Terence (Type 1 Diabetes Mellitus) Flashcards
Diabetes mellitus
Diabetes mellitus is a condition where there is chronically raised blood glucose concentration due to an absolute or relative lack of the hormone insulin and/or a deficiency in insulin action.
(either there isn’t enough insulin being produced or the insulin isn’t working as it should).
Type 1
- presents in childhood (peak age of onset is 12 years old)
- accounts for approx. 8% of all diabetics
Type 2
- presents in middle age (peak age of onset is 60 years old)
- accounts for approx. 90% of all diabetics
- >85% of type 2 diabetics are obese
Gestational diabetes
- 4-5% of all pregnancies
Rarer forms
- monogenetic forms of diabetes (MODY)- caused by mutations in specific genes
- endocrinopathies/steroid induced- caused by endocrine disorders
Type 1 DM
Also known as autoimmune diabetes, insulin dependant diabetes mellitus or juvenile onset diabetes
Approx 8% of diabetics in the UK have type 1 diabetes
It is a chronic medical condition usually caused by the autoimmune destruction of the pancreatic beta cells (type 1a). Type 1b is idiopathic so has no known cause.
Clinical presentation of type 1 diabetes
- Hyperglycaemia- high levels of glucose in the blood
- Glycosuria- high levels of glucose in the urine
- Polyuria- production of abnormally large quantities of urine
- Weight loss- accelerated breakdown of fat and muscle
- Pear drop breath (sweet smell)- ketone bodies
- Lethargy- tiredness
The 4Ts
- Toilet- need a wee more often, especially at night
- Thirsty- being constantly thirsty and not being able to quench it
- Tired- being incredibly tired and having no energy
- Thinner- losing weight without trying to or looking thinner than usual
Genetic predisposition- makes you susceptible to developing type 1 but still need other factors to increase the risk of developing it.
Environmental factor/inflammation/beta-cell stress/virus can cause immune activation leading to development of type 1.
Stage 1- 2 or more islet auto antibodies
- detect auto antibodies directed against islet proteins
- will take a while before they are diabetic. Risk at 5 yrs is 44%. Risk at 15 yrs is 80%
- no symptoms
- normal blood sugar
Stage 2- 2 or more islet auto abs dysglycaemia
- disregulation in BG conc but not diabetic yet
- will be diabetic in a short amount of time. risk at 5 yrs is 75%. risk at 15 yrs is 100%
- no symptoms
Stage 3- clinical diagnosis
Teplizumab- targets T cells, delays onset but doesn’t stop onset
Type 1- autoimmune disease
Caused by the loss of pancreatic beta-cells
- 90% of cases caused by an autoimmune response (type 1a)
- 10% of cases are idiopathic (no known cause) (type 1b)
Autoimmune disease occurs when an adaptive immune response is mounted against self antigens
Evidence for a cell mediated immune response in type 1 DM
Many T-cells in the infiltrate.
In many samples cytotoxic T-cells (CD8+) predominate.
Fewer T-cells of helper phenotype (CD4+)
Evidence for a humoral response in type 1 DM
Many B-cells and macrophages found associated with beta cells.
Antibodies can be detected (which are directed against islet cell proteins) in 85-90% of type 1 diabetics. These include islet cell antibodies (ICA):
- proinsulin (IAA)
- Glutamic acid decarboxylase (GAD)
- IA-2
- Zinc transporter (ZnT8A)
These autoantibodies are detected before the onset of diabetes.
The number of different autoantibodies detected is predictive of progression to diabetes.
More ICA = more likely to have severe diabetes.
Autoimmune destruction of beta cells
Beta cell injury due to infection and/or stress results in release of islet antigens and cytokines.
In a genetically susceptible individual, pancreatic self-antigens are processed by resident antigen presenting cells (APC)/B-cells.
APCs including B-cells present via MHCII to auto reactive CD4+ T-cells that become activated and clonal expand.
B cells generate autoantibodies.
Activated auto reactive CD$+ T cells recruit CD8+ cytotoxic T cells and other inflammatory cells to site of inflammation.
The production of pro-inflammatory cytokines by APCs and T cells leads to the further recruitment and activation of T lymphocytes.
Stages and beta cell function
Pre-stage 1- beta cell stress.
Stage 1- beta cells stress, reduction in cell function but enough insulin being released for it not to be a problem.
Stage 2- beta cell death, sufficient insulin being released but getting lower
Stage 3- virtual loss of C-peptide, only way to manage BG is to use insulin, insulin therapy required.
C-peptide is released with insulin and can be used to measure insulin release. Insulin is taken up by the liver so cannot be measured whereas C-protein is not so this can be measured.
Genetics of type 1 diabetes
Population studies
- Scandinavia: 30-35 per 100,000/year
- Oriental countries: 0.5-3 per 100,000/year
Could be genetic or environmental factor influence.
Family studies
- 50% concordance in identical twins
- 2% with mother
- 6% with father or sibling
- 11% with fraternal twin (intrauterine effects must have an impact as fraternal twins have a higher risk than siblings but they will share the same % of DNA)
Genetics and type 1 diabetes
Genome wide association studies have identified single nucleotide polymorphisms/allelic variations that increase the probability of developing type 1 diabetes. The genes that these are found in are called diabetes susceptibility genes (increase the likelihood of developing type 1).
The strongest associations are allelic variations in human leukocyte antigen (HLA) system or complex is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans.
The major genetic determinants in this region are polymorphisms of class II HLA genes encoding DQ and DR.
95% of Caucasian type 1 diabetic subjects carry HLA-DR3/DR4 calotype compared to 50% non-diabetic.
50% of people in the US carry these variants but only 1% have diabetes.
Revision of cell mediated immune response- TCR, MHC, APC
T-cell receptor (TCR)- T cells express an antigen binding receptor on their membrane.
Major histocompatibility complex (MHC) is a group of genes that code for proteins found on the surfaces of cells. There are two major types of MHC protein molecules- class I and class II. These presents antigens to TCR and activated the T cell.
- All nucleated cells express MHC I and presents antigenic peptides to cytotoxic T cells.
- Antigen presenting cells (APC)- include dendritic cells, macrophages, Langerhans cells, and B cells. Express MHC II and presents antigenic peptides to Helper T cells
Environmental triggers of type 1 diabetes
Viruses- Coxsackie-B virus, Rubella, Munps, respiratory viruses. Correlation between some viruses and trigger of diabetes- they either attack beta cells or are involved in recruitment of immune cells.
Toxins- streptozotocin and alloxan.
Diet- cows milk, smoked fish.
Vitamins- low vitamin D.
Increase in winter months as many children come down with illnesses.
Revision: adaptive immune system/acquired immune system
Occurs after exposure to an antigen e.g. pathogen or vaccination.
Involves a memory to provide the host with long-term protection from reinfection.
There are two arms to the adaptive immune response
- cell mediated immune response- T-cell response
- humoral/antibody mediated immune response- B-cell response
Revision: cell mediated immune response
Helper T-cells (CD4 cells)- secrete cytokines when activated and recruit other immune cells i.e. stimulate B cells to proliferate.
Cytotoxic T-cells (CD8)- secrete enzymes (perforin and granzyme) when activated and kill infected cells
