Diabetes Flashcards
Definition & classification of type 1 diabetes
Ambiguity:
- Autoimmune (Type I) diabetes leading to insulin deficiency can present LATE (after decades of life) = this is Latent Autoimmune Diabetes in Adults (LADA)
- T2DM can present in childhood (linked to an increasing prevalence of childhood obesity)
- Diabetic ketoacidosis: more common in T1DM
(some people with T2DM can also present with it)
Monogenic causes of diabetes:
- MODY
- mitochondrial diabetes
Other causes:
- Pancreatitis
Endocrinological causes:
- Phaeochromocytoma
- Cushing’s Syndrome
- Acromegaly
(All of these cause hyperglycemia)
Current Classification of Diabetes based on aetiology
- Causation: Normally in type 1 there is an environmental trigger of some sort (usually in autumn) +
- The environmental trigger occurs in a background of a genetic component =
Together, this leads to autoimmune destruction of islet cells
- In T2DM there is a BIGGER genetic component
- Eventually T2DM patients will also develop insulin deficiency as their beta cells become exhausted and fail
Recall the pathophysiology of T1DM
Pathogenesis of Type I Diabetes
- C peptide can be measured in the blood and is a marker of insulin function because it is linked to insulin production
- If C peptide levels reduce then the patient is insulin-deficient
- Over time as insulin secretion decreases, the C peptide levels decrease as well
- There are various environmental triggers and regulators which come into play and lead to the destruction of beta cells
- Eventually, auto-antibodies are produced
- Patients will then go on to lose their first phase insulin
- The loss of first-phase insulin production is an indicator that the patient will develop diabetes later on -> this can take years
Diabetes as a ‘Relapsing-Remitting Disease’
- Over time the beta cells reduce, then stabilise then reduce again
- There is a theory that this is due to an imbalance between effector T cells and T9 regulatory cells
- NOTE: effector T cells cause the destruction of beta cells and T9 regulatory cells control this destruction
- Over time the effector T cells increase in number and the T9 regulatory cells decrease
Importance of the Autoimmune Basis of T1DM
- Increased prevalence of other autoimmune disease e.g. rheumatoid arthritis, thyroid disease, fertility problems
- Risk of autoimmunity in relatives
- More complete destruction of beta cells (all the beta cells will be destroyed over time in T1DM)
- Auto-antibodies can be clinically useful (to see how the disease is progressing and to confirm the autoimmune basis of the diabetes)
- Immune modulation offers the possibility of novel treatments
Histological features of T1DM:
- There is a lot of lymphocyte infiltration of the beta cells which destroys it so it can no longer release insulin
Discuss Genetic Susceptibility to Type 1 Diabetes Mellitus
- HLA is located on chromosome 6
- There are various DR alleles that may confer a risk (in particular DR3 and DR4
- NOTE: increased prevalence in the autumn
Theory: there is some pathogen (bacterial or viral) in the environment around this time of the year that triggers the onset of diabetes
Important markers for clinically defining someone who may have type 1 diabetes
TWO MOST SIGNIFICANT MARKERS:
- Islet Cell Antibodies (ICA) K group O human pancreas
- Glutamic Acid Decarboxylase Antibodies (GADA) (widespread neurotransmitter)
Other two antibodies:
- Insulin Antibodies (IAA)
- InsulinomaKassociatedK2 autoantibodies (IAK2A)Kreceptor like family
- These aren’t measured in clinical practice
Discuss the clinical presentation of T1DM
SYMPTOMS
- polyuria
- nocturia
- polydipsia
- blurring of vision
- ‘thrush’
- weight loss
- fatigue
SIGNS
- dehydration
- cachexia
- hyperventilation
- smell of ketones
- glycosuria
- ketonuria
Thrush - because of the increased risk of infections
Hyperventilation - they have metabolic acidosis so the body tries to get rid of the acid by blowing off CO2
This is called Kussmaul Breathing
Action of insulin in the body
- The liver is a large source of glucose (mainly from glycerol)
- Glucose goes out into the periphery where it can be utilised by the tissues
- Amino acids from the muscle goes out into the circulation and can be taken up by the liver
- In adipocytes you have triglycerides which can be broken down into glycerol and fatty acids
Insulin has a negative effect on:
- Hepatic glucose output
- Protein breakdown in the muscle
- Glycerol being taken out from the fatty tissue into the periphery
Insulin has a positive effect on:
- Glucose being taken up by the muscle
So in the case of insulin deficiency:
- A lot of glucose goes out into the circulation but isn’t taken up by the tissues
Other hormones that increase hepatic glucose output:
- Catecholamines
- Cortisol
- Glucagon
- Growth Hormone
Mechanism of diabetic ketoacidosis
Mechanism of Diabetic Ketoacidosis
- Glucose isn’t taken up into cells and utilised so a lot of our energy comes from fatty acids
- So the lipid in the adipocytes is broken down
- Normally, you get glycerol coming out of the adipocytes and going to the liver but in the case of insulin deficiency, you get FATTY ACIDS coming out of the adipocytes into the circulation
- Fatty acids then go to the liver where they are converted to ketones (this process is normally inhibited by insulin)
