Type 1 Diabetes Flashcards
Why is Type 1 Diabetes important?
Type 1 Diabetes affects 0.5% of Australians = 140,000
but…
Its incidence is rising
It carries a significant burden of disease and high risk of heath complications; particularly to the retina, kidneys and RBCs
It is largely diagnosed in childhood but is a life-long condition with continued treatment through adulthood
What is the pathophysiology behind Type 1 diabetes?
Type 1 diabetes is an absolute deficiency of insulin arising from autoimmune attacks that destroy pancreatic þ-cells
The consequences of insulin deficiency are:
- Hyperglycaemia
- Uncontrolled lipolysis; and
- Elevated protein catabolism
This commonly presents as weight loss associated with polyuria and polydipsia
Describe and illustrate the “stages” in the development of Type 1 diabetes
How are beta-islet cells destroyed in Type 1 diabetes?
**The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells specific for islet antigens. **
This failure of tolerance may be a result of some combination of defective:
- Primary tolerance=clonal deletion of self-reactive T cells in the thymus,
- Peripheral tolerance= deficit is functions of regulatory T cells or resistance of effector T cells to suppression by regulatory cells.
Thus, autoreactive T cells not only survive but are poised to respond to self-antigens.
The activated T cells traffic to the pancreas, where they cause β-cell injury. TH1 cells (which may secrete cytokines, including IFN-γ and TNF, that injure β cells), and CD8+ CTLs (which kill β cells directly) are involved
What is the role of insulin auto-antibodies in type 1 diabetes?
Insulin auto-antibodies are one of the dominant signs of diabetes patients
They are not thought to be part of the pathogenesis of T1DM ( not clear )
They are used as a marker of T1DM presence and severity
The risk of getting T1DM at the age of 15 increases with the number of the different types of insulin auto-antibodies:
- None = 0.4%
- 1 = 12.7%
- 2 = 61.6%
- 3 = 79.1%
There is a subclinical period between the time auto-antibodies are detectable to the time at which clinical features of T1DM present
What can be seen histologically when viewing islet cells of the pancreas of a T1DM patient?
-
Reduced insulin staining
* progressive loss of beta islet cells and their ability to produce, store and release insulin - Evidence of chronic inflammation
- CD4+ & CD8+ lymphocytes in and around the islets
- CD8+ T-cells contain perforin and granzyme B that are thought to mediate a significant portion of pancreas damage.
How would you describe the pattern of islet loss over time with T1DM?
Islet loss is patchy, even in the years after diagnosis.
What is the association between autoimmune polyendocrine syndrome type 1 (APS-1 Syndrome) and T1DM?
**Autoimmune polyendocrine syndrome type 1 (APS-1 ) **is a syndrome characterised by the loss of central tolerance following mutations to the AIRE gene.
The AIRE gene is found cell of the thymus and is responsible for the transcription of organ specific antigens expressed by non-thymus cells -> ensuring that tolerance against all antigens can be developed; not just thymus antigents.
18% of patients with APS-1 develop T1DM
The syndrome leads to many different endocrine autoimmune disorders such as Addison’s disease, Hypothyroidism and mucocutaneous candidiasis.
What is the association between immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) and T1DM?
**Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) **is an autoimmune disease resulting from the loss of peripheral tolerance.
It arises from mutations to the FoxP3 gene which controls the functions of regulatory T-cells.
It is rare
**80% of children with the syndrome develop T1DM **
What environmental triggers may activate autoimmunity in patients (with or without T1DM)?
- UV
- Diet
- Drugs
- Hygiene
- Infection
- Tissue specific causes
What is C peptide?
C peptide or connecting peptide is a protein that connects the A-chain and B-chain of insulin molecules in the proinsulin molecule
It is commonly used as a **measure of endogenous insulin production. **
C-peptide levels are measured instead of insulin levels because C-peptide can assess a person’s own insulin secretion even if they receive insulin injections.
What is wrong with current T1DM treatments?
Current diabetes treatment revolves around the administration of exogenous insulin into the body to maintain blood glucose.
This form of treatment is incapable of mimicking physiological glucose control and therefore can’t prevent complications of hypoglycaemic attacks and long term exogenous dependence.
Patients must inject themselves with insulin mutiple times a day -> is burdensome
Is not a cure
What treatments for T1DM are in development for the future?
Ideally, a cure to abolish the disease by correcting autoimmunity is a long term objective of therapy development.
In the mean time, treatment being developed include:
- Islet transplantation
- Artifical pancreas
What are the benefits of islet transplantation in the treatment of T1DM?
- Islet cells can be manufactured reproducibly at multiple site using a common manufacturing process
- * Independence from exogenous insulin* is achieved in half of all islet recipients at one year following infusion - with one or two infusions needed
- Glycaemic control is excellent - even when full insulin indepence is not achieved
- Hypoglycaemia awareness is treated effectively by transplantation - giving freedom from hypoglycaemic events.
**Hypoglycaemia is uncommon in patients with iselt transplants **
What are the problems with islet transplantation?
- Availability of organ donors
- Viability and function of islets are variable
- Immunosuppression treatment is required
- The longevity of graft function
- Allo-sensitisation = hypoxia to islets during the transplant conversion is problematic
- Cost
