Pathophysiology and Treatment of Type I Diabetes Mellitus Flashcards
Name a form of type 1 diabetes that presents late.
Latent Autoimmune Diabetes in Adults (LADA)
NOTE: Form of type 1 diabetes because it is autoimmune
State some features of T2DM which could cause ambiguity when trying to identify the type of diabetes someone is affected with.
T2DM:
- May present is childhood
- Has diabetic ketoacidosis as a feature
These could cause ambiguity as they are commonly considered features of T1DM
State two monogenic causes of diabetes.
Maturity Onset Diabetes of the Young (MODY)
Mitochondial diabetes
NOTES:
- Monogenic = single gene defect
- MODY
- Various single gene defects can be responsible
- Mitochondrial diabetes
- Single gene defect in mDNA impacts ATP production
- In beta cells ATP required for insulin release (ATP sensitive K+ channels)
- Therefore if ATP production is disrupted, then insulin release is disrupted
Following what may diabetes present?
Diabetes may present following:
- Pancreatic damage
- Other endocrine disease
Describe the relative presence of different types of diabetes.
The bigger the circle, the more prevalent
Describe the current classification of type 1 and 2 diabetes mellitus.
Based on aetiology (cause)
Which type of diabetes has a cause with a bigger genetic infuence?
Type 2 Diabetes Mellitus
What can be measured in the blood to give an indication of insulin production?
C-peptide
- Part of proinsulin molecule - cleaved in the insulin synthesis process
- Once cleaved, the C-peptide and mature insulin are both stored in the secretory granules of the beta cells so both are released at the same time
- C-peptide has a longer half life than insulin
Describe the pathogenesis of T1DM.
- You get gradual autoimmune destruction of beta cells resulting in gradually reducing levels of insulin (and C-peptide)
- i.e. Antibodies directed against beta cells
- You get a prediabetic phase of elevated plasma glucose but some insulin is still being produced
- One of the first signs will be the loss of first phase insulin response (FIPR)
- FIPR is release of stored insulin when glucose is given IV - very fast
- Loss of this is one of the first signs of impaired insulin secretion
- There will be eventual destruction of all beta cells → severe insulin deficiency
- Overt = easily observable phase
Why is T1DM described as a ‘relapsing-remitting’ disease?
- Over time the beta cell mass appears to reduce, then stabilise, then reduce again
- There is a theory that this is due to the imbalance in effector T-cells and regulatory T-cells
- Effector T cells cause the destruction of beta cells
- Regulatory T cells control this destruction
- Initially an increase in the numbers of autoreactive effector T cells is controlled by an increase in the number of regulatory T cells - cyclical pattern
- However, over time, a gradual disequilibrium of the cyclical behavior could occur, leading to the number of autoreactive effector T cells surpassing the number of regulatory T cells
- This leads to autoimmune destruction of beta cells to the point where you no longer have enough to produce sufficient insulin to control blood glucose levels anymore
- The stabilisation may also be due to increase in beta cell proliferation over time which could be triggered by the inflamatory process
NOTE: Honeymood phase = the period of time shortly following diabetes diagnosis when the pancreas is still able to produce a significant enough amount of insulin to reduce insulin needs and aid blood glucose control
- BUT once these cells die you will have hyperglycaemia
What is the importance of the autoimmune basis of T1DM?
- Increased prevalence of other autoimmune disease
- Risk of autoimmunity in relatives
- More complete destruction of B-cells
- Autoantibodies can be useful clinically
- As a marker of certain diseases
- Immune modulation offers the possibility of novel treatments
What are the histological features of T1DM?
Lymphocyte infiltration of beta cells
- Islets of Langerhans (shown in the picture) are mainly made up of beta cells
- Lymphocytes lead to production of auto-antibodies and beta cell destruction
On which chromosome is the HLA found?
Chromosome 6
NOTE:
- HLA = human leukocyte antigen
- In humans the MHC proteins are coded for by the HLA gene complex/group
Which alleles convey a risk of diabetes? Which of these alleles is associated with the most significant risk?
DR alleles
- DR3 and DR4 = significant risk
NOTE: HLA-DR is one of the isotypes of MHC II proteins
Describe how environmental factors may affect type 1 diabetes.
