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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

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

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/eth

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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.

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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.

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

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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

• 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

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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