Lecture 13 - Historical perspective + Pathogenesis of T1D Flashcards
What is normal metabolism?
- Glucose travels through the bloodstream towards pancreas
- Glucose stimulates release of insulin by beta cells in the pancreas
- Insulin travels through blood stream to liver, muscle and adipose tissue (to help store glucose as an energy source)
- Glucose is taken up by the cells which has glucose receptors
- Metabolic pathways
- CO2 + biochemical energy (ATP) is released as a result
Where is Insulin produced?
In the islets of Langerhans in the pancreas (beta cells)
After a meal, BGL is high, glucose is released into islets and into the beta cells
- triggers release of insulin that is stored in granules in the beta cells
How does metabolism occur when one has T1D?
- Glucose travels through the bloodstream towards pancreas
- Insufficient insulin produced
- Impaired glucose uptake
- Increased glucose and blood in the urine
- High ratio of glucagon: insulin
- Increased glycogen, fat and protein catabolism
- Increased ketone body synthesis
- Decreased blood pH/dehydration
- Unconsciousness if not treated with exogenous insulin
What are the 3 main destinations of glucose and insulin?
Liver, muscle, adipose tissue
Insulin helps these tissues pick up the glucose molecules in the blood and store as an energy source
Insulin causes cells to upregulate GLUT and allow glucose to enter the cells
>decreases BGL
>glucose now stored as energy for future use
>storage molecule is glycogen
What is type 1 diabetes?
A Metabolic disorder where immune cells infiltrate and destroy the insulin-producing beta cells
Results in hyperglycaemia
What causes the loss of insulin in type 1 diabetes?
- Chronic autoimmune disease
- Immune cells kill the body’s own beta cells
- Islets shrink as beta cells are killed
- Remaining beta cells produce insulin insufficiently
What are the symptoms of T1D?
Polyuria (increased urination)
Glycosuria (increase in glucose in urine)
Polydipsia (excessive thirst which results in excessive drinking)
Polyphasia (increased hunger which is paradoxical because there is energy/sugar there but its not being used)
What is the immunopathogenesis of T1D?
- Antigen presenting cells (dendritic cells, macrophages, and B cells) activate autoreactive lymphocytes
- Activated T cells mediate the destruction of insulin-producing beta cells
- Beta-cell destruction is exacerbated by the release of pro-inflammatory cytokines and reactive oxygen species (ROS) from adaptive and innate immune cells
- Activated B cells produce auto-antibodies that serve as biomarkers for diagnosing type 1 diabetes
Once the beta cell mass has been reduced below a certain threshold, ____
the body can no longer regulate blood glucose levels
> without insulin, the body’s cells are not stimulated to take up glucose
What are the pancreatic and islet abnormalities in type 1 diabetes?
Endocrine compartment (secrete hormones)
>overexpression HLA class I molecules (that present antigen to T cells)
>variable distribution and severity of infiltrating immune cells
>loss of beta cells and insulin expression
Exocrine compartment (secreting digestive enzymes)
>loss of pancreatic volume
>exocrine tissue atrophy
>healthy adult pancreas >80g, T1D pancreas <40g
>note: islet mass is only 2% of pancreatic mass
Non-endocrine islet cells
>possible changes in islet vasculature and extracellular structure, but still under investigation
What is the basic diagnostic criteria for T1D?
A diagnosis of diabetes is based on a fasting blood glucose concentration >7.0 mmol/L, a random blood glucose concentration above 11.1 mmol/L with symptoms
A diagnosis of diabetes can also be made with glycated haemoglobin concentration > 48mmol/L this is less sensitive because dysglycaemia progression can be rapid
Autoantibodies against beta-cell antigens (e.g., insulin)
What symptoms do children with T1D typically have?
Children with T1D commonly present with symptoms of polyuria, polydipsia and weight loss; approx. 1/3 present with diabetic ketoacidosis
What are the environmental factors for T1D? Why are they controversial?
