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TYPE 1 DIABETES MELLITUS R A C H E L S TA H L CHARACTERISTICS OF DIABETES TYPE 11 • autoimmunity against pancreatic β-cells • T-cell mediated2 • loss of β-cells • insulin deficiency FUNCTIONS OF THE PANCREAS • Exocrine3 –digestion • Endocrine3 –glucose regulation • Islets of Langerhans • α-cell - glucagon • β-cell - insulin • δ-cell – somatostatin Picture from: Lehninger Principles of Biochemistry T1D DIFFERS FROM T2D IN: • Time of onset4 • Target cell effect4 • Role of insulin4 • Associated genes4 • Diagnostic tests5 Picture from: Lehninger Principles of Biochemistry EPIDEMIOLOGY OF T1D6 • Rising in industrialized areas • Accounts for 7-12% of diabetic cases • Affects ~29-50 million people worldwide (out of 300 million with DM overall) • Affects ~1 million in US • Most common metabolic children’s disease: 1 in ~500 • Patients with T1D have higher risk of cardiovascular disease, renal disease, and heart attacks STAGES OF DIABETES DEFINED BY AMOUNT OF BETA CELLS AND BLOOD GLUCOSE7 Picture from Simmons et al. Note: by the time symptoms are visible, ~80% of β-cells are destroyed SYMPTOMS OF T1D ARE DUE TO DYSGLYCEMIA8 • 4 T’s of diagnosis • • • • 1. Toilet (excessive urination) 2. Thirsty 3. Tired 4. Thinner (weight loss) • Diabetic ketoacidosis • • • • High glucose Ketone production Leading cause of mortality/ morbidity in T1D patients Symptoms: Vomiting, Abdominal pain, Reduced consciousness GENETIC AND GEOGRAPHIC FACTORS LEAD TO T1D SUSCEPTIBILITY • Genetic Factors1 • Immune-focused - HLA complex • Hygiene hypothesis4 • Geographic Location1 • Industrialized countries • Environment over genetics T CELL AUTOIMMUNITY RESULT FROM MULTIPLE FACTORS2 • Viral infections (e.g. mumps, congenital rubella, coxsackievirus) • T-cell response – more aggressive against islet cell antigens • Th1/ Th2 imbalance – Inflammatory response • FasLigand expression – apoptosis Picture from: http://viviennebalonwu.tumblr.com/post/117643407703/rubella- GLUTAMIC ACID DECARBOXYLASE IS ONE AUTOANTIGEN OF TYPE 1 DIABETES • Neurons and δ-cells make GABA9 • In pancreas, cleaved into peptides10 • Peptides presented on APC10 • T cell Activation10 picture from 11Boehmer and Sarukham Picture from http://www.nara-wu.ac.jp/life/health/ueno/_src/sc516/gad_reaction.jpg TYROSINE PHOSPHATASE IS ANOTHER AUTOANTIGEN IN T1D11 • Islet cell Antigen (IA)-2 / IA-2β • transmembrane protein • Neurons, endocrine cells • • • • Highly conserved IA-2 – secretory response IA-2β – Islet development Both - Insulin expression Pictures from: Torii11 T1D PATIENTS HAVE INCREASED ANTIBODIES AGAINST BOTH IA-2 AND GAD12 SELF-MANAGEMENT EDUCATION RECOMMENDED EARLY IN DIAGNOSIS13 • Glucose monitoring and Insulin injections • Adolescence provides challenges to proper care • • • • Time constraints Fear – self-injection Peer pressure Discipline Picture from https://www.drugs.com/cg/how-to-give-aninsulin-injection.html Picture from http://www.healthable.org/the-evolution-of-the-insulin-pump/ Β-CELL REPLACEMENT AS A NEW TREATMENT TYPE14 • Turn Progenitor cells into β-cells • Considerations: • Viability of cells • Increased tumor formation • Access to blood vessels • Sources of cells: • Pluripotent from somatic • Multipotent from bone marrow • Non-β-endocrine cells (e.g. α to β) Picture from Vieira et al.15 REFERENCES • • • • • • • • • • • • • • 1 Needell JC, Zipris D. 2016. The Role of the Intestinal Microbiome in Type 1 Diabetes Pathogenesis. Current Diabetes Reports 16: doi: 10.1007/S11892-016-0781-2 2 Devendra D, Liu E, Eisenbarth GS. 2004. Type 1 diabetes: recent developments. British Medical Journal 328: 750-754. 3Nelson DL, Cox MM. 2013. Principles of Biochemistry. New York (NY): W. H. Freeman and Co; 1340p. 4Paun A, Danska JS. 2016. Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome. Pediatric Diabetes 17: 469-477 5Turner J. 2016. Common Diabetes Dilemmas. Pulse: 70-75. 6Leung SS, Forbes JM, Borg DJ. 2016. Receptor for Advanced Glycation end Products (RAGE) in type 1 Diabetes Pathogenesis. Current Diabetes Reports 16: doi: 10.1007/S11892-016-0782-y 7Simmons KM, Gottlieb PA, Michels AW. 2016. Immune Intervention and Preservation of Pancreatic Beta Cell Function in Type 1 Diabetes. Current Diabetes Report 16: doi: 10.1007/S1 1892-016-0739-8. 8Dowling L. 2013. The 4 ‘Ts’ – aiding prompt diagnosis of Type 1 diabetes in children. Practice Nurse 43: 18-21. 9Franklin IK, Wollheim CB. 2004. GABA in the Endocrine Pancreas: Its Putative Role as an Islet Cell Paracrine-Signalling Molecule. The Journal of General Physiology 123: 185–190. 10Boehmer H, Sarukhan A. 1999. GAD, a Single Autoantigen for Diabetes. Science 284: 1135-1137 11Torii S. 2009. Expression and Function of 1A-2 Family Proteins, Unique Neuroendocrine-specific Protein-tyrosine phosphatases. Endocrine Journal 56: 639-648. 12Borg H, Fernlund P, Sundkvist G. 1997. Protein tyrosine phosphatase-like protein IA2-antibodies plus glutamic acid decarboxylase 65 antibodies (GADA) indicates autoimmunity as frequently as islet cell antibodies assay in children with recently diagnosed diabetes mellitus. Clinical Chemistry 43: 2358-2363. 13Abualula NA, Jacobsen KH, Milligan RA, Rodan MF, Conn VS. 2016. Evaluating Diabetes: Educational Interventions With a Skill Development Component in Adolescents With Type 1 Diabetes. The Diabetes EDUCATOR 42: 515-528. 14Vieira A, Courtney M, Druelle N, Avolio F, Napolitano T, Hadzic B, Navarro-Sanz S, Ben-Othman N, Collombat P. 2016. β-cell replacement as a treatment for type 1 diabetes: an overview of possible cell sources and current axes of research. Diabetes, Obesity and Metabolism 18: 137-143. SHORT ESSAY 1.The 4 T’s of T1D are Tired (lethargy), Thirsty (dehydration), Toilet (urination), and Thinner (weight loss). Explain why each of these symptoms occur in diabetic patients, focusing on the role of insulin and how body processes are altered when it is no longer produced. MC QUESTIONS 1. What are the characteristics of Stage 2 Diabetes? 1. 2. 3. 4. Increased urination and weight loss with hyperglycemia Presence of islet autoimmunity, asymptomatic, and normal blood glucose levels Human Leukocyte Antigen genes identifiable with normal levels of β-cells Dysglycemia, antibodies against islet cell antigens present but no symptoms visible 2. Which is not true of IA-2β? 1. 2. 3. 4. It is a transmembrane protein found in both endocrine and neuronal cells Functions include secretion responses, islet development, and insulin expression Antibodies against IA-2β can be detected as early as stage 1 Diabetes Along with GAD, it is an autoantigen that is attacked by T-cells in T1D 3. What is the function of the β-cell? 1. 2. 3. 4. Secrete insulin and somatostatin in response to low levels of glucose Participates in the exocrine response by secreting digestive enzymes in response to food intake In the endocrine response, secretes insulin in order to promote uptake of glucose from the blood Regulates immune response to insulin by deactivating B cells 4. T1D and T2D differ in all these ways except? 1. T1D arises predominantly in early life, and T2D arises predominantly in adulthood 2. T2D is caused by environmental factors, but T1D is determined only by genetics 3. T1D is diagnosed by high levels of islet cell antibodies, whereas T2D results in high C-peptide concentration 4. T2D-associated genes control cell cycle regulation; T1D-associated genes control immune response