Stress and metabolism 4 Flashcards
2 divisions of adrenals?
Cortex and medulla
Where are the adrenal glands embedded?
Adrenal glands embedded above each kidney in a capsule of fat
Of the adrenal glands which is the inner and which is the outer part?
Cortex is the outer part
Medulla is the inner part
What does the adrenal cortex have similar origin to?
What group of hormones does it make?
What are the types of hormones in outer gland, middle and inner glands give examples:
Similar origin to gonads
Make steroids hormones
Mineralocorticoids (outer gland) – aldosterone
Glucocorticoids (middle gland) – cortisol (corticosterone)
Androgen sex steroids (inner gland) – DHEA (dehydroepiandrosterone)
What is the adrenal medulla composed of?
Where does it originate from?
What group of hormones are here give the 2 examples:
Chromaffin cells
Originates from sympathetic nervous system
Catecholamines
– epinephrine (adrenaline)
– norepinephrine (noradrenaline)
What are the 3 layers/zones that the adrenal cortex consists of?
Zona glomerulosa – outermost layer
Zona fasciculata – middle and largest portion
Zona reticularis – innermost zone
Categories of adrenal steroids?
Mineralocorticoids
Glucocorticoids
Sex hormones
Mineralocorticoids is mainly and what balance does it influence?
Aldosterone
Influence mineral balance, specifically Na^+ and K^+ balance
Glucocorticoids are primarily? and what is the major roles?
Primarily cortisol
Major role in glucose metabolism as well as in protein and lipid metabolism
Sex hormones in adrenal glands are identical or similar to those produced by gonads - which is the most abundant and physiologically important?
Most abundant and physiologically important is dehydroepiandosterone (male “sex” hormone)
Aldosterone is major mineralocorticoid and maintains electrolyte balance - explain the 4 steps of feedback:
- low plasma Na++ or high K+
- activates renin-angiotensin system
- Angiotensin II increases aldosterone release from adrenal glands
- acts on distal renal tubules
* increase Na++ & water retention
* increase excretion of K+ & H+ ions
What is another name for the major glucocorticoid in humans: cortisol?
In what rhythm is cortisol secretion regulated?
Hydrocortisone
Secretion is regulated by diurnal rhythm
What does cortisol play a role in?
What does it do to blood glucose?
What does it do to blood fatty acids?
What does it do for water and electrolyte balance?
Does it create an inflammatory/anti-inflammatory response?
Plays role in stress
Increase blood glucose
Increase blood fatty acids
Control water and electrolyte balance
Anti-inflammatory/immunosuppressive
What feedback does cortisol have and on what?
Negative feedback on hypothalamus (CRH) & anterior pituitary (ACTH)
Adrenal cortex - secretes both male and female
sex hormones in both sexes what is the only hormone that has any biological importance ?
Dehydroepiandrosterone (DHEA)
What is DHEA overpowered by in males?
Overpowered by testicular testosterone in males
What about DHEA in females what happens?
Physiologically significant in females where it governs
– Growth of pubic and axillary hair
– Enhancement of pubertal growth spurt
– Development and maintenance of female sex drive
Primary stimulus of epinephrine and norepinerphrine?
Primary stimulus: activation of sympathetic nervous
system by stress
Where is adrenaline secreted into?
In response to?
What does it maintain?
What does it do blood glucose?
What does it do fat metabolism?
– Secreted into blood
– “fight-or-flight” responses
– Maintenance of arterial blood pressure
– Increases blood glucose
– Increases fat metabolism (increase blood fatty acids)
4 glucocorticoids?
Hydrocortisone, prednisolone, dexamethasone, betamethasone
When is replacement therapy used for glucocorticoids?
In adrenal failure (Addison’s disease)
What do these glucocorticoids try to do in anti-inflamatory/immunosuppressive disorders?
Reduce T cell proliferation, release of IL2, TNF-a, IL1
Glucocorticoids therapy for:
asthma?
eczema?
arthritis?
ulcerative colitis?
transplant?
cancer patients?
– asthma (inhaler)
– eczema (topical cream)
– arthritis (systemic injections)
– ulcerative colitis (rectal suppositories)
– prevent graft rejection of the transplant
– cancer patients (anti-emetic; reduce oedema in brain tumours)
Is the benefit greater than the risk of glucocorticoid use or no?
