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Pathophysiology of Type 1 Diabetes 1 Type 1 Diabetes Mellitus • Characterized by absolute insulin deficiency • Pathophysiology and etiology – Result of pancreatic beta cell destruction • Prone to ketosis – Total deficit of circulating insulin – Autoimmune – Idiopathic 2 Type of Diabetes in Youth by Race/Ethnicity and Etiology SEARCH for Diabetes in Youth Study (N=2291) Distribution of etiologic categories by race/ethnicity 100% 6.2 11.1 15.9 28.3 80% 40.1 19.8 40.8 6.6 60% 21.3 40% 67.8 9.4 10.8 18 15.1 62.9 32.5 19.5 Non-autoimmune + IR Non-autoimmune + IS Autoimmune + IR 3.2 12.9 43.7 20% 10.1 Autoimmune + IS 54.5 33.3 16.1 0% NHW Hispanic AA API AI Total AA, African American; AI, American Indian; API, Asian/Pacific Islander; IR, insulin resistant; IS, insulin sensitive; NHW, non-Hispanic white. Dabelea D, et al. Diabetes Care. 2011;34:1628-1633. 3 Type 1 Diabetes Pathophysiology Inflammation • -cell destruction FasL – Usually leading to absolute insulin deficiency IFN-g TNF-a T cell • Immune mediated • Idiopathic Autoimmune Reaction Macrophage Class I MHC TNF-a Class II MHC IL-1 -cell NO Dendritic cell CD8+ T cell -cell Destruction CD8, cluster of differentiation 8; FasL, Fas ligand; IFN-g, interferon g; IL-1, interleukin 1; MHC, major histocompatibility complex; NO, nitric oxide; TNF-a, tumor necrosis factor a. Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497. 4 Pathophysiologic Features of Type 1 Diabetes • Chronic autoimmune disorder – Occurs in genetically susceptible individuals – May be precipitated by environmental factors • Autoimmune response against – Altered pancreatic -cell antigens – Molecules in -cells that resemble a viral protein • Antibodies – Approximately 85% of patients: circulating islet cell antibodies – Majority: detectable anti-insulin antibodies – Most islet cell antibodies directed against GAD within pancreatic -cells GAD, glutamic acid decarboxylase. Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497. 5 Trends in T1D Immunophenotype at Diagnosis • Prevalence of IA-2A and ZnT8A has increased significantly, mirrored by raised levels of IA-2A, ZnT8A, and IA-2β autoantibodies (IA-2βA) • IAA and GADA prevalence and levels have not changed • Increases in IA-2A, ZnT8A, and IA-2βA at diagnosis during a period of rising incidence suggest that the process leading to type 1 diabetes is now characterized by a more intense humoral autoimmune response Autoantibodies to insulin, IAA; GAD, GADA; islet antigen-2, IA-2A; T1D, type 1 diabetes; zinc transporter 8, ZnT8A. Long AE, et al. Diabetes. 2012;61:683-686. 6 Autoimmune Basis for Type 1 Diabetes Immune dysregulation Environmental triggers and regulators IAA -Cell mass GADA, ICA512A, ICA Interactions between genes imparting susceptibility and resistance Variable insulinitis -cell sensitivity to injury Loss of first-phase insulin response (IVGTT) Glucose intolerance Overt T1D Prediabetes Time Atkinson MA. Diabetes. 2005;54:1253-1263. C-peptide undetectable 7 Models for Pathogenesis of T1D van Belle TL, et al. Physiol Rev. 2011;91:79-118. 8 Models for Pathogenesis of T1D van Belle TL, et al. Physiol Rev. 2011;91:79-118. 9 Models for Pathogenesis of T1D: Fertile Field Hypothesis van Belle TL, et al. Physiol Rev. 2011;91:79-118. 10 How Type 1 Diabetes Might Arise van Belle TL, et al. Physiol Rev. 2011;91:79-118. 11 Insulin and Glucose Metabolism Major Metabolic Effects of Insulin • Stimulates glucose uptake into muscle and adipose cells • Inhibits hepatic glucose production Consequences of Insulin Deficiency • Hyperglycemia osmotic diuresis and dehydration 12 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 levels Insulin effects: inhibits ketogenesis • Consequences 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 wasting 13