Endocrine Kidney & Diabetes Flashcards
1
Q
Explain the half life and solubility properties of insulin and glucagon
A
- Water soluble
- Short half life to allow constant monitoring and changing of glucose concentration
- Once binds to receptor and enters cell, internalised and inactivated
2
Q
Which cells are insulin and glucagon made in
A
Insulin made in pancreatic ß-cell
Glucagon made in pancreatic α cells
3
Q
Describe the structure of insulin
A
- Structure - α helix with A and B chains, and C-peptide
- A and B chains linked covalently by two disulphide bonds
- Another inter-chain disulphide bond within A chain to maintain curve
4
Q
Describe how insulin is synthesized
A
- Preproinsulin made in ribosomes associated with RER
- Signal peptide removed to become proinsulin when it enters ER and folds
- Proinsulin travels to Golgi and packaged into storage vesicles
- Proteolysis removes C-peptide, forming two chains connected by disulphide bridge
- Vesicles contain insulin and C peptide separately and marginate to cell surface and remain there
- When needed, insulin and C peptide released from vesicles
- C peptide - helps prevent vascular damage in patients with diabetes
5
Q
What happens when insulin binds to its receptor on target cell surface
A
- Insulin binds to target cells through insulin receptor
- Stimulates insertion of glucose transporter (GLUT-4) onto target cell membrane
- Glucose moves from plasma inside the cell
6
Q
How is glucagon synthesized
A
- Synthesised from pre-proglycogen in RER and stored in vesicles until release (similar to insulin)
7
Q
Describe the structure of glucagon
A
Structure - single chain with no disulphide bonds
8
Q
What happens when glucagon binds to its receptor on target cell surface
A
- Glucagon binds to GPCR receptors which activate adenylyl cyclase
- Increases cyclic AMP which activates protein kinase A
- Phosphorylates and thereby activates important enzymes in target cells
9
Q
Describe how the structure of the ß-cell relates to the synthesis and storage of insulin
A
- Contain ATP sensitive potassium channels (KATP) - allows efflux of potassium
- Channels hyperpolarise cell membrane
- Inhibited by ATP
- In presence of high plasma glucose:
- Glucose increases ATP which closes channel to cause depolarisation
- By depolarising membrane, voltage gated calcium channels open to increase intracellular calcium
- Cause vesicles containing insulin to fuse with membrane of ß cell and released
10
Q
How does ATP sensitive-potassium channels regulate insulin synthesis
A
- Process also regulates insulin synthesis
- In low metabolism, KATP channels open so insulin not secreted
- In high metabolism, ATP causes KATP to close so insulin secreted
11
Q
What are the effects of insulin
A
- Stimulated at glucose concentration > 5mmol/L
- Increase glucose transport into adipose tissue and skeletal muscle
- Increase glycogenesis and decrease glycogenolysis in liver and muscle
- Increase lipogenesis and decrease lipolysis in adipose tissue
- Decrease ketogenesis in liver
- Increase amino acid uptake and protein synthesis in liver, muscle and adipose tissue
- Decrease proteolysis in liver, muscle and adipose tissue
12
Q
What are the effects of glucagon
A
- Stimulated at glucose concentration > 5mmol/L
- Increase glycogenolysis and decrease glycogenesis in liver
- Increase gluconeogenesis in liver (synthesize glucose from amino acids)
- Increase ketogenesis in liver
- Increase lipolysis in adipose tissue
- Stimulated in high amino acid in starvation - digestion of muscle
13
Q
Explain the timing response of the effects of insulin and glucagon
A
- Glucose uptake rapid response to insulin
- Glycogen synthesis/breakdown intermediate response to hormones
- Gluconeogenesis intermediate response to glucagon
- Lipogenesis/lipolysis/ketogenesis delayed response to hormones
- Amino acid uptake rapid response to insulin
- Protein synthesis intermediate response to insulin
14
Q
What is normal glucose concentration
A
Normally 3.3-6mmol/L
15
Q
At what glucose concentration does polyuria occur
A
Plasma glucose > 10mmol/L
16
Q
Define diabetes mellitus
A
- Diabetes mellitus is a group of metabolic disorders characterized by chronic hyperglycaemia
- Prolonged elevation of glucose > 6mmol/L
17
Q
Describe Type 1 diabetes
A
- Type 1 - insulin deficiency
- Common in young people
- Autoimmune destruction of ß cells
- Absolute - pancreatic ß cells destroyed
- Relative - ß cells not responding properly leading to relative deficiency in insulin
- Insulitis - inflammation of Islet’s of Langerhans
- Chronic inflammation leading to infiltration of T lymphocytes and macrophages
- Mutation of 2 subunits in ATP sensitive potassium channel which becomes insensitive to ATP
- Insulin not released so plasma glucose does not decrease
- Presence of high ketone bodies - breakdown product of fat
18
Q
Describe Type 2 diabetes
A
