ENDOCRINOLOGY - DIABETES Flashcards
What’s the structure of insulin?
A 51 amino acid peptide hormone comprising 2 polypeptide chains
Where is insulin synthesised?
Beta cells of the pancreatic islets of Langerhans
What is insulins prime target organ?
The liver - 50% of secreted insulin is extracted and degraded in the liver with the remainder being broken down by the kidneys
Why does C-peptide provide a useful index of the rate of insulin secretion?
It is produced in equimolar amounts to endogenous insulin
C-peptide can assess a person’s own insulin secretion even if they receive insulin injections, and because the liver metabolizes a large and variable amount of insulin secreted into the portal vein but does not metabolise C-peptide, meaning blood C-peptide may be a better measure of portal insulin secretion than insulin itself
Where are most peptide hormones synthesised?
Pituitary gland
Pancreas
Parathyroid gland
What are insulins effects on muscle and adipose tissue?
- it increases the rate of glucose transport across the cell membrane
- it increases glycolysis by increasing hexokinase and 6-phosphofructokinase activity
- it increases glycogenesis
- decreases lipolysis and hence lowers the plasma fatty acid level
- it stimulates lipogenesis
- it increases the rate of transport of some amino acids into tissues
- it increases the rate of protein synthesis
- it decreases the rate of protein degradation in muscle
Why do glucose levels rise overnight aka the sundowner effect?
Low blood sugars from intake mean the body reacts by increases glycogenolysis, gluconeogenesis and decreases glycogenesis
Why is the pancreas known as a heterocrine gland?
Because its got exocrine and endocrine cells
What cells are present in endocrine pancreas? What are their functions?
Alpha cells - glucagon
Beta cells - insulin
What cells are present in exocrine pancreas? What are their functions?
Acinar cells - secrete digestive enzymes
What are islets of langerhans?
Areas of endocrine pancreas consisting of alpha and beta cells
What proportion of the pancreas is endocrine?
5%
Outline what happens in beta cells in a hyperglycaemic situation?
Glucose enters beta cell through GLUT-2 receptor -> glucose undergoes glycolysis -> ATP production -> ATP binds to a channel on the cell membrane, inhibiting it -> K+ now cannot leave the cell and so builds up inside the cell -> this increased membrane potential opens a voltage gated Ca2+ Channel so calcium floods in to the cell -> calcium links the cell membrane and vesicles of insulin and C-peptide and amylin -> fuse and move into the blood
Outline what happens when insulin reaches the liver?
Insulin binds to a tyrosine kinase receptor on the surface of the liver -> glucose enters the cell, independent of insulin, through the GLUT-2 receptor -> insulin can convert glucose into glycogen (glycogenesis) or convert it into pyruvate (glycolysis)
What happens when insulin reaches the muscles?
Glucose uptake : Insulin activates the tyrosine kinase receptor which stimulates GLUT-4 increasing glucose uptake into the muscle cell -> glucose can now undergo glycolysis
Insulin also stimulates the amino acid channels which increases amino acid uptake. This increases protein synthesis.
Insulin can also stimulate glycogenesis in the muscles
What happens when insulin reaches the adipose tissue?
Insulin binds to receptor which stimulates GLUT-4 and moves glucose into the cell. Glucose can now undergo glycolysis or be converted to glycerol or convert acetyl coA to fatty acids.
Glycerol and fatty acids combine to form triglycerides.
What are the susceptibility genes for T1 diabetes?
HLA DR3 and HLA DR4
What other autoimmune disease are the diabetes susceptibilit genes associated with?
RA
SLE
Coeliacs disease
Vitiligo
What do autoantibodies attack in diabetes? What are they called?
Beta cells in pancreas
Anti-islet cell antibodies
Anti-glutamic acid antibodies
Anti-insulin antibodies
Outline the pathophysiology of diabetes?
Antibodies damage beta cells in the pancreas which decreases insulin production which can lead to hyperglycaemia - this is because GLUT transporters expression is diminished
What is metabolic syndrome?
You need 3 of the following…
Fasting glucose >100mg/dL
Triglycerides >150mg/dL
HDL <50 if female or 40 if male
Blood pressure >130/85
BMI >35 in females or 40 in males
What’s the pathology behind the insulin resistance in type 2 diabetes?
A defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin
What’s the pathology behind type 2 diabetes?
defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin relative to increased demand leads to insulin hypersecretion by a depleted β-cell mass and progression towards absolute insulin deficiency
What symptoms does diabetes cause?
Polyuria
Glucosuria
Thirst
Weight loss
Increased hunger
Why does diabetes cause polyuria?
Glucose is osmotically active so glucosuria causes water to follow
Why does diabetes cause polydypsia?
