Metabolism S8 - Diabetes Flashcards
Describe diabetes mellitus
A heterogenous group of multifactorial, polygenic syndromes characterised by chronic hyperglycaemia due to insulin deficiency, insulin resistance or both
How does ketoacidosis develop in a person with Type I diabetes?
- Acetyl CoA is at high concentrations due to increased fatty acid oxidation as glucose cannot be taken up by cells
- Noradrnaline, a stress hormone, is released stimulating hormone sensitive lipase to begin lipolysis
- Lack of insulin means that the enzyme lyase is no longer inhibited ao acidic ketone bodies are synthesised from the already high levels of Acetyl CoA
- Ketoacidosis occurs as concentration of ketone bodies exceeds buffering capacity
What is the typical presentation of a person with type I diabetes?
- Genetic markers (HLA DR3 & DR4) and auto-antibodies detected
- Impaired glucose tolerance
- Development of diabetes
- Total insulin dependence
What is the typical presentation of a person with type II diabetes?
- Insulin resistance
- Impaired glucose tolerance
- Diabetes
- Eventually become totally insulin dependant
What is Hba1c? Why is it used?
- Glycated haemoglobin
- Produced when glucose in blood reacts with a terminal valine
- A good marker of how well diabetes is being manages (120 days circulation of RBCs)
- Above 6.5 indicates poorly managed diabetes
List metabolic, microvascular and macrovascular long term side effects of diabetes
Metabolic - Polyuria, polydipsia
Microvascular - Retinopathy, neuropathy, nephropathy
Macrovascular - increased risk of stroke, myocardial infarction, poor circulation to the periphery
How is retinopathy caused in diabetic patients?
- Excess glucose is converted to sorbitol by aldose reductase
- This depletes NADPH reserves leading to increased disulphide bond formation whilst the accumulation of sorbitol causes osmotic damage to cells
Describe the structure of beta cells
- ATP sensitive potassium channels
- Voltage gated calcium channel
- GLUT 2 receptor
- Insulin secretory granules
- Large amounts of RER and golgi for insulin production
What stimulates insulin production?
- Glucose at high concentrations is transported into beta cells through GLUT 2 receptors by facilitated diffusion
- Glucose metabolised to ATP
- ATP blocks ATP sensitive potassium channels
- Prevents potassium moving out leading to depolarisation of the membrane
- Voltage gated calcium ion channels open and calcium ions move in to beta cells
- Stimulates release of insulin secretory granules by exocytosis
How can diabetes be diagnosed?
Triad of symptoms - Polyuria, polydipsia, unexplained weight loss
- Random venous plasma glucose concentration above 11.1mmol/l
- Fasting plasma glucose concentrations above 7 mol/L
- Plasma glucose concentration above 11.1mmol/L two hours after 75g anhydrous glucose in oral glucose tolerance test
TWO must be used to confirm diabetes if no symptoms present
How does polyuria occur?
- Glucose normally reabsorbed from blood at the proximal tubule with water following it
- The reabsorption here is isosmotic
- In diabetes mellitus, large quantities of glucose are filtered by the kidney and not all of it can be reabsorbed
- The extra glucose remains in the nephron tube
- This places an extra osmotic load on the nephron, and means less water is reabsorbed to maintain the isosmotic nature
What are the features of keto-acidosis?
Prostration, hyperventilation, nausea, vomiting, dehydration and abdominal pain
What symptoms do type I sufferers suffer from?
Triad of symptoms:
1) Polyuria
2) Polydipsia
3) Unexplained weight loss
What symptoms do type II sufferers suffer from?
- Triad of symptoms
- Lack of energy
- Persistent infections
- Slow healing of minor skin damage
- Visual problems
What is hypoglycaemia and what are its consequences?
- Blood glucose concentration less than 3mmol/L
- Acute effects include sweating, slurred speech, trembling, palpitations, headache, sickness and staggering
- Can rapidly lead to unconsciousness and death if untreated as CNS starved of oxygen
How is insulin synthesised and stored?
- Synthesised as preproinsulin
- Pre-signal cleaved off in ER
- Proinsulin cleaves by endopeptidase which removes C-peptide
- Mature insulin packaged by golgi into secretory granules with C-peptide in equal amounts
- Marginate to cell membrane when secretion is stimulated
- C-peptide levels are a good measure of endogenous insulin when administering exogenous insulin
What metabolic processes are stimulated by insulin?
- Glycolysis
- Glycogenesis
- Lipogenesis
- Cholesterol synthesis
- Uptake of amino acids
- Protein synthesis
What metabolic processes are inhibited by insulin?
- Ketone body synthesis
- Gluconeogenesis
- Lipolysis
- glycogenolysis
How does insulin effect target cells?
- Insulin binds to specific insulin receptors on the cell surface of the target tissues
- Alpha chains fold around the insulin molecule stimulating beta chains spanning the plasma membrane to move together and form an active tyrosine kinase
- This stimulates a phosphorylation cascade which causes an increased expression of GLUT 4 receptors so glucose can be taken up by the cell
What is the mechanism of action of glucagon?
- Glucagon binds to specific G protein-coupled receptors
- Binding activates adenylyl cyclase, which increases cAMP levels
- High levels of cAMP activate protein kinase A, which phosphorylates and therefore activates a number of important target cell enzymes
How does type II diabetes mellitus differ from type I?
- More gradual onset
- Caused by insulin resistance and/or defective insulin secretory response
- Normally adult onset
- Do not usually develop ketoacidosis
- Treated, at least initially with diet, drugs and exercise
- Strong genetic component
Explain why hyperglycaemia occurs in diabetics
- Reduced uptake of glucose by adipose tissue and skeletal muscle
- Reduced storage of glucose by liver and skeletal muscle ( decreased glycogenesis and increased glycogenolysis)
- Increased production of glucose (increased gluconeogenesis and decreased glycolysis_
Describe the metabolic basis of insulin’s action in lowering blood glucose concentration
- Stimulating glucose uptake into muscle and adipose tissue
- Stimulating storage of glucose as glycogen in muscle and liver
- Stimulating glucose oxidation in liver
- Stimulating lipogenesis and esterification in liver and adipose tissue
- Inhibiting gluconeogenesis in the liver