Key Point: as you are deficient in insulin, you get a lot more ketone bodies being produced by the liver
Explain the physiological basis of treatment of T1DM
Aims of Treatment of Type I Diabetes Mellitus
- Reduce early mortality
- Avoid acute metabolic decompensation
- Type I diabetics need exogenous insulin to preserve life
- KETONES DEFINE INSULIN DEFICIENCY
- Prevent long-term complications:
- Retinopathy
- Nephropathy
- Neuropathy
- Vascular Disease
1. Diet in Type 1 Diabetes Mellitus
- Reduce calories as FAT
- Reduce calories as REFINED CARBOHYDRATES
- Increase calories as COMPLEX CARBOHYDRATES
- Increase SOLUBLE FIBRE
Balance distribution of food over the course of a day with regular meals and snacks
2. Insulin Treatment
- With Meals
- Short acting insulin
- Human insulin
- Insulin analogues: engineered to mimic what happens in normal physiology (Lispro, Aspart, Glulisine
Background Insulin: 9 50% of insulin requirement is a basal form:
- Long acting
- Non-C bound to zinc or protamine
Insulin analogues
- Glargine
- Detemir
- Degludec
Genetic engineering to alter absorption, distribution, metabolism and excretion of the insulin
Insulin Profiles of Treatment Normal Person
- Therapy is trying to replicate what happens in normal physiology
- Basal insulin is being produced
- Twice daily insulin with intermediate insulin
- They can inject themselves with the short-acting insulin after meals
- They have the intermediate insulin to mimic the basal insulin level
Newer insulin analogues
- With newer analogues you can give a basal amount of insulin that lasts longer
- These are given to patients who suffer from severe hypoglycaemia
- Basal analogues have a lower rate of hypoglycaemia than the human insulins
- In reality, the human insulin is cheaper and just as effective
3. Insulin Pump
- Continuous insulin delivery
- Pre-programmed basal rates and a bolus for meals
- Does NOT measure blood glucose, so it can’t form a feedback loop and completely replace the beta-cell function
- The pumps need to be attached to the patients constantly and if it is taken off then there is a risk of acidosis
- It could also just stop working, which is why patients are advised to keep subcutaneous insulin with them
4. Islet Cell Transplants
- Islet cells are harvested, isolated and injected into the liver
- There is a risk of rejection so patients must be on immunosuppressants for life
- Islet cells are difficult to get a hold of so there is a very long waiting list
- People who are legible for islet cell transplants have long term type 1 diabetes mellitus with complications and occurrences of severe hyopglycaemia that can’t be controlled by the instant pump
Monitoring glucose levels
Capillary Monitoring
- Capillary glucose levels can be measured by pricking the finger tips
- This is reflective of venous blood glucose
- The patients can titrate their insulin does based on the capillary glucose reading
- You can get a continuous glucose monitor which is attached to the subcutaneous tissue
- However, this isn’t as accurate as the capillary glucose measurement so it needs to be regularly calibrated using capillary glucose
HbA1c
- Long-term blood glucose control is monitored by measuring HbA1c
- This is a marker of glucose control over the last 3 months (as red cell lifespan is about 120 days)
- Rate of glycation may be faster in some people
- Them more glucose that is present in the blood, the more the haemoglobin is glycosylated
- There is a good correlation between plasma glucose over a reasonably long period of time and HbA1c
- In type 1 diabetics you are aiming for an HbA1c < 7%
- Lower HbA1c is associated with a lower risk of complication particularly microvascular complication
- As this measurement relies on haemoglobin, if anything causes an increased turnover of haemoglobin (e.g. haemolytic anaemia or haemoglobinopathy) then the HbA1c may not be accurate
Complications of T1DM
Acute Complications
Rapid decompensation of type 1 diabetes
- Main Consequence = HYPERGLYCAEMIA
- Reduced tissue glucose utilisation
- Increased hepatic glucose production
- METABOLIC ACIDOSIS
- Circulating acetoacetate and hydroxybutyrate
- Results from increased ketone body production in the liver
- Osmotic dehydration and poor tissue perfusion
It tends to be patients with Type 1 that get ketoacidosis but there is a subset with T2DM that also get ketoacidosis
- DKA is relatively common black and Asian patients with T2DM
- DKA in T2DM may be due to pancreatic insufficiency at a time of stress (when they present as an in patient)
Hypoglycaemia in Diabetes - ‘Hypos’
- Occasional hypos are inevitable as a result of treating diabetes
- This a major cause of anxiety in patients and relatives
Source of misconceptions in the media
Definitions:
- Hypoglycaemia = plasma glucose < 3.6 mmol/L
- Severe Hypoglycaemia = any event that needs another person to treat it
- Most mental processes impaired at < 3 mmol/L
- Consciousness impaired at < 2 mmol/L
- Severe hypoglycemia may contribute to arrhythmia and sudden death
- May have long-term effects on the brain
- Recurrent hypos result in loss of warnings -> hypoglycemia unawareness
- Hypoglycaemia unawareness is associated with poor diabetes control
Who gets hypoglycaemic?
