Pathophysiology of Type 1 Diabetes

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 1 Diabetes Inflammation

• Beta cell destruction

FasL

IFNg

TNFa

– Usually leading to absolute insulin deficiency

T cell

• Immune mediated • Idiopathic

Autoimmune Reaction Macrophage Class I MHC

TNFa Class II MHC

IL-1 Beta cell NO

CD8+ T cell

Dendritic cell

Beta cell Destruction

3 Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.

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 4 Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.

Autoimmune Basis for Type 1 Diabetes

5 Atkinson MA. Diabetes. 2005;54:1253-1263.

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 6 Autoantibodies to insulin, IAA; GAD, GADA; islet antigen-2, IA-2A; zinc transporter 8, ZnT8A. Long AE, et al. Diabetes. 2012;61:683-686.

Etiological Approach to Diabetes Type Characterization

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Proportional distribution of etiologic categories among SEARCH participants by race/ethnicity. 2,291 subjects aged