Download Pathophysiology of Type 1 Diabetes

Pathophysiology
of Type 1 Diabetes
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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
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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.
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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.
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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.
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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.
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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. Adapted from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221-229.
C-peptide
undetectable
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Models for Pathogenesis of T1D
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
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Models for Pathogenesis of T1D
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
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Models for Pathogenesis of T1D:
Fertile Field Hypothesis
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
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How Type 1 Diabetes Might Arise
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
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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
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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
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