Main risk factor is the quality of glycaemic control
- Most frequent in patients with low HbA1c
When do they become hypoglycaemic?
- Can occur at any time but there is often a clear pattern
- Pre-lunch hypos are common
- Nocturnal hypos are very common and often not recognised
Why do they become hypoglycaemic?
- Unaccustomed exercise
- Missed meals
- Inadequate snacks
- Alcohol (if they have too much then they can become unaware of the hypoglycaemia)
- Inappropriate insulin regime
Signs, symptoms and treatment of hypoglycaemia
Hypoglycaemia symptoms & signs
Due to increased autonomic activation
- palpitations (tachycardia)
- tremor
- sweating
- pallor / cold extremities
- anxiety
Due to impaired CNS function
- drowsiness
- confusion
- altered behaviour
- focal neurology
- coma
Treating Hypoglycaemia
- ORAL: feed the patient!
- glucose: rapidly absorbed as solution or tablets
- complex CHO: to maintain blood glucose after initial treatment
- PARENTERAL: give if consciousness impaired
* IV dextrose e.g 10% glucose infusion
* 1mg Glucagon IM:avoid concentrated solutions if possible (e.g 50% glucose)
Define T2DM and understand its relation to other types of diabetes
Definition of Diabetes
- A state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidneys, nerves and arteries
- T2DM is NOT ketosis prone
- T2DM is NOT mild
- T2DM often involves weight, lipids and blood pressure (disease of intermediary metabolism)
Defining Values
- Diabetes is defined as a fasting blood glucose > 7 mmol/L
- The space in between the defining markers for diabetes and being normal is considered:
- Impaired Fasting Glucose - when measuring fasting blood glucose
- Impaired Glucose Tolerance - when measuring the 2 hour response in a glucose tolerance test
Describe the epidemiology and aetiology of diabetes
Epidemiology of T2DM
- There is a genetic predisposition and an environmental precipitant to T2DM
- Intrauterine environment- There will be epigenetic changes that take place in utero, which affect blood glucose control in the future
- Adult environment
MODY
- Mature onset diabetes of the young (8 types)
- It is autosomal dominant
- Ineffective pancreatic beta cell insulin production
- Caused by mutations of transcription factor genes (glucokinase gene)
- Positive family history with NO obesity
Describe the pathophysiology of diabetes
- MODY (maturity onset diabetes of the young) is relatively uncommon but gives useful metabolic insights
Causes:
- T2DM is caused by insulin resistance and insulin secretion defects
- Fatty Acids are important in the pathogenesis and complications of T2DM
Illustration of the pathogenesis of T2DM
- Genes can contribute to risk - they can cause insulin resistance modulated by various adipocytokines through adult life before someone develops diabetes
- The insulin resistance is likely to have been present for a long time before the glucose gets elevated
- Small babies are more likely to develop T2DM intrauterine growth restriction (IUGR)
- In adulthood, obesity and some fatty acids can alter the risk
- High BP: Insulin resistance leads to dyslipidaemia and stimulates the mitogenic pathway causing smooth muscle hypertrophy and an increase in blood pressure
- The dyslipidaemia and hypertension increase the risk of macrovascular disease (progressive atheroma in big arteries)
(This can all happen while the blood sugar is normal)
- 50% of patients present with complications of diabetes
- Insulin resistance is progressive and damages the beta cells leading to gradual
NOTE: microvascular disease is found in diabetes with hyperglycaemia
NOTE: twin studies showed that T2DM follows an almost autosomal dominant pattern whereas in T1DM there is less genetic input
Low birth weight is also linked to diabetes:
- Low birth weight increases the risk of impaired glucose tolerance and diabetes
- This is believed to be due an epigenetic effect
T2DM - insulin resistance and insulin secretion:
- We all make less and less insulin as we grow older
- At the same time, we become more and more insulin resistant
- At some point, the insulin resistance and insulin secretion lines will intersect - beyond this point we wont be able to make enough insulin for our insulin resistance
In Caucasians, this intersection normally occurs around 110 years of age
In other ethnic groups it intersects much sooner
Metabolism of T2DM
Metabolism and Presentation of T2DM
- Obesity is present in about 80% of patients with T2DM