Benefit > Risk of glucocorticoid use
Why is the benefit > Risk of glucocorticoid use? What are lots of the risks assoicated?
– Immune system limited (delay tissue repair, gastric/peptic ulcers)
– Cushing’s symptoms
– Osteoporosis (alter function of bone cells osteoblasts/osteoclasts)
– Adrenal insufficiency due to sudden withdrawl (patient card – ”do not stop my steroid treatment abruptly”)
What does the drug fludrocortisone have in it?
What is it used in and give an example?
Fludrocortisone has glucocorticoid and mineralocorticoid activity
Used in mineralocorticoid replacement therapy (eg) in Addison’s disease
What are the main targets of mineralcorticoids?
Kidneys, bladder and colon are the major targets of mineralocorticoids
Addison’s disease is one of low corticoids - which ones?
low glucocorticoid (cortisol) & mineralocorticoid
(aldosterone)
Primary and secondary causes of Addison’s disease?
Primary Addison’s: damage adrenal gland (TB or autoimmunity)
Secondary Addison’s: low ACTH release
JFK had Addison’s disease
Symptoms of Addison’s disease? 10
hypoglycaemia, decreased liver glycogen, fatigue, anorexia, nausea, weight loss, dizziness, hypotension, psychiatric, death if untreated
Treatment of Addison’s disease?
Steroid replacement therapy
What is Cushing’s disease?
Causes?
Treatment? 3
High glucocorticoids - excess glucocorticoids (cortisol)
ACTH secreting tumor in pituitary
Treatment involves removing tumor, using antiglucocorticoids or surgical adrenalectomy
Symptoms of Cushing’s disease? 7 main points
- hyperglycemia
- elevated blood pressure
- obesity (abdominal fat, thin arms & legs)
- muscle wasting, osteoporosis, cataracts
- poor wound healing
- buffalo hump, moon face, red cheeks
- psychiatric symptoms (depression, euphoria, hallucinations)
a. What is Conn’s syndrome?
b. Primary and secondary causes?
c. Symptoms? 4
d. Treatment? 2
a. High mineralocorticoids - excessive mineralocortocoids (aldosterone)
b. primary - tumour
secondary - excessive renin-angiotensin action in kidney disease, cirrhosis of liver, congestive heart failure
c. sodium and water retention, increase in extracellular fluid and hypertension
d. antagonist of aldosterone (spirono-lactone) and unilateral adrenalectomy
Stress and depression: Hypothalamus-Pituitary-Adrenal Axis
During a generalised stress response - What is secreted from adrenal medulla?
What does mobilises metabolic resources?
What raises blood glucose and fatty acids?
What systems and hormones maintains blood volume and blood pressure?
↑ epinephrine secretion from adrenal medulla
(chromaffin cells)
↑ CRH-ACTH-cortisol (HPA axis) that mobilises
metabolic resources
↓ insulin & ↑ glucagon secretion to raise blood
glucose & fatty acids
↑ renin-angiotensin-aldosterone system &
vasopressin secretion to maintain blood volume
and blood pressure
What diseases does chronic stress cause?
Heart disease, hypertension, atherosclerosis, immune-suppression
What does prolonged release of CRH- Corticotropin releasing hormone cause?
Anxiety and depression
What drugs may treat anxiety, depression, drug dependence and IBS?
CRF1 receptor antagonists
What is the action of a stressor on the body?
A stressor is put on the body and then 2 responses occur:
1. Specific response characteristic of type of stressor
2. Non specific generalised response regardless of type of stressor- stress response
What change occurs to adrenaline during the stress response and what purpose does this serve?
Adrenaline is increased
Reinforces the sympathetic nervous system to prepare the body for “fight or flight”
Mobilises carbohydrate and fat energy stores which increases blood glucose and blood fatty acids
What change occurs to CRH-ACTH-Cortisol during the stress response and what purpose does this serve?
CRH-ACTH-Cortisol is increased which mobilises energy stores and metabolic building blocks for use as needed, this increases blood glucose, blood amino acids and blood fatty acids
ACTH facilitates learning and behaviour
What change occurs to glucagon and insulin during the stress response and what purpose does this serve?
