1. Type-I Diabetes

2. Background Information Diabetes mellitus type-1 -Also called Insulin dependent diabetes or Juvenile diabetes. -Autoimmune destruction of insulin-producing (beta cells) of the pancreas -Results in total insulin deficiency. -Affects 1 in 300 children and more adults. 4

4. Pathophysiology of T1DM Chronic autoimmune disorder occurring in genetically susceptible individuals May be precipitated by environmental factors Immune system is triggered to develop an autoimmune response against Altered pancreatic beta cell antigens Molecules in beta cells that resemble a viral protein ~ 85% of T1DM patients have circulating islet cell antibodies Majority also have detectable anti-insulin antibodies Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic beta cells Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.

5. Diabetes: not just an American problem...

6. Beta Cells: secrete insulin. The Pancreas Alpha Cells: secrete glucagon Autoimmunity occurs in islet of Langerhans against the beta cells...

7. What is Insulin? What does it do? -Peptide Hormone, regulates blood sugar. -Causes body cells to take up glucose from the blood. -Insulin receptors found on: Liver cells Skeletal muscles Adipose tissue

8. Symptoms Symptoms include: - Hyperglycemia -Polyuria: Excessive urine -Polydipsia: Excessive Thirst -Lipidemia -Polyphagia :Excessive Hunger -Glycosuria: Sugar in the urine - Lipidemia: Lack of insulin starves body of glucose, body begins metabolizing fatty acids as energy source. - Ketoacidoses: Ketones build up in blood, dropping Ph - Ketouria: Ketones in urine - Macular degeneration 4 4

9. Risk Factors Mostly Genetic: alleles of HLA-DQB1, a MHC-II -DQB1*0201 -DQB1*0302 -Both DQB1*0201 and DQB1*0302 = greatest relative risk. 1 1

10. Environmental Factors: -Diagnosed rates between subjects with high-risk HLA genotypes (decreased) and low-risk or even protective HLA genotypes (increased). -Twin studies -Cold Temperatures -Diet, stress, etc. Risk Factors con’t new studies are pointing to the importance of the environment... 1 1 1

11. Pathophysiology: Overview Triggers: -Poorly understood, plenty of theories. -Molecular mimicry… -Injury to islets… -Random failure of tolerance… Cell mediated response: -Type 1 diabetes is caused by a T cell–mediated autoimmune destruction of th e pancreatic beta cells. KAI W. WUCHERPFENNIG1 AND GEORGE S. EISENBARTH.:Type 1 Diabetes 5 5

12. Autoimmune Basis for Type 1 Diabetes Atkinson MA. Diabetes. 2005;54:1253-1263.

13. Autoimmune Basis for Type 1 Diabetes Atkinson MA. Diabetes. 2005;54:1253-1263.

14. Models for Pathogenesis of T1DM van Belle TL, et al. Physiol Rev. 2011;91:79-118.

15. Molecular mimicry : similar epitopes between pathogen and host. -Viruses can produce proteins similar to those of the host. -Immune cells present viral protein homologous to self protein. Failure of tolerance and autoimmunity. Injury to Islet cells: macrophages provoke insulitis by release of interleukin. -Can lead to presentation of cryptic antigens.... HGAD65: auto antigen Coxsackie & hCMV: Viral peptides Image from ROEP et al.: MOLECULAR MIMICRY IN TYPE 1 DIABETES Pathophysiology: Triggers 3 3

16. van Belle TL, et al. Physiol Rev. 2011;91:79-118. Models for Pathogenesis of T1DM

17. Th cells secrete Interferon-gamma: Activates macrophages and granulocytes: Induce apoptosis of beta cells APCs phagocytize apoptotic bodies Presentation of cryptic antigens from within Beta cells on MHC Activation of further Tc and Th cells Cryptic Antigens: epitopes not presented for recognition by T cells unless they are produced in unusually large concentrations or are freed from their configuration in body. Cycle is self perpetuating… Cell-mediated Response 2

18. Type 1 Diabetes Beta cell destruction Usually leading to absolute insulin deficiency Immune mediated Idiopathic Inflammation T cell TNF  IFN  FasL Autoimmune Reaction Macrophage Beta cell CD8 + T cell TNF  IL-1 NO Class I MHC Dendritic cell Beta cell Destruction Class II MHC Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.

