4.8 - An Introduction to Diabetes Mellitus Flashcards
1
Q
What are the features of GLUT-4 transporters?
A
- common in myocytes and adipocytes
- highly insulin-responsive
- lies in vesicles
- recruited and enhanced by insulin
- 7-fold increase glucose uptake
2
Q
What are the effects of insulin on protein in myocytes in the fed state?
A
- 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)
3
Q
What is the effect of glucagon on the liver in the fasting state?
A
- 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
4
Q
What is the effect of insulin on the liver in the fed state?
A
- 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
5
Q
How long do carbohydrate, protein and fat stores in the body last before they are depleted as fuel?
A
- carbohydrate (liver and muscle) - 16 hours –> depletable within a one day fast
- protein - 15 days
- fat - 30-40 days
6
Q
What happens to triglycerides in the blood when they reach adipocytes?
A
- 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
7
Q
How does insulin interact with adipocytes in the fed state?
A
- 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
8
Q
What happens to adipocytes in fasting state?
A
- 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
9
Q
How is the circulation adapted for quick reactions to changes in blood glucose?
A
- 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
10
Q
What happens when glycerol reaches the liver in a fed vs fasting state?
A
- 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
11
Q
What fuel can the brain use?
A
- glucose - preferred energy source
- ketone bodies
- cannot use NEFA - inability to use fatty acids as a fuel makes the brain unique
12
Q
How are ketone bodies produced?
A
- 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
13
Q
What is hepatic glycogenolysis?
A
- 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
14
Q
What happens in myocytes when glucose is high vs low? (How does the glucose itself interact with the cell)?
A
- 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
15
Q
What overall happens in the body in fasted state?
A
- 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
16
Q
What overall happens in the body in fed state?
A
- 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
17
Q
How is diabetes mellitus diagnosed?
A
- 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
18
Q
What is the pathophysiology in type 1 diabetes mellitus (T1DM)?
A
- 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)
19
Q
How do T1DM patients present?
A
- 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
20
Q
What diagnostic tests distinguish between T1DM and T2DM?
A
- markers like antibodies - GAD, IA2
- low C-peptide
- presence of ketones
21
Q
What happens if T1DM patients take too much exogenous insulin?
A
- 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
22
Q
What is the counterregulatory response to hypoglycaemia?
A
- increased glucagon, catecholamines, cortisol and GH
- this leads to increased HGO with glycogenolysis and gluconeogenesis, and increased lipolysis
23
Q
Why is it important to avoid hypoglycaemia?
A
- 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)
24
Q
What are symptoms and signs of hypoglycaemia?
A
Autonomic:
- sweating
- pallor
- palpitations
- shaking
Neuroglycopenic:
- slurred speech
- poor vision
- confusion
- seizures
- loss of consciousness
25
Q
How is severe hypoglycaemia defined?
A
An episode where a person needs third party assistance to treat
26
Q
What is the management for T1DM like?
A
- exogenous insulin (basal-bolus regime) –> multiple daily injections (long-acting injection once a day, short-acting ones before you eat)
- self-monitoring of glucose e.g. finger-prick test
- structured education
- technology like insulin pumps and continuous glucose monitoring tech
- monitoring and prevention of long-term diabetes complications like retinopathy, neuropathy etc
27
Q
What is T2DM?
A
- insulin resistance residing in liver, muscle and adipose tissue - at all metabolic sites and all arms of intermediary metabolism of glucose and fatty acids
- however, there is enough insulin to suppress ketogenesis and proteolysis
28
Q
How does insulin resistance work at a cellular level? PI3K-Akt pathway
A
- when insulin binds to receptor, this activates the PI3K-Akt pathway which results in metabolic actions of glucose and fat metabolism –> insulin resistance is in this pathway
- in early stages of insulin resistance, the body compensates by producing more insulin so for a while you can get away with this which can maintain your blood pressure = you can have insulin resistance without T2DM early on
29
Q
How does insulin resistance work at a cellular level? MAPK pathway
A
- the MAPK pathway leads to growth and proliferation
- there is no insulin resistance in this pathway
- so when insulin increases due to resistance of other pathway (to compensate), this leads to side effects with this pathway e.g. growth of arterioles –> high BP and other effects
30
Q
What are the consequences of insulin resistance?
A
- dyslipidaemia - derangement of lipids
- hypertension
- increased weight
- high glucose
- inflammatory state in body
- increases energy expenditure
- adipocytokines
- high triglycerides and low HDL
31
Q
How do T2DM patients present?
A
- hyperglycaemia
- overweight
- dyslipidaemia
- less osmotic symptoms than T1DM
- with complications - most patients present later in life where they have been insulin resistant for a while
- later insulin deficiency
- major cause of renal failure and end stage renal impairment requiring dialysis
- can cause nerve problems
- can lead to amputations
- can lead to macrovascular complications like stroke and MI
32
Q
What are risk factors for developing T2DM?
A
- age
- higher BMI
- ethnicity - Asians are high risk
- PCOS
- family history
- inactivity
33
Q
What is treatment for T2DM?
A
- healthy eating / diet - total calories control, reduce calories as fat and refined carbohydrates, increase calories as complex carbohydrates and soluble fibre, decrease sodium
- oral medication
- structured education
- may need insulin later if beta cells stop working
- monitoring and prevention of long-term conditions (retinopathy, neuropathy, nephropathy, cardiovascular)