Glucagon increases and insulin decreases
Acts in concert to increase blood glucose and blood fatty acids
What change occurs to renin-angiotensin-aldosterone-vasopressin during the stress response and what purpose does this serve?
Is increased to conserve salt and H2O to expand the plasma volume, help sustain blood pressure when acute loss of plasma volume occurs
Angiotensin 2 and vasopressin cause arteriolar vasoconstriction to increase blood pressure
Vasopressin facilitates learning
SLIDE 17 - integration of stress response by the hypothalamus diagram
What is CRH released by?
What is it carried by and into what?
What release does ACTH stimulate?
CRH is released by hypothalmic neurosecretory cells
CRH carried by portal vessels into anterior pituitary where ACTH is released
ACTH stimulates cortisol release by adrenal cortex
What is the long loop of cortisol feedback?
Cortisol acts on CRH neurons in hypothalamus and stops CRH release
What is the short loop of cortisol feedback?
Cortisol acts on anterior pituitary cells stops ACTH
release
Main glucocorticoid?
Upstream hormone of glucocorticoids?
Hypersecretion?
Hypsecretion?
Cortisol
ACTH: Adreno-corticotropic hormone
Cushing’s disease: high glucocorticoids
Addison’s disease: low corticoids
Main mineralocorticoids?
Upstream hormone of mineralocorticoids?
Hypersecretion?
Hypsecretion?
Aldosterone
Angiotensin 2
Conn’s syndrome: high mineralocorticoids
Addison’s disease: low corticoids
Difference in fed and hungry states in the body?
fed state: store amino acids, glucose and triglycerides
hungry state: mobilise stored reserves
Give the reaction and consequence for the metabolic processes:
1. Glycogenesis
2. Glycogenolysis
3. Glucogenesis
4. Protein synthesis
5. Protein degradation
6. Fat synthesis: lipogenesis/triglyceride synthesis
7. Fat breakdown: lipolysis/triglyceride degradation
- Glucose -> glycogen which causes a decrease in blood glucose
- Glycogen -> glucose which causes an increase in blood glucose
- Amino acids -> glucose which causes an increase in blood glucose
- Amino acids -> protein which causes a decrease in blood amino acids
- Protein -> amino acids which causes an increase in blood amino acids
- Fatty acids and glycerol -> triglycerides which causes a decease in blood fatty acids
- Triglycerides -> fatty acids and glycerol which causes an increase in blood fatty acids
What is glycogenolysis?
Pathway in which glycogen breaks down into glucose-1-phosphate and glucose.
What is anabolism?
Does it require ATP?
Build up or synthesis of larger organic macromolecules from small organic subunits
Reactions usually require ATP
What do anabolism reactions result in? 2
Manufacture of materials needed by the cell
Storage of excess ingested nutrients not immediately needed for energy production or needed as cellular building blocks
What is catabolism?
Breakdown or degradation of large energy rich organic molecules within cells - releases energy
2 levels of breakdown of catabolism?
Hydrolysis of large cellular molecules into smaller subunits
Oxidation of smaller subunits to yield energy for ATP
production
SLIDE 24 - Summary of the major pathways involving organic nutrient molecules
Where do most interconversions of organic molecules occur? What kind of nutrients?
In the liver
Essential nutrients - certain amino acids and vitamins
With interconversions among organic molecules - how is food taken in and what is this for?
Food intake is intermittent - nutrients must be stored for use between meals
Where is excess circulating glucose stored and where does it go when these stores are full?
Stored in liver and muscle as glycogen
Once liver and muscle stores are “filled up”, additional glucose is transformed into fatty acids and glycerol and stored in adipose tissue
What do excess circulating fatty acids get incorporated into?
Triglycerides
What are excess circulating amino acids converted to?
Glucose and fatty acids
Carbohydrate is the metabolic fuel
1. What is the circulating form?
2. Storage form?
3. Storage site?
4.% Of total body energy content + calories?
5. Reservoir capacity?
6. Role?
- Glucose
- Glycogen
- Liver and muscle
- 1% - 1500 calories
- Less than a day’s worth energy
- 1st energy source, is essential for the brain
Fat is the metabolic fuel
1. What is the circulating form?
2. Storage form?
3. Storage site?
4.% Of total body energy content+calories?
