Download Beta cell Destruction

Type-I Diabetes
Background Information
Diabetes mellitus type-1
-Also called Insulin dependent
diabetes or Juvenile diabetes.
-Autoimmune destruction of
insulin-producing (beta cells)
of the pancreas
-Results in total insulin
deficiency.
-Affects 1 in 300 children and more adults. 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. Endocrinol Metab Clin North Am. 2010;39:481-497.
Diabetes: not just an American problem...
The Pancreas
Beta Cells: secrete
insulin.
Alpha Cells: secrete
glucagon
Autoimmunity occurs in islet of Langerhans
against the beta cells...
What is Insulin? What does it do?
-Peptide Hormone,
regulates blood
sugar.
-Causes body cells to
take up glucose
from the blood.
-Insulin receptors
found on:
Liver cells
Skeletal muscles
Adipose tissue
Symptoms
Symptoms include:
-Hyperglycemia
-Polyuria: Excessive urine
-Polydipsia: Excessive Thirst
-Lipidemia
-Polyphagia :Excessive Hunger
-Glycosuria: Sugar in the urine 4
-Lipidemia: Lack of insulin starves body of glucose,
body begins metabolizing fatty acids as energy
source.4
- Ketoacidoses: Ketones build up in blood, dropping Ph
- Ketouria: Ketones in urine
- Macular degeneration
Risk Factors
Mostly Genetic: alleles of HLA-DQB1, a MHC-II
1
-DQB1*0201
-DQB1*0302
-Both DQB1*0201 and DQB1*0302 = greatest relative risk.
1
Risk Factors con’t
Environmental Factors:
-Diagnosed rates between subjects with high-risk HLA
genotypes (decreased) and low-risk or even protective
1
HLA genotypes (increased).
1
-Twin studies
-Cold Temperatures 1
-Diet, stress, etc.
new studies are pointing to the
importance of the environment...
Pathophysiology: Overview
Triggers:
-Poorly understood, plenty of theories.
-Molecular mimicry…
-Injury to islets…
-Random failure of tolerance…
Cell mediated response:
-Type 1 diabetes is caused by a T cell–mediated autoimmune
destruction of the pancreatic beta cells.5
KAI W. WUCHERPFENNIG1 AND GEORGE S. EISENBARTH.:Type 1
Diabetes
5
Autoimmune Basis for
Type 1 Diabetes
Atkinson MA. Diabetes. 2005;54:1253-1263.
Autoimmune Basis for
Type 1 Diabetes
Atkinson MA. Diabetes. 2005;54:1253-1263.
Models for Pathogenesis of T1DM
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
Pathophysiology: Triggers
Molecular mimicry: similar epitopes between pathogen and host.
HGAD65: auto antigen
Coxsackie & hCMV:
Viral peptides
3
Image from ROEP et al.: MOLECULAR MIMICRY IN TYPE 1 DIABETES
-Viruses can produce proteins similar to those of the host.
-Immune cells present viral protein homologous to self protein.
Failure of tolerance and autoimmunity.
Injury to Islet cells: macrophages provoke insulitis by release of
interleukin.
-Can lead to presentation of cryptic antigens.... 3
Models for Pathogenesis of T1DM
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
Cell-mediated Response
Th cells secrete
Interferon-gamma:
Activates
macrophages and
granulocytes:
Induce apoptosis of
beta cells
APCs
phagocytize
apoptotic
bodies
2
Activation of
further Tc and Th
cells
Cryptic Antigens: epitopes not
presented for recognition by T
cells unless they are produced in
unusually large concentrations or
are freed from their configuration
in body.
Presentation of cryptic
antigens from within Beta
cells on MHC
Cycle is self
perpetuating…
Type 1 Diabetes
Beta cell destruction
Inflammation
FasL
IFNg
TNFa
Usually leading to
absolute
insulin deficiency
T cell
Autoimmune Reaction
Immune mediated
Idiopathic
Macrophage
Class I
MHC
TNFa
Class II
MHC
IL-1
Beta cell
NO
CD8+ T cell
Dendritic cell
Beta cell Destruction
Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.
How Type 1 Diabetes Might Arise
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
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
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
Diagnosis
-Fasting plasma glucose levels.
-Detection of antibodies against islet antigens (insulin, beta cells, etc.) in the serum.
 Detects autoimmunity before diabetes is clinical.
-Hemoglobin A1c
(glycolated hemogolobin)
test.
Treatment
Type 1 diabetes is fatal if not
treated with external insulin.
Insulin:
-fast acting and slow acting
Delivery:
-subcutaneous injection
-insulin pump
A Future Cure?
Type-1 Diabetes is currently non-preventable but…
Drugs?
Diet?
… Mostly in experimental stages. Further
research is required.
Pancreas transplantation?
Some success in mice
Islet cell transplantation?
Study Questions!
1) What cells are responsible for insulin secretion:
a) Alpha cells, b) Beta cells, c) Gamma Cells,
d) Islet of Langerhans
2) Which of the following statements is false.
a) Type 1 diabetes is caused by a T cell–mediated autoimmune
destruction of the pancreatic beta cells.
b) Having one or both copies of a certain MHC-II allele leads to
greater relative risk in developing type-1 diabetes.
c) It is believed that molecular mimicry between viral pathogens and
beta cell protein explains the loss of tolerance in type 1 diabetes.
d) Eosinophils play an important role in mediating the humoral
response of type-1 diabetes by use of IgE Fc receptors.
Study Questions!
3) Which of the following is true about the immune response of
Type 1 diabetes:
a)Type 1 diabetes is caused by a T cell–mediated autoimmune
destruction of the pancreatic beta cells.
b) Primarily chronic phagocytosis by cells of the innate immune
system always begins the destruction of insulin producing cells.
c) IgA penetrates the pancreases and mediate complement on beta
cells.
d) In type 1 diabetes insulin begins to directly attack the pancreas
resulting in beta cell destruction.
Study Questions!
4) Which genetic factor results in the greatest relative risk in
developing type 1 diabetes?
a) Having one or both copies of a certain MHC-II allele.
b) Mutant forms of CD8.
c) Auto reactive IgM associated with the BCR complex,
d) Non antigen specific coupling of MHC TCR complex
Study Questions!
5) Molecular mimicry is an important trigger in the onset of
Type-1 Diabetes. Describe how molecular mimicry can lead to
autoimmune disorders.
References.
1) Morran MP, Omenn GS, and Pietropaolo M. 2008.Immunology and Genetics of
Type 1 Diabetes. Mount Sinai Journal of Medicine. 75: 314-327.
2) Pear-Yafe M, Kaminitz A, Yolcu E, Yanic I, Stein J, and Askenasy N. 2007.
Pancreatic Islets Under Attack: Cellular and Molecular Effectors.
Current Pharmaceutical Design.13: 749-760.
3) Roep BO, Hiemstra HS, Schloot NC, De Vries RRP, Chaudhuri A, Behan PO, and
Drijfhout JW. 2002. Molecular Mimicry in Type 1 Diabetes. Annals of New
York Academy of Sciences. 958:163-165.
4) Tisch R, and McDevitt H. 1996. Insulin-Dependent Diabetes Mellitus. Cell. 85:
291-297.
5) Wucherpenning KW, AND Eisenbarth G. 2001. Type 1 diabetes. Nature
Publishing Group. News & Views: 1-2.
(http://www.nature.com/immuno/index.html)