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Pathophysiology of Type 1 Diabetes

Pathophysiology of Type 1 Diabetes. 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. Type 1 Diabetes. Inflammation.

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Pathophysiology of Type 1 Diabetes

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  1. Pathophysiology of Type 1 Diabetes

  2. 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

  3. Type 1 Diabetes Inflammation FasL IFNg TNFa • Betacell destruction • Usually leading to absolute insulin deficiency • Immune mediated • Idiopathic T cell Autoimmune Reaction Macrophage Class IMHC TNFa Class IIMHC IL-1 Beta cell NO CD8+ T cell Dendritic cell Betacell Destruction Maahs DM, et al.EndocrinolMetabClin North Am. 2010;39:481-497.

  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.EndocrinolMetabClin North Am. 2010;39:481-497.

  5. Autoimmune Basis forType 1 Diabetes Atkinson MA. Diabetes. 2005;54:1253-1263.

  6. Rising Incidence of T1DM Associated With Altered 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; zinc transporter 8, ZnT8A. • Long AE, et al. Diabetes. 2012;61:683-686.

  7. Etiological Approach to Diabetes Type Characterization Proportional distribution of etiologic categories among SEARCH participants by race/ethnicity. 2,291 subjects aged <20 years. Dabelea D, SEARCH for Diabetes in Youth Study. Diabetes Care. 2011;34:1628-1633.

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

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

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

  11. Models for Pathogenesis of T1DMFertile Field Hypothesis van Belle TL, et al. Physiol Rev. 2011;91:79-118.

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

  13. Insulin and Glucose Metabolism

  14. Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency

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