- Type 2 - normal insulin secretion but peripheral tissue resistant to insulin
- Common in older or obese individuals
- Slow progressive loss of ß-cells along with defective insulin secretion and tissue resistance to insulin
- Defective insulin receptor mechanism
- Or Excessive or inappropriate glucagon secretion
- Normal ketone bodies
19
Q
Distinguish between Type 1 and Type 2 diabetes
A
- Type 1 is autoimmune destruction of ß cells, Type 2 is defective insulin receptor mechanism
- Type 1 has high ketone bodies, Type 2 has normal
- Type 1 more common in young people, Type 2 more common in adults
20
Q
Describe the presentation of Type 1 diabetes
A
- Polyuria - large amount of glucose not reabsorbed into blood
- Increases osmotic pressure inside nephron so less water is reabsorbed
- Polydipsia - due to excess water loss
- Weight loss - fat and protein metabolised by tissues as glucose not entering cells
- Ketoacidosis - hyperventilation, nausea, vomiting, dehydration, abdominal pain, coma, prostration (collapse)
- Acetone smell in patient’s breath
21
Q
Describe the presentation of Type 2 diabetes
A
- Polyuria
- Polydipsia
- Weight loss
- Lethargy
- Persistent infections - particularly thrush infections in genitalia (infection thrives on glucose from polyuria)
- Infections on feet
- Slow healing minor skin damage
- Visual problems
22
Q
Explain the sequence of events leading to ketoacidosis in the uncontrolled diabetic
A
- High rates of ß-oxidation of fats in the liver coupled with low insulin leads to vast production of ketone bodies
- Acetone can be breathed out - patients breath
- Increased ketone body production leads to keto-acidosis
- Presents as prostration, hyperventilation, nausea, vomiting, dehydration, abdominal pain
23
Q
What are consequences of hyperglycaemia
A
- Uptake of glucose into peripheral nerves, eye and kidney do not require insulin - determined by plasma glucose concentration
- Glucose metabolised which needs NADPH - causes NADPH depletion
- Increased disulphide bone formation - alter cellular protein struture and function
- Osmotic changes in cells
- Increased glycation of plasma proteins - affects protein function
- Ketoacidosis - leading to coma
- Glucosuria
- Polyuria - dehydration - polydipsia and confusion
24
Q
What tests do you do on suspected diabetic patient
A
- Fasting glucose concentration > 7mmol/L
- Random venous plasma glucose concentration > 11.1mmol/L
- Oral glucose tolerance test - plasma glucose concentration > 11.1mmol/L 2 hours after glucose given
- HbA1c > 10%
- Urine dipstick - test glucose and ketone
- Finger prick - test glucose and ketone
25
Q
What are treatments of Type 1 diabetes
A
- Subcutaneous insulin injection - life long
- Need to maintain regular eating schedule
- Exercise and diet
- Exercise increases insulin sensitivity
26
Q
What are treatments of Type 2 diabetes
A
- Exercise and diet
- Exercise increases insulin sensitivity
- Metformin - reduces gluconeogenesis
- Sulphonylureas - makes KATP more sensitive to ATP, so more insulin released
- Increase glucose excretion through urine - however causes vagina thrush
27
Q
Explain the principle and practice of measuring glycated haemoglobin as an index of blood glucose control in the diabetic
A
- HbA1c test > 10%
- Test measures 3 month average glucose concentration (red blood cell life time = 120 days)
- Normally only a small percentage of plasma glucose is bound to haemoglobin
- For diabetes, glycated haemoglobin levels high
28
Q
What are macrovascular complications of diabetes
A
- Increased risk of stroke
- Increased risk of myocardial infarction
- Poor circulation to the periphery - particularly to feet
29
Q
What are microvascular complications of diabetes
A
- Diabetic eye disease - osmotic changes in glucose
- Cataracts
- Retinopathy - damage to blood vessels in retina leading to blindness
- Vessels may leak and form protein exudates, or rupture
- Diabetic kidney disease (nephropathy)
- Damage from infections of urinary tract
- Damage to glomeruli
- Poor blood supply because of changes in kidney blood vessels
- Diabetic neuropathy
- Diabetes damages peripheral nerves
- Loss of sensation
- Diabetic feet
- Poor blood supply, damage to nerves and increased risk of infection
30
Q
Discuss the aetiology of metabolic syndrome and its consequences for health
A
- Cluster of most dangerous risk factors associated with cardiovascular disease
- Diabetes and raised fasting plasma glucose
- Abdominal obesity
- High cholesterol
- High blood pressure
- To have metabolic syndrome
- Waist measurement > 94cm for men and > 80cm for women + any 2 of the following
- Raised triglyceride levels
- Reduced HDL cholesterol
- Raised blood pressure
- Raised fasting glucose level
- Waist measurement > 94cm for men and > 80cm for women + any 2 of the following
- Causes - insulin resistance and central obesity, genetics, physical inactivity, aging
