4.8 - An Introduction to Diabetes Mellitus Flashcards
What are the features of GLUT-4 transporters?
- common in myocytes and adipocytes
- highly insulin-responsive
- lies in vesicles
- recruited and enhanced by insulin
- 7-fold increase glucose uptake
What are the effects of insulin on protein in myocytes in the fed state?
- protein breakdown inhibited
- along with IGF-1 and GH, converts amino acids to protein for storage
- gluconeogenic amino acids (e.g. alanine) can leave myocyte if needed elsewhere like in the liver - cortisol helps with this by inhibiting protein synthesis (facilitate protein –> AA)
What is the effect of glucagon on the liver in the fasting state?
- gluconeogenic amino acids released from myocytes enter the liver, which glucagon helps
- glucagon encourages breakdown of protein into AA in liver to enter gluconeogenesis
- glucagon increases gluconeogenesis to form glucose to increase hepatic glucose output (HGO) –> cortisol also does this
What is the effect of insulin on the liver in the fed state?
- the same amino acids that enter the liver are encouraged to be made into proteins by insulin
- insulin also inhibits gluconeogenesis in the liver to reduce HGO
How long do carbohydrate, protein and fat stores in the body last before they are depleted as fuel?
- carbohydrate (liver and muscle) - 16 hours –> depletable within a one day fast
- protein - 15 days
- fat - 30-40 days
What happens to triglycerides in the blood when they reach adipocytes?
- lipoprotein lipase in capillary wall/adipocyte is activated by insulin and breaks down triglycerides into glycerol and non-esterified fatty acids (NEFA)
- NEFA and glycerol are taken up by adipocytes
How does insulin interact with adipocytes in the fed state?
- glucose can be taken up by adipocytes through GLUT-4 - encouraged by insulin
- insulin promotes reformation of triglycerides for later use when needed by combining glycerol and NEFA in adipocytes
- insulin also inhibits breakdown of triglycerides in adipocytes as you do not need an alternative energy source
What happens to adipocytes in fasting state?
- BGC and insulin is low so growth hormone (GH) and cortisol is secreted
- these encourage triglyceride breakdown in adipocytes into NEFA and glycerol, which leave adipocytes and are taken to the liver
How is the circulation adapted for quick reactions to changes in blood glucose?
- there is a separate hepatic portal circulation - allows blood to go straight from heart through GI tract, picking up nutrients, to liver for processing
- insulin is released straight into hepatic portal circulation, so an increase in BGC can quickly be responded to
What happens when glycerol reaches the liver in a fed vs fasting state?
- glycerol enters the liver and is converted into glycerol-3-phosphate
- in a fed state (glucose is not needed), G3P is converted into triglycerides for storage
- in a fasting state (glucose needed), G3P undergoes gluconeogenesis to make glucose and increase HGO
What fuel can the brain use?
- glucose - preferred energy source
- ketone bodies
- cannot use NEFA - inability to use fatty acids as a fuel makes the brain unique
How are ketone bodies produced?
- NEFA released from adipocytes are taken up by the liver
- in a fed state, insulin is released which inhibits conversion of fatty-acyl-CoA into ketone bodies
- in fasting state, glucagon is released which promotes conversion of NEFA into ketone bodies to be used as an alternative energy source
What is hepatic glycogenolysis?
- when glucose levels are low, glucagon acts on liver and promotes breakdown of glycogen into glucose-6-phosphate
- G6P converted into glucose and outputted from liver to increase BGC
- alternatively, when glucose levels are high, glucose enters the liver through GLUT-4 which is encouraged by insulin
- insulin then promotes G6P to be converted into glycogen to be stored
What happens in myocytes when glucose is high vs low? (How does the glucose itself interact with the cell)?
- in fed state, insulin encourages glucose to enter myocyte where it is converted into glycogen and stored in the muscle to use, for the muscle to use only (cannot release glucose into system)
- NEFA can also be used as energy source by myocyte
- in fasting state, GH and glucagon inhibit glucose from entering myocyte so it can stay in circulation and be used in more important parts e.g. brain
What overall happens in the body in fasted state?
- low insulin : glucagon ratio
- [glucose] maintained at 3.0 - 5.5 mmol/L
- increased [NEFA] from increased lipolysis
- increased proteolysis = increased amino acids (but they decrease when prolonged fast)
- increase in HGO from glycogen and gluconeogenesis
- muscles use lipids and brain uses glucose + later ketones
- increased ketogenesis when prolonged
What overall happens in the body in fed state?
- stored insulin released in 1st phase, then slow release in 2nd phase
- high insulin : glucagon ratio
- stop HGO
- increased glycogen storage, lipogenesis and protein synthesis
- decrease gluconeogenesis and proteolysis
How is diabetes mellitus diagnosed?
- fasting glucose levels >7.0 mmol/L
- random glucose >11.1 mmol/L
- oral glucose tolerance test (fasting glucose, 75g glucose load, 2-hour glucose)
- HbA1c (>48 mmol/mol) –> gives average glucose over last three months
- a diagnosis requires two positive tests, or one positive test + symptoms
What is the pathophysiology in type 1 diabetes mellitus (T1DM)?
- autoimmune disease of T-cell-mediated destruction of insulin-producing beta cells in pancreas –> absolute insulin deficiency
- leads to proteolysis into AAs, and increased HGO
- also high glucose in urine = water osmoses into urine = high urine production - osmotic diuresis
- fat starts to be broken down into glycerol + NEFA –> if this happens for prolonged period you get ketone bodies forming –> high glucose and high ketone bodies in blood –> diabetic ketoacidosis (serious acute complication)
How do T1DM patients present?
- weight loss
- hyperglycaemia
- glycosuria (glucose in urine) with osmotic symptoms:
- polyuria - lots of urine made
- nocturia - passing of urine in night
- polydipsia - feeling very thirsty due to losing so much fluid
- ketones in blood and urine
What diagnostic tests distinguish between T1DM and T2DM?
- markers like antibodies - GAD, IA2
- low C-peptide
- presence of ketones
What happens if T1DM patients take too much exogenous insulin?
- they get hypoglycaemic
- you eventually stop HGO so glucose levels fall even further
- normally insulin in body switches off production of more, but taking exogenous insulin means the mechanism is not there = stays in circulation
- glucose continues to be taken up by muscle and BGC continues to drop
What is the counterregulatory response to hypoglycaemia?
- increased glucagon, catecholamines, cortisol and GH
- this leads to increased HGO with glycogenolysis and gluconeogenesis, and increased lipolysis
Why is it important to avoid hypoglycaemia?
- makes people feel awful and lethargic
- recurrent episodes of hypoglycaemia can lead to impaired awareness of hypoglycaemia where our body gets used to being hypoglycaemic = reduced ability to recognise symptoms until glucose much lower (loss of counterregulatory response)
What are symptoms and signs of hypoglycaemia?
Autonomic:
- sweating
- pallor
- palpitations
- shaking
Neuroglycopenic:
- slurred speech
- poor vision
- confusion
- seizures
- loss of consciousness