How Can We Cure Diabetes?

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? • What is diabetes? • People & More People • $ • Know how diabetes develops • People • $ • Good/Great Ideas! • People • $

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

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

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

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) GDM Type 1 Type 2

7. Making the Diagnosis of Type 1 Diabetes Symptoms of diabetes Polyuria, polydipsia, polyphagia, diabetic plus ketoacidosis (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 tolerancetest (OGTT) with 2-hour value200 mg/dL* (11mmol/L) and confirmed by Presence of islet autoantibodiesGADA, ICA, IA-2A, IAA *Requires confirmation by repeat testing American Diabetes Association. Diabetes Care January 2012 35:S1-S2

8. Who does Type 1 diabetes strike? 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 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? • What is diabetes? • People & More People • $ • Know how diabetes develops • People • $ • Good/Great Ideas! • People • Even more $

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

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

13. What do you need to cure diabetes? • What is diabetes? • People & More People • $ • Know how diabetes develops • People • $ • Great Ideas! • People • Even more $

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

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

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

18. Inherited Susceptibility Loci

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

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

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

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? • What is diabetes? • People & More People • $ • Know how diabetes develops • People • $ • Great Ideas! • People • Even more $ Potential Diabetes Therapeutic Targets Modified from Bluestone et al : April 2010jdoi:10.1038/nature08933 with permission

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

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