Polyuria means blood volume starts to drop but glucose levels are still high (low fluid levels and high glucose = hyperosmolar blood)
This stimulates osmoreceptors in hypothalamus which triggers an increase in thirst
Why does diabetes cause unexplained weight loss?
When glucose is not being utilised in cells we get decreased ATP production. In response, other pathways must be used for sources of fuels
Increased lipolysis and proteolysis means breaking down fat and protein stores
Why does diabetes cause polyphagia?
Tissues aren’t getting the energy they need from glucose because of the insulin resistance. The body responds increasing hunger
How do you diagnose diabetes?
Diabetes symptoms plus…
Fasting glucose >7 mmol/L
Random glucose >11 mmol/L
Haemoglobin A1C >48mmol/mol
If asymptomatic then 2 abnormal glucose of HbA1c tests are required
What is haemoglobin A1C
Glycated haemoglobin (RBCs lifespan 3 months so this is a 3 month test)
When is the oral glucose tolerance test required?
Where there is diagnostic uncertainty
As well as for diagnosis of cystic fibrosis-related diabetes and gestational diabetes
What is pre-clinical diabetes?
a condition characterized by slightly elevated blood glucose levels, regarded as indicative that a person is at risk of progressing to Type 2 diabetes
This is when a person has impaired fasting glycemic and impaired glucose tolerance
What is non-enzymatic glycation?
excessive chemical attachment of glucose to proteins/lipids without the involvement of enzymes
Why can diabetes cause accelerate atherosclerosis?
Non-enzymatic glycation with proteins and lipids causes the synthesis of very inflammatory molecules which can cause inflammation to occur in blood vessels and LDL deposition.
Why can diabetes cause hyaline arteriolosclerosis?
Non enzymatic glycation results in protein deposits occurring in vessels and around the basemenebt membrane (hyaline arteriolosclerosis)
Whats the effect of atherosclerosis and hyaline arteriolosclerosis?
Decreased blood flow distal and decreases gas exchange across tissue because BM is thickened
What disease are associated with non-enzymatic glycation?
Coronary artery disease
Peripheral artery disease
Stroke
Retinopathy
Nephropathy
What are the 3 things classified with diabetic retinopathy?
Microaneurysms
Cotton wool spots
Flame haemorrhages
(All affect vision)
Why can diabetes lead to progression of cataracts?
the denaturation of the protein and other components of the lens of the eye, which renders it opaque
What proportion of those with diabetes does diabetic retinopathy affect?
One third
What are the earliest changes seen in the retina?
Background retinopathy
Microaneurysms which may leak small amounts of bloods but sights is not affected
Cotton wool spots are also seen where occluded vessels cause micro infarcts
What is stage 2 diabetic retinopathy?
Pre-proliferative retinopathy
Damage to walls of veins causes venous beading and elongation to occur, causing venous loops
At this stage you’re at high risk of vision being affected
You will be advised to have more frequent screening appointments
What is stage 3 diabetic retinopathy?
Proliferative retinopathy
Blockage of blood vessels leads to ischaemia = release of VEGF which promotes neovascularization
Haemorrhage and retinal detachment can occur as a result and now you’re at very high risk of losing vision
Treatment will now be offered to stabilise your vision but it cannot restore it
What is maculopathy?
Fluid from leaking vessels is cleared poorly in the macular area because the anatomy is different. If clearance fails then macular oedema can occur which can distort and thicken the retina at the macula, causing a loss of central vision
What are some treatment options for diabetic retinopathy?
Laser photocoagulation
Eye injections - anti-VEGF drugs
Vitreoretinal surgery
Outline the eye screening for diabetics in the UK?
All people with diabetes over the age of 12 years are offered annual measurement of their acuity and retinal photographs.
What is diabetic nephropathy?
gradually increasing urinary albumin excretion and blood pressure as the glomerular filtration rate falls insidiously towards end-stage renal disease
What’s the pathophysiology of diabetic nephropathy?
As the kidney becomes damaged by diabetes, the afferent arteriole becomes vasodilated to a greater extent than the efferent glomerular arteriole. This increases the intraglomerular filtration pressure, further damaging the glomerular capillaries. This contributes to mesangial cell hypertrophy and increased secretion of extracellular mesangial matrix material, eventually leading to glomerular sclerosis. These changes result in disruption of the protein cross-linkages that normally make the membrane an effective filter. In consequence, there is a progressive leak of proteins into the urine.
How do we screen for diabetic nephropathy?
The urine of all people with diabetes should be checked at least annually for the presence of microalbuminuria
How do we manage diabetic nephropathy?
Similar to CKD:
- antihypertensives to reach bp <130/80
ACEi and ARBs
- meticulous glycemic control
Whats the main cause of diabetic neuropathy?
occlusion of the vasa nervorum leading to ischaemia of nerves
What are early signs of diabetic peripheral neuropathy?
