Week 4 - Metabolic

Question 1

What is obesity?

Answer 1

An abnormal or excessive fat accumulation that may impair health and a BMI of >30km/m2.

Question 2

Pathophysiology of obesity 1: role of appetite hormones

Answer 2

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.

Question 3

Obesity mechanism 2 - leptin resistance

Answer 3

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).

Question 4

What are the potential causes of leptin resistance?

Answer 4

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.

Question 4

What is the role of leptin?

Answer 4

Makes us feel full

Question 5

What is the role of adiponectin?

Answer 5

Anti-inflammatory, increases insulin sensitivity.

Question 6

Weight gain vs weight loss (fat)

Answer 6

Increase in fat increases number AND size of fat cell (adipocytes)
Decrease in fat reduces ONLY size of adipocytes.

Question 7

What are the consequences of obesity and altered adipokine regulation?

Answer 7

Leptin resistance (hyperleptinemia)
Lower levels of adiponectin
Visceral fat accumulation
Insulin resistance

Question 8

Consequences of leptin resistance

Answer 8

Stimulates SNS
Vascular inflammation
Oxidative stress
May contribute to HTN, atherosclerosis and LVH

Question 9

Consequences of lower levels of adiponectin

Answer 9

Increases inflammatory markers of IL6 and CRP
Related to increased risk of CVD and T2D.

Question 10

Consequences of visceral fat accumulation

Answer 10

Dysfunctional adipocytes - increase in proportion to increased fat mass

Question 11

Requirements to be prescribed orlistat

Answer 11

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.

Question 12

What is the mechanism of action for orlistat?

Answer 12

Inhibits gastric and pancreatic lipases (the enzymes that breakdown triglycerides).
The triglycerides are not hydrolysed into absorbable free fatty acids and so are excreted.

Question 13

side effects of orlistat

Answer 13

Embarrassment
Faecal urgency
Faecal incontinence
Small decreases in vitamins A, D, E and beta carotene levels.

Question 14

What type of drug is liraglutide?

Answer 14

GLP-1

Question 15

Give an example of a GLP-1

Answer 15

Liraglutide

Question 16

What is type 2 diabetes?

Answer 16

T2D mellitus is a metabolic disorder (unable to metabolise glucose) that results in hyperglycaemia.

Question 17

What is the cause of hyperglycaemia in T2D patients?

Answer 17

They are ineffective at using the insulin produced (insulin resistance)
Unable to produce enough insulin

Question 18

Pathophysiology of T2D

Answer 18

Central obesity, genetic predisposition and physical inactivity all lead to:
Pancreatic beta cell apoptosis (death) and reduction in insulin production.

Question 19

What are the consequences of reduced insulin production?

Answer 19

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.

Question 20

What do incretins do?

Answer 20

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.

Question 21

How does exercise benefit T2D patients?

Answer 21

Increased the number if GLUT4 = opens more channels to get glucose into the cells.

Question 22

What are potential causes of insulin resistance?

Answer 22

Reduced beta cell responsiveness
Decreased secretion
Beta cell death
Insulin receptor defect
Altered GLUT-4 function

Question 23

Physiological changes observed in T2D that may impact exercise

Answer 23

Metabolic inflexibility (ability to switch the fuels source)
Reduced oxidative capacity - reduced VO2max
Fibre type - shift from type I to IIa in men

Question 24

NICE guidance to determine risk of progression to T2D

Answer 24

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

Question 25

NICE guidance to identify possible T2D

Answer 25

Fasting plasma glucose >7mmol
OR
HbA1c of > 48mmol/litre
OR
OGTT - oral glucose tolerance test plasma glucose >11.1 after 2hrs.

Question 26

How long does it take to build up the target dose of metformin?

Answer 26

4-6 weeks

Question 27

Mechanism of action for Metformin

Answer 27

Decreases liver glucose production, decreases insulin resistance.
Makes sure that glucose is taken up into the cells

Question 28

Common side effects of metformin

Answer 28

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

Question 29

What is the main issue with taking metformin?

Answer 29

Can cause renal issues when it accumulates so need good kidney function.

Question 30

What is type 1 diabetes?

Answer 30

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.

Question 31

How is T1D identified and diagnosed?

Answer 31

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

Question 32

Why are ketones tested for in T1D?

Answer 32

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

Question 33

Pathophysiology of T1D

Answer 33

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.

Question 34

What is a basal bolus insulin regime?

Answer 34

Long-acting basal insulin
Rapid-acting bolus insulin
It attempts to roughly emulate how a non-diabetic person’s body delivers insulin.