Week 4 - Metabolic Flashcards
What is obesity?
An abnormal or excessive fat accumulation that may impair health and a BMI of >30km/m2.
Pathophysiology of obesity 1: role of appetite hormones
Appetite hormones circulate at levels proportionate to fat mass and provide signals to acuate nucleus (ARC) in hypothalamus where appetite and metabolism is regulated.
ARC is 2 sets of neurons
- Produces NPY and AGRP which stimulate eating.
- Produces POMC which stimulates aMSH/CART neurons which inhibit eating.
Obesity is associated with increased leptin (due to more adipocytes), insulin, ghrelin and PPY - interaction at hypothalamus influences fat mass.
Obesity mechanism 2 - leptin resistance
When high, levels of leptin are ineffective at decreasing appetite and increasing energy expenditure.
This promotes overeating and excessive weight gain (number and size of adipocytes increases).
What are the potential causes of leptin resistance?
Adipocyte derived inflammation
Inability for leptin to cross the blood-brain barrier due to binding to C reactive protein released by adipocytes
Defect in leptin receptors.
What is the role of leptin?
Makes us feel full
What is the role of adiponectin?
Anti-inflammatory, increases insulin sensitivity.
Weight gain vs weight loss (fat)
Increase in fat increases number AND size of fat cell (adipocytes)
Decrease in fat reduces ONLY size of adipocytes.
What are the consequences of obesity and altered adipokine regulation?
Leptin resistance (hyperleptinemia)
Lower levels of adiponectin
Visceral fat accumulation
Insulin resistance
Consequences of leptin resistance
Stimulates SNS
Vascular inflammation
Oxidative stress
May contribute to HTN, atherosclerosis and LVH
Consequences of lower levels of adiponectin
Increases inflammatory markers of IL6 and CRP
Related to increased risk of CVD and T2D.
Consequences of visceral fat accumulation
Dysfunctional adipocytes - increase in proportion to increased fat mass
Requirements to be prescribed orlistat
Only as part of an overall plan for managing obesity in adults who either have a
BMI > 28 with other risk factors or BMI >30.
Therapy should be continued only if the person has lost at least 5% of their initial bodyweight.
What is the mechanism of action for orlistat?
Inhibits gastric and pancreatic lipases (the enzymes that breakdown triglycerides).
The triglycerides are not hydrolysed into absorbable free fatty acids and so are excreted.
side effects of orlistat
Embarrassment
Faecal urgency
Faecal incontinence
Small decreases in vitamins A, D, E and beta carotene levels.
What type of drug is liraglutide?
GLP-1
Give an example of a GLP-1
Liraglutide
What is type 2 diabetes?
T2D mellitus is a metabolic disorder (unable to metabolise glucose) that results in hyperglycaemia.
What is the cause of hyperglycaemia in T2D patients?
They are ineffective at using the insulin produced (insulin resistance)
Unable to produce enough insulin
Pathophysiology of T2D
Central obesity, genetic predisposition and physical inactivity all lead to:
Pancreatic beta cell apoptosis (death) and reduction in insulin production.
What are the consequences of reduced insulin production?
Energy needs to be taken from somewhere else as glucose cannot get into the cells - taken from liver - increase in gluconeogenesis.
Increased lipolysis - changes lipid profiles and so cardiovascular risk increases.
What do incretins do?
They are a group of hormones that stimulate a decrease in blood glucose levels.
They are released after eating and improve the secretion of insulin from pancreatic beta cells.
How does exercise benefit T2D patients?
Increased the number if GLUT4 = opens more channels to get glucose into the cells.
What are potential causes of insulin resistance?
Reduced beta cell responsiveness
Decreased secretion
Beta cell death
Insulin receptor defect
Altered GLUT-4 function
Physiological changes observed in T2D that may impact exercise
Metabolic inflexibility (ability to switch the fuels source)
Reduced oxidative capacity - reduced VO2max
Fibre type - shift from type I to IIa in men
NICE guidance to determine risk of progression to T2D
Fasting blood glucose of 5.5 to 6.9 mmol/litre
HbA1C level of 42 to 47mmol - average sugar control over a 3-month period. Attachment of sugar to haemoglobin
NICE guidance to identify possible T2D
Fasting plasma glucose >7mmol
OR
HbA1c of > 48mmol/litre
OR
OGTT - oral glucose tolerance test plasma glucose >11.1 after 2hrs.
How long does it take to build up the target dose of metformin?
4-6 weeks
Mechanism of action for Metformin
Decreases liver glucose production, decreases insulin resistance.
Makes sure that glucose is taken up into the cells
Common side effects of metformin
GI discomfort and symptoms but usually only on initiation
Possible reduced exercise tolerance
Reduced hepatic glucose production
SAFE - doesn’t cause hypoglycaemia
Can cause small weight loss
Need good kidney function as accumulation can cause renal issues
What is the main issue with taking metformin?
Can cause renal issues when it accumulates so need good kidney function.
What is type 1 diabetes?
An autoimmune disease that causes the insulin-producing beta cells in the pancreas to be destroyed, preventing the body from being able to produce enough insulin to adequately regulate blood glucose levels.
How is T1D identified and diagnosed?
Blood glucose test
Urinalysis to detect glucose and/or ketones
Additional tests to can be done if unsure whether T1D/T2D.
Ketone testing to avoid dangerous ketoacidosis (ST complication) when BG >17mmol/L, or when BG is repeatedly >13mmol/L
GAD autoantibodies test – presence of antibody that destroys own GAD cells. Autoantibodies found in 85-90% of T1D
C-peptide test – amount of insulin produced
Why are ketones tested for in T1D?
Ketones are produced during weight loss but also when insufficient insulin production
An alternative energy source to glucose which is a product of fat breakdown. This occurs when insufficient insulin leads to impaired glucose uptake from blood
Pathophysiology of T1D
It is the result of a genetic-environmental interaction but not a lifestyle impact - stressful event (environmental).
Cell-mediated destruction of beta-cells - immune cells e.g. B lymphocytes target/kill beta cells –> pancreatic atrophy.
What is a basal bolus insulin regime?
Long-acting basal insulin
Rapid-acting bolus insulin
It attempts to roughly emulate how a non-diabetic person’s body delivers insulin.
