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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 of Diabetes in Youth by Race/Ethnicity and Etiology
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.
NHW Hispanic AA API AI Total0%
20%
40%
60%
80%
100%
62.9
43.732.5 33.3
16.1
54.5
19.8
21.3
18 15.1
12.9
19.5
11.1
6.6
9.4 10.8
3.2
10.1
6.2
28.340.1 40.8
67.8
15.9
Non-autoimmune + IRNon-autoimmune + ISAutoimmune + IRAutoimmune + IS
SEARCH for Diabetes in Youth Study(N=2291)
Dis
trib
uti
on
of
etio
log
ic
cate
go
ries
by
race
/eth
nic
ity
4
Type 1 Diabetes PathophysiologyInflammation
T cell
TNF-a IFN-gFasL
Autoimmune ReactionMacrophage
-cell
CD8+ T cell
TNF-a
IL-1
NO
Class IMHC
Dendritic cell
-cell Destruction
Class IIMHC
CD8, cluster of differentiation 8; FasL, Fas ligand; IFN-, interferon ; IL-1, interleukin 1; MHC, major histocompatibility complex; NO, nitric oxide; TNF-, tumor necrosis factor .
Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.
• -cell destruction– Usually leading to
absolute insulin deficiency
• Immune mediated• Idiopathic
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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.
6
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.
Autoimmune Basis forType 1 Diabetes
Atkinson MA. Diabetes. 2005;54:1253-1263.
GADA, ICA512A, ICA
Environmental triggers and regulators
Time
-C
ell
mas
s Interactions between genes
imparting susceptibility
and resistance
Variable insulinitis
-cell sensitivity to injury
Prediabetes Overt T1D
Immune dysregulation
IAA
C-peptide undetec-
table
Loss of first-phase insulin response (IVGTT)
Glucose intolerance
7
8
Models for Pathogenesis of T1D
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
9
Models for Pathogenesis of T1D
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
10
Models for Pathogenesis of T1D: Fertile Field Hypothesis
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
11
How Type 1 Diabetes Might Arise
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
12
Insulin and Glucose Metabolism
• Stimulates glucose uptake into muscle and adipose cells
• Inhibits hepatic glucose production
Major Metabolic Effects of Insulin
• Hyperglycemia osmotic diuresis and dehydration
Consequences of Insulin Deficiency
13
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