Loss of vibration, pain and temperature sensation in the feet
What do diabetic feet look like?
High arch, clawing of toes which causes abnormal distribution of pressure on walking resulting in callus formation under first metatarsal head or tips of toes
What are the effects of autonomic neuropathy?
Sweating
Cardiac denervation
Postural hypotension
Gastroparesis
Diarrhoea
Atonic bladder
Erectile dysfunction
What are the effects of somatic neuropathy?
Ocular palsies
Carpal tunnel syndrome
Small muscle wasting
Amyotrophy
Painful neuropathy
Neuropathic foot
What is Charcot neuroarthropathy?
a chronic, devastating, and destructive disease of the bone structure and joints in patients with neuropathy
it is characterized by painful or painless bone and joint destruction in limbs that have lost sensory innervation
How is diabetic foot screened for?
Healthcare professionals should screen for foot problems at least once a year; this process should include questions about past or present ulceration, an examination of the foot to detect structural abnormalities or callus formation and an assessment of neuropathy and peripheral vascular disease
How can you distinguish between ischaemia and neuropathy in the diabetic foot?
Ischaemia - claudation, rest pain, trophic changes on inspection, cold, pulseless, painful ulceration on heels and toes
Neuropathy - painless, high arch, clawing of toes, no trophic changes, warm, bounding pulses, painless ulcers on plantar region
What are some macrovascular complications of diabetes?
Heart failure
Stroke
MI
PVD
How do you manage atherosclerotic cardiovascular risk?
Tight glycemic control - SGLT2 inhibitors and GLP-1 receptor agonists have protective effect
Anti-hypertensive treatment - ACEi and ARBs
Statins for those over 40 or after 10 year history of diabetes with micro vascular complications
Smoking cessation
Low dose aspirin but is associated with morbidity from bleeding
What cancers are more common in type 2 diabetes?
Cancer of uterus and pancreas is doubled in risk
20-50% increase in risk of colorectal and breast cancer
Why is fracture risk increased in both type 1 and type 2 diabetes?
Type 1 have lower bone mineral density due to deficiency in insulin and insulin-like growth factors
Type 2 - unknown reason
How is type 1 diabetes treated?
Insulin
How is type 2 diabetes treated?
Exercise
Diet
Anti diabetic meds
Insulin
How do you treat diabetic neuropathy?
Gabapentin and pregabalin
How do you treat diabetic nephropathy?
ACEi and ARBs
Monitor kidney function
Check microalbuminuria
What are symptoms of hypoglycaemia?
Sweating
Confusion
Drowsiness
Coma
Palpitations
Weakness
Blurred vision
Seizures or fits
Collapsing or passing out
What are possible causes of hypoglycaemia?
Taking too much anti-diabetic drugs e.g. insulin, sulfonylureas, glinides
Skipping or delaying a meal
Not eating enough carbs
Unplanned or intense exercise
Drinking alcohol
How do you treat hypoglycaemia?
If conscious and able to swallow then have 15-20g fast-acting carbohydrate by mouth e.g. pure fruit juice or dextrosol tablets, glucojuice, 3-4 heaped tsps sugar dissolved in water
If unconscious or seizing and IV access available then give 100ml of 20% glucose over 15 mins or 200ml of 10% glucose over 15 mins
If the patient doesnt have IV access then give IM glucagon or glucose
What are the physiologic mechanisms to prevent hypoglycaemia?
Insulin decreases and counter regulatory hormones increase
Glucagon increases through glycogenolysis
Autonomic nervous system gets activated - causes symptoms
Neuroglycopenia
What are some counter regulatory hormones against insulin?
Cortisol
Growth hormone
Catecholamines
How much glucose is usually required to correct hypoglycaemia?
15 rule: have 15g carbs, wait 15 mins and measure blood sugar again
(Or 300ml of 5% dextrose)
What are the DVLA rules for driving with diabetes?
You have to let DVLA know when you have a diagnosis of diabetes but you can continue to drive unless you become hypglycaemia unawareness
What is hypoglycaemia unawareness
when someone doesn’t experience or perceive the symptoms of hypoglycemia
What are the major classes of antidiabetic drugs?
Biguanides
Sulfonylureas
Meglitinide
Thiazolidinedione
DPP-4 inhibitors
SGLT2 inhibitors
Whats the moa of Biguanides?
Increase insulin sensitivity and decreases hepatic gluconeogenesis
What are the side efefcts of metformin?
GI upset
Lactic acidosis
Vitamin B12 deficiency
Why isn’t metformin used in type 1 diabetes?
it acts only in the presence of endogenous insulin it is effective only if there are some residual functioning pancreatic islet cells.
What are contraindications for metformin?
Acute metabolic acidosis (DKA and lactic acidosis)
EGFR <30ml/min