- Hygiene hypothesis: early exposure to infectious microbes/gut microbiome can temper/educate the immune system to increase tolerance to self-tissues especially for genetically pre-disposed individuals
- Virus infection: might trigger local inflammation, attracting autoantibodies to migrate and target islet cells
- Sunlight and vitamin D
- Accelerator hypothesis: obesity and high sugar diets places additional stress on beta cells and so would accelerate T1D
Hard to determine the effect of these factors in individuals that have already developed T1D. Controversial. Poor predictive value. May act throughout natural history of disease and vary by geographic region.
What are the different classifications of diabetes?
- Type 1 Diabetes (insulin-dependent diabetes mellitus, juvenile diabetes)
o Immune-mediated destruction of insulin-producing beta cells
o Autoimmune disease - Type 2 Diabetes (non-insulin dependent diabetes mellitus)
o Insulin resistance and insulin deficiency - Other specific types of diabetes mellitus
o Genetic defects affecting beta-cell function or insulin action - Gestational diabetes
o Insulin resistance and relative insulin deficiency during pregnancy
What is the current treatment for T1D?
Exogenous insulin
Glycaemic control requires:
* Multiple blood glucose measurements per day
* Multiple injections per day of exogenous insulin
What are the metabolic complications of T1D?
Ketoacidosis:
* Treatment: fluids, insulin, electrolytes (K+)
Hypoglycaemia:
* Decreased blood glucose concentration due to suboptimal insulin treatment
* Recurrent hypoglycaemia results in an increased likelihood of hypoglycaemia unawareness
Microvascular complications:
* Hyperglycaemia is the primary risk factor
* Intensive management of blood glucose within a normal range = slower progression and reduced incidence
Diabetic retinopathy - eye
* New blood vessels form at the back of the eye and burst causing vitreous haemorrhages
* Can lead to blindness if not managed properly
Diabetic nephropathy - kidney
* Increased protein (albumin) excretion in the urine in the absence of other renal conditions, micro and macroalbuminuria
* Progressive decline in glomerular filtration rate
What are the macrovascular complications of T1D?
- Coronary heart disease
- Cerebrovascular disease
- Peripheral artery disease
These conditions are not specific to diabetes but T1D increases the risk of developing these conditions
What is the honeymoon period in T1D?
Pancreas is still able to produce a significant amount of its own insulin. Can help to reduce blood sugar levels and reduce the amount of exogenous insulin that is required. Usually begins about 3 months after you start treatment for T1D.
Why is insulin an inappropriate measure for whether someone has T1D? What’s a better measure?
- Residual insulin at the clinical stage makes measuring insulin during this stage inaccurate because this assumes that every pancreatic beta cell has been destroyed but when an individual is diagnosed with T1D this is not the case -
- Blood glucose concentration is a better diagnostic criterion than insulin because this is the only way to determine if the person is producing enough insulin to regulate blood glucose levels
Who gets Diabetes Mellitus? Prevalence and Incidence
Most individuals diagnosed with T1d are between ages of 5-19, but still can get diagnosed after 19 (if autoimmune response started later in life)
~95% of diabetes diagnosed in children is T1D
What is the genetic predisposition of T1D?
> 90% individuals with T1D do not have first degree family history
> 3-5% chance if you have a parent with T1D
> 8% chance if you have a sibling with T1D
> 50% chance if you have an identical twin with T1D
What is the conceptual model for the natural history and pathogenesis of T1D?
- Genetic + environmental factors
- Environmental factors also likely to influence disease progression
- Presence of islet autoantibodies might represent asymptomatic T1D
- Overall loss of beta cells is potentially linear but could show a relapsing or remitting pattern
- Increasing glucose level deviation as individual approaches symptomatic onset
- Beta cell mass and function always zero in patients
Explain odds ratio
> measure of association between an exposure and an outcome
OR=1: exposure does not affect odds of outcome
(not contributory to T1D)
OR>1: Exposure associated with higher odds of outcome
(pathogenic/risk factor for T1D)
OR<1: Exposure associated with lower odds of outcome
(protective)