19. How Type 1 Diabetes Might Arise van Belle TL, et al. Physiol Rev. 2011;91:79-118.

20. Insulin and Glucose Metabolism Stimulates glucose uptake into muscle and adipose cells Inhibits hepatic glucose production Major Metabolic Effects of Insulin Hyperglycemia  osmotic diuresis and dehydration Consequences of Insulin Deficiency

21. Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency Insulin effects: inhibits breakdown of triglycerides (lipolysis) in adipose tissue Consequences of insulin deficiency: elevated FFA levelsConsequences of insulin deficiency: elevated FFA levels Insulin effects: Inhibits ketogenesis Consequences of insulin deficiency: ketoacidosis, production of ketone bodiesConsequences of insulin deficiency: ketoacidosis, production of ketone bodies Insulin effects in muscle: stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription Consequences of insulin deficiency: muscle wastingConsequences of insulin deficiency: muscle wasting

22. Diagnosis -Fasting plasma glucose levels. -Detection of antibodies against islet antigens (insulin, beta cells, etc.) in the serum.  Detects autoimmunity before diabetes is clinical. -Hemoglobin A1c (glycolated hemogolobin) test.

23. Treatment Type 1 diabetes is fatal if not treated with external insulin. Insulin: -fast acting and slow acting Delivery: -subcutaneous injection -insulin pump

24. A Future Cure? Type-1 Diabetes is currently non-preventable but… Drugs? Diet? … Mostly in experimental stages. Further research is required. Pancreas transplantation? Islet cell transplantation? Pancreatic Lymph Therapy and Node removal Some success in mice

25. Study Questions! 1) What cells are responsible for insulin secretion: a) Alpha cells, b) Beta cells, c) Gamma Cells, d) Islet of Langerhans 2) Which of the following statements is false. a) Type 1 diabetes is caused by a T cell–mediated autoimmune destruction of the pancreatic beta cells. b) Having one or both copies of a certain MHC-II allele leads to greater relative risk in developing type-1 diabetes. c) It is believed that molecular mimicry between viral pathogens and beta cell protein explains the loss of tolerance in type 1 diabetes. d) Eosinophils play an important role in mediating the humoral response of type-1 diabetes by use of IgE Fc receptors.

26. Study Questions! 3) Which of the following is true about the immune response of Type 1 diabetes: a)Type 1 diabetes is caused by a T cell–mediated autoimmune destruction of the pancreatic beta cells. b) Primarily chronic phagocytosis by cells of the innate immune system always begins the destruction of insulin producing cells. c) IgA penetrates the pancreases and mediate complement on beta cells. d) In type 1 diabetes insulin begins to directly attack the pancreas resulting in beta cell destruction.

27. Study Questions! 4) Which genetic factor results in the greatest relative risk in developing type 1 diabetes? a) Having one or both copies of a certain MHC-II allele. b) Mutant forms of CD8. c) Auto reactive IgM associated with the BCR complex, d) Non antigen specific coupling of MHC TCR complex

28. Study Questions! 5) Molecular mimicry is an important trigger in the onset of Type-1 Diabetes. Describe how molecular mimicry can lead to autoimmune disorders.

29. References. 3) Roep BO, Hiemstra HS, Schloot NC, De Vries RRP, Chaudhuri A, Behan PO, and Drijfhout JW. 2002. Molecular Mimicry in Type 1 Diabetes. Annals of New York Academy of Sciences. 958:163-165. 1) Morran MP, Omenn GS, and Pietropaolo M. 2008.Immunology and Genetics of Type 1 Diabetes. Mount Sinai Journal of Medicine. 75: 314-327. 4) Tisch R, and McDevitt H. 1996. Insulin-Dependent Diabetes Mellitus. Cell. 85: 291-297. 2) Pear-Yafe M, Kaminitz A, Yolcu E, Yanic I, Stein J, and Askenasy N. 2007. Pancreatic Islets Under Attack: Cellular and Molecular Effectors. Current Pharmaceutical Design.13: 749-760. 5) Wucherpenning KW, AND Eisenbarth G. 2001. Type 1 diabetes. Nature Publishing Group. News & Views: 1-2. (http://www.nature.com/immuno/index.html)