5. Reservoir capacity?
6. Role?
- Free fatty acids
- Triglycerides
- Adipose tissue
- 77% - 143,000 calories
- About 2 months’ worth of energy
- Primary energy reservoir, energy source during a fast
Protein is the metabolic fuel
1. What is the circulating form?
2. Storage form?
3. Storage site?
4.% Of total body energy content + calories?
5. Reservoir capacity?
6. Role?
- Amino acids
- Body proteins
- Muscle
- 22% - 41,000 calories
- Death results long before capacity is fully used because of structural and functional impairment
- Source of glucose for the brain during a fast, last resort to meet other energy needs
Role of liver in metabolic states?
Primary role in maintaining normal blood glucose levels
Principal site for metabolic interconversions such as gluconeogenesis
Role of adipose tissue in metabolic states?
Primary energy storage site
Important in regulating fatty acid levels in the blood
Role of muscle in metabolic states?
Primary site of amino acid storage
Major energy user
Role of brain in metabolic states?
Normal can only use glucose as an energy source
Does not store glycogen
Mandatory blood glucose levels are maintained
Are the factors that affect blood glucose concentration subject to hormonal control to maintain blood glucose level?
Yes
Which factors increase blood glucose levels?
Glucose absorption from digestive tract
Hepatic glucose production: Through glycogenolysis of stored glycogen and through gluconeogenesis
Factors that decrease blood glucose levels?
Transport of glucose into cells:
For utilisation for energy production
For storage as triglycerides and as glycogen through glycogenesis
Urinary exertion of glucose (occurs only abnormally, when blood glucose levels becomes so high that it exceeds the reabsorptive capacity of kidney tubules during urine formation)
Hormones that regulate metabolism from:
1. Anterior Pituitary gland
2. Liver
3. Thyroid gland (T3+T4)
4. Gonads
5. Adrenal cortex
6. Adrenal medulla
7. Pancreatic (Islets of Langerhans)
- Growth hormone, ACTH, TSH
- Somatomedins (IGFs)
- Thyroxine
- Sex steroids
- Glucocorticoids (cortisol)
- Adrenaline (noradrenaline)
- Insulin and glucagon
What cells are in the Islets of Langherhans?
Pancreas exocrine and endocrine glands
What do the exocrine glands of the Islets of Langerhans secrete and into where?
Proteases into small intestine
The endocrine Islets of Langerhans:
1. Make up how much of pancreas?
2. What are they for hormone drainage?
3. What are clusters made up of?
4. What are they surrounded by?
5. What way are they arranged in pancreas?
- Comprise 1 % of pancreas
- Rich blood supply for hormone drainage
- Clusters composed ~3000 endocrine secretory cells
- Surrounded by capsule
- Scattered throughout pancreas
What does pancreas removal cause?
Symptoms of diabetes
Pancreas removal causes symptoms of
diabetes - what happens to glucose in plasma and what are the values?
Increased [glucose]plasma 20-30mM
SLIDE 31 -> Shows location and structure of the pancreas and cell types in the Islets of Langerhans
Islets of Langerhans have 3 secretory cells making peptide hormones - what are they and what is the role?
- Beta cells - insulin - which promote glucose uptake
- αlpha cells - glucagon - they have the opposite effect to insulin, i.e. do not promote glucose uptake
- delta cells – somatostatin - potentiates the glycogen breakdown activity of glucagon
What is insulin stores and secreted from?
Cytoplasmic granules
- Glycogenolysis/lytic ?
- gluconeogenesis
- Lipolysis
- Lipogenesis
- Glycogen breakdown
- Glucose synthesis
- Lipid/fat breakdown
- Lipid/fat synthesis
- Insulin what state is it in and is it anabolic or catabolic?
- What about glucagon?
- Fed state: insulin is anabolic hormone
- Hungry state: glucagon is a catabolic hormone
Insulin - What 3 processes does it allow?
Glucose to glycogen
Fatty acids to triglycerides
Amino acid to protein
Insulin -What happens to glucose, amino acid and fatty acids in blood, muscle and what does it breakdown?
Decreased glucose, amino acid and fatty acid
in blood
↑ glucose, amino acid and fatty acid uptake in muscle
↓ breakdown of glycogen, fat (triglycerides) and protein
3 processes glucagon allows?
Glycogen to glucose
Triglycerides to fatty acids
Protein to amino acid
Does glucagon allow opposite processes of insulin?