- Insulin secretion deteriorates with progressive impairment of glucose tolerance
- If you give a normal person some glucose, then they will have TWO phases of insulin secretion
- 1st Phase: stored insulin that is ready to be released
- 2nd Phase: over a period of time, more insulin is produced and released
- People who are developing diabetes will still have some insulin production but they will lose their 1st phase insulin response
- They can make insulin eventually but it takes a longer time for them to do it
- You can get around this by eating complex carbohydrates which release the glucose more slowly thus reducing the need for a first phase insulin response
- Decreases glucose disposal and increased hepatic glucose output contribute to increased blood glucose in T2DM
- Insulin lowers blood glucose by reducing HGO
- When we have NOT eaten, our hepatic glucose output maintains our blood glucose at 4 mmol/L
- After we’ve eaten, insulin stops HGO because you don’t need this output from the liver once you’ve just eaten
- Once we’ve eaten and the glucose from the meal has entered our blood, insulin drives the glucose into muscle and adipose tissue
Both of these effects are absent in T2DM
There is insufficient insulin to inhibit hepatic glucose output and insufficient insulin to move glucose into muscle and fat
Relationship between insulin sensitivity and insulin secretion
- There isn’t a single correct amount of insulin that you should make: it is dependent on how insulin resistant you are
- As years go by your insulin sensitivity decreases and so your insulin secretion should increase to move leftwards along this path and maintain normal blood glucose levels
- People developing diabetes will not increase their insulin secretion sufficiently to balance the decrease in insulin sensitivity so they will fail to make enough insulin for their given insulin sensitivity
Effects of Insulin Resistance
- Adipocytes are full of triglycerides which can be broken down to glycerol and non-esterified fatty acids (NEFA)
- Insulin would stop this breakdown of triglycerides because there is no need to break down fat stores after you’ve had a meal
- The glycerol and NEFA travel to the liver
- This breakdown of triglycerides is particularly marked for omental adipocytes - which is why waist circumference is predictive of ischaemic heart disease
- In the liver, glycerol can be used to make glucose: gluconeogenesis
- Glucose can also be released from the liver via glycogenolysis
- Insulin resistance means that there is increased hepatic glucose output and decreased glucose uptake into tissues
- The fatty acids go to the liver, are chopped up into 29 carbon segments and
- CANNOT be used to make glucose
It is instead used to make very low density lipoprotein triglycerides which are ATHEROGENIC
This contributes to the atherogenic profile of insulin resistant subjects
NOTE: omental adipocytes have a privileged position as they drain directly through the liver and they are more active from an endocrine perspective
Obesity
- Obesity appears to be part of the mechanism of T2DM
- Adipocytokines don’t directly cause the diabetes but they modulate insulin resistance
Preturbations in Gut Microbiota
- The gut microbiome appears to be associated with obesity, insulin resistance and T2DM
- This may be important through signalling to the host
- Various lipopolysaccharides are fermented by the gut bacteria to short chain fatty acids
- These short chain fatty acids can enter the circulation and modulate bile acids
- So they aren’t just in the gut, they can also modulate host metabolism
- They also appear to be important in inflammation and are involved in adipocytokine pathways
- Microbiota transplants are being investigated as a treatment for obesity
NOTE: weight gain is a common side effect of diabetes treatment (METFORMIN is the only agent that reduces weight)
Changes in insulin secretion and insulin resistance as diabetes progresses
The intrauterine environment is important : epigenetic changes may influence insulin secretion in later life
NOTE: as the pancreas fails, it starts to make immature insulin - they don’t have first phase insulin so they make insulin that doesn’t work properly
Eventually, there is an absolute insulin deficiency
Presentation of T2DM
- Osmotic symptoms
- Infections
- Screening test
- at presentation of complication
–Acute; hyperosmolar coma,
–Chronic; ischaemic heart disease, retinopathy
