PREVENTION THERE CAN NEVER BE A CURE

26. INTERVENING IN TYPE 1 DIABETES INTERVENING IN TYPE 1 DIABETES Control Autoimmunity Beta Cell Regeneration/ Transplantation Protect Beta Cell Mass Cure Prevention