Yes
Glucagon -What happens to glucose, amino acid and fatty acids in blood, muscle and what does it breakdown?
Increased glucose, amino acid and fatty acid in
blood
↓ glucose, amino acid and fatty acid uptake in muscle
↑ breakdown of glycogen, fat (triglycerides) and protein
How is insulin made and what does it cleave to?
Synthesised as pro-hormone and cleaved to mature peptide
Do insulin and glucagon have short lives and if so what are they?
Yes
Insulin -> t1/2 = 30 minutes
Glucagon -> t1/2 = 10 minutes
9 Steps of stimulation of insulin secretion by glucose via excitation secretion coupling:
- Glucose enters beta cells by facilitated diffusion via GLUT-2.
- Glucose is phosphorylated to glucose-6-phopshate.
- Oxidation of glucose-g-phosphate makes ATP.
- ATP acts on ATP-sensitive K^+ channel, closing it
- Reduced exit of K^+ depolarises membrane
- Depolarisation opens voltage gates Ca^2+ channels
- Ca^2+ enters beta cell.
- Ca^+2 triggers exocytosis of insulin vesicles
- Insulin is secreted
SLIDE 36 -> Factors controlling insulin secretion
Insulin secretion what does it do to:
1. Blood glucose?
2. Blood fatty acids?
3. Blood amino acids?
4. Protein synthesis?
5. Fuel storage?
- Decreased
- Decreased
- Decreased
- Increased
- Increased
Most common of all endocrine disorders?
Diabetes Mellitus
What is the most prominent feature of diabetes?
Hyperglycemia: elevated blood sugar
What is the only hormone capable of lowering blood sugars?
Insulin
What does diabetes mean and what does it reference to for this disease?
What does Mellitus mean and where did it get this name from?
Diabetes means “siphon” or “running through” – reference to the large urine volume accompanying this condition
Mellitus means “sweet” – acquires its sweetness from secretion of excess glucose in this condition
TYPE 1 DIABETES:
1. How quick do symptoms develop?
2. Onset is?
3. Affects how many diabetics?
4. What is it due to?
5. Is there insulin secretion?
6. Treatment involves?
- Symptoms develop rapidly
- Childhood onset
- Affects 10-20% diabetics
- Loss of b cell function
- Insulin secretion none/low
- Insulin injections for treatment
TYPE 2 DIABETES:
1. How quick do symptoms develop?
2. Onset is?
3. Affects how many diabetics?
4. What is it due to?
5. Is there insulin secretion?
6. Treatment involves?
- Symptoms develop slowly
- Adulthood onset
- Affects 80-90% diabetics
- Insulin insensitivity
- Insulin secretion normal/high
- Diet/exercise and oral drugs
SLIDE 40 -> Counteracting actions of glucagon and insulin on blood glucose during absorption of a high protein meal
4 Effects of severe diabetes:
- Excessive eating
- Dehydration and thirst
- Coma
- Brain cells are glucose obligate cells
Excessive eating is an effect of severe diabetes why?
Cells starved of carbohydrate
Hypothalamic center leads to excessive eating
Dehydration and thirst is an effect of severe diabetes why?
Low glucose uptake, blood glucose rises
Glucose appears in urine, increases urinary vol
Dehydration and thirst
Coma is an effect of severe diabetes - why?
Cells unable to use glucose increases
Lipolysis generates fatty acids and ketoacids
Ketoacids lower blood pH
Decreased brain O2 and coma
Brain cells are glucose obligate cells - effect of severe diabetes why?
Low glucose, brain stops working
Coma and respiratory paralysis
What is the counteractions of glucagon and insulin on blood glucose during absorption of a high protein meal?
High protein meal has little carbohydrate which increases blood amino acid concentration.
This has a positive effect on beta cells which increases insulin levels which promotes cellular uptake and assimilation of amino acids.
Increased insulin increases glucose uptake by cells and decreases hepatic glucose output leading to hypoglycemia.
At the same time this increased blood amino acids concentration has a positive effect on alpha cells which increases glucagon and then increases hepatic glucose output leading to hyperglycemia.
These 2 effects counteract each other and blood glucose remains normal.
SLIDE 41+42 SEE TABLE which summarises the hormonal control of fuel metabolism