T1DM prevalence:
- Increased in autumn
- Decreased in summer
Theory:
- There may be certain pathogens in the environment that trigger the onset of diabetes but is more prevalent in certain seasons
- Infections that target beta cells and promote strong inflammation within the islets may induce autoimmunity
State some antibody markers of type 1 diabetes.
- Islet cell antibodies (ICA) - blood group O human pancreas
- Insulin antibodies (IAA)
- Glutamic acid decarboxylase antibodies (GADA)
- GAD synthesises GABA which is a widespread nuerotransmitter
-
GABA is released by beta cells to have a paracrine function
- e.g. activation of GABA receptors in beta cells increases insulin release
- Insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family
- Insulinoma-associated protein 2 is associated with the membrane of secretory granules
- If these are affected it would lead to reduced insulin release
State some symptoms of T1DM.
Symptom = experienced by the person who has the condition
- Polyuria
- Nocturia
- Polydipsia
- Blurring of vision
- Short term - hyperglycaemia can lead to swelling of the lens, which can result in temporary blurring of eyesight
- Long term - diabetic retinopathy
- Thrush
- Poorly controlled diabetes leads to increased risk of infection as the hyperglycaemic enviroment leads to immune system dysfunction
- Weight loss
- Fatigue
- Insulin facilitates glucose uptake into cells so lack of insulin results in reduced uptake (e.g. muscle cells)
- Reduced uptake means reduced glucose avalailable for ATP production
What are the signs of T1DM?
Sign = the effect of a health problem that can be observed by someone else
- Dehydration
- Cachexia
- Cachexia = severe weight loss and muscle wasting
- Leads to extreme weakness
- Hyperventilation (Kussmaul breathing)
- Kussmaul breathing = deep laboured breathing that occurs in response to severe metabolic acidosis (in this case: diabetes ketoacidosis)
- Smell of ketones
- Glycosuria
- Ketonuria
What are the triglycerides in adipocytes broken down to?
Glycerol
Fatty Acids
What does insulin have an inhibitory effect on?
- Hepatic glucose output (i.e. glucose release from liver)
- Protein breakdown in muscle
- Glycerol release from the adipocytes
- Ketone body generation by the liver
Describe some of the processes which take place if you are insulin deficient.
Hyperglycaemia
- You lose the inhibitory effect on insulin on hepatic glucose output (HGO) so you get more glucose being released into the bloodstream from the liver
- You lose the stimulatory effect of insulin on glucose uptake, so you get reduced glucose uptake into muscle
- This exacerbates the hyperglycaemia
Other metabolic effects
- You get increased breakdown of muscle protein as this is no longer being inhibited by insulin
- The AAs are taken up by the liver and the glucogenic ones can be used in gluconeogenesis
- You get increased release of glycerol from adipocytes which is taken up by the liver and used in gluconeogenesis
- Gluconeogenesis → increased HGO
Describe how insulin deficiency leads to diabetic ketoacidosis (DKA).
Insulin has an inhibitory effect on:
- Glycerol AND fatty acid release from the adipocytes
- Essentially insulin inhibits lipolysis
- Ketone body generation by the liver
Process:
- Triglyceride breakdown → glycerol and fatty acids
- Released into circulation due to lack of inhibition by insulin
- Fatty acids enter liver and are converted into ketone bodies as it is not being inhibited by insulin
- These ketone bodies enter:
- Blood → diabetic ketoacidosis as they are acidic
- Urine → ketonuria
- Muscle → provides energy
- Some ketones are taken up by muscle but it is not as good of a fuel as glucose
Describe the insulin profile of a non-diabetic.
3 main peaks - one after each meal
Basal insulin:
- Low (basal) levels of insulin being produced by the pancreas througout
-
This allows blood glucose levels to be regulated while fasting
- Keeps blood glucose levels under control when glucose is being released by energy stores
- Allows this glucose to be taken up by other body tissues to provide them with energy
Describe what treatment you would give a patient who has meals twice a day and what the insulin profile would look like.
NOTES:
Intermediate-acting insulin:
- Intermediate duration of action and half-life
- Takes longer to have an effect than short-acting insulin
- Has a peak but it is not as high as short-acting insulin
- Given as a supplement to basal insulin
Arrows represent meals
Describe 2 the two different treatments you could give in patients who have 3 meals a day (i.e. most patients) and what the insulin profile would look like.
