Transcript ANPS 020 May 03-14

ANPS
Anatomy & Physiology
Endocrinology III
Stress
- anything that perturbs homeostasis
Bad
Good
Emotional – exams, bills, bad job
Physical – drugs, hard labor, wound
Metabolic – starvation, cold, heat
Combination – car accident, combat, rape
Exercise
Nervous system activation
Sympathetic stimulation - adrenal chromaffin release of epinephrine (E)
β1 receptor - heart; increase rate and pulse pressure
β2 - vasodilation in muscles (more blood to do work)
- fiber release of norepinephrine (NE)
α1 – vasoconstriction in peripheral tissues and gut
Endocrine system activation
Hypothalamic-pituitary-adrenal (HPA) axis stimulation – cortisol release
- redistribution of fuel
- enhances sympathetic E function
- activates genes for stress adaptation
ACTH and HypothalamicPituitary-Adrenal (HPA)
Axis Responses
• Stress, pain, circadian drive activate
hypothalamic CRH release
•
CRH binds GPCRs on anterior
pituitary corticotroph cells
•
Corticotrophs release ACTH
•
ACTH binds to adrenal cortical
GPCRs for cortisol release
•
Cortisol binds to steroid receptors
• Cortisol has long feedback to
hypothalamus and pituitary gland
Pro-opiomelanocortin (POMC)
Precursor to adrenocorticotropin (ACTH) and
-endorphin
Anterior
pituitary
ACTH
Hypothalamus
brain
-endorphin
(anorexic peptide
suppresses appetite)
Adrenal gland
• cortex – 3 contiguous layers
• medulla – sympathetic
-chromaffin cells (E)
Adrenal glands
Aldosterone
Cortisol
Androgens
Epinephrine
(adrenalin)
Cholesterol
ACTH
zona glomerulosa
Aldosterone
zona fasciculata
Cortisol
Corticosterone
Glucocorticoids
zona reticularis
Androgen
Cortisol
• cortisol is lipophilic and enters cells
• cortisol binds to cytosolic glucocorticoid (steroid) receptors (GR)
associated with chaperone heat-shock protein (HSP90)
• bound GR complex translocates into nucleus
• complex acts as transcription factor to activate
or repress genes on a variety of tissues
(-)
cortisol
glucocorticoid receptor
(GR)
(+)
Cortisol actions:
• metabolic
• vascular
• anti-inflammatory/immunosuppressive
Metabolic:
• “gluco” in glucocorticoids implies increased
blood glucose levels
• liver – stimulates gluconeogenesis
• fat – stimulates lipolysis, inhibits
glucose uptake
• muscle – stimulates protein catabolism;
amino acids for gluconeogenesis,
inhibits glucose uptake
net effect – diabetogenic (important in fasting)
Vascular:
• enhances epinephrine function to
maintain vascular tone and pressure
Anti-inflammatory / immunosuppressive:
• **cortisol inhibits inflammatory mediators
(prostaglandins, interleukins, thromboxane,
TNF, etc)
• reduces T lymphocytes / interferon production*
• decreases antibody production (long term)*
* important in transplants to inhibit rejection
But ... in excess (chronic stress or medication):
centripetal (trunk) obesity
muscle wasting and thin skin from
connective tissue loss – poor wound healing
increased infections from immune suppression
bone resorption/loss – osteoporosis
sodium retention and potassium loss from binding
to mineralocorticoid receptors
Glucocorticoids: the good vs bad in therapeutics
The good:
The bad:
• the anti-inflammatory/immunosuppressive effects
of glucocorticoids (hydrocortisone, dexamethasone)
are used therapeutically to blunt severe inflammation,
allergic reactions, autoimmune responses and
transplant rejections
• long term use can lead to immunosuppression
(bad for infections), muscle wasting,
osteoporosis, hyperglycemia, obesity,
neural/psychiatric disorders
Pancreas, Islets and Glucose Homeostasis
• Insulin is the key regulator of blood glucose
• Insulin actions are opposed and balanced by glucagon
exocrine/endocrine pancreas
endocrine Islets of Langerhans
• β-islet cells – insulin (green)
• α-islet cells – glucagon (red)
Glucose transporters (GLUT): the other key players
, brain
Triggering insulin release
•
•
•
•
•
increase in blood glucose (after a meal) result in glucose entry into β-cells via GLUT2
cellular glucose metabolism result in increased ATP
increase in ATP inhibits intracellular K+ efflux (KATP channels)
increase in cellular K+ results in cell depolarization and calcium entry
increased calcium stimulates insulin release from secretory granules
Islet β-cells
depolarization
Islet β-cell insulin production
• synthesized as 84 amino acid chain
• 3 disulfide bonds
• intervening connecting peptide (also called C-peptide)
is removed by dibasic RR/KR cleavage
Insulin-receptor signaling
• insulin binds to tyrosine receptor kinase in muscle, fat and other tissues
• different signaling pathways from scaffold increase
cell survival/proliferation, decrease glucose synthesis,
and increase GLUT4 transporter insertion to enhance cell glucose entry
α
insulin receptor
dimerization
β
glucose entry
P
P
IRS
Shc
P
Sos Grb2 P
Ras
PI3K
Raf
P
P
MEK
P
ERK
P
P
Akt
P
increase cell survival/proliferation
decrease gluconeogenesis
increase GLUT4
translocation into membrane
(muscle/fat)
GLUT2
GLUT4
Triglycerides
(fat storage)
(muscle / liver
storage)
Elevated glucose levels will:
• increase insulin-depdendent GLUT4 insertion into tissues for glucose entry
• increase tissue glycogen production and storage
(from excess glucose) in liver and muscle
• increase fatty acid/triglyceride synthesis/storage in fat
• increase amino acid into tissues for protein synthesis
• inhibit glycogen breakdown (inhibits glycogenolysis)
• inhibit new glucose synthesis (inhibits gluconeogenesis)
• inhibit lipolysis and reduce circulating free fatty acids
• net result is glycogen and triglyceride storage (i.e., fuel storage)
From decreased in blood glucose levels (between meals, fasting):
• glucagon is released from islet α-cells
• glucagon binds to target tissue G protein-coupled receptors
• receptor activation of cAMP/PKA pathways result
in enzyme phosphorylation and activity
Glucagon effects are (opposite to insulin):
• increased glycogenolysis (breakdown
of glycogen) to release glucose
• increased gluconeogenesis in liver
• increased lipolysis to free fatty acids
and keto acids
• increased protein breakdown to amino acids
• net effect is fuel mobilization to serve
metabolic demands
Diabetes – 2 types
Type I diabetes mellitus (juvenile onset diabetes)
About 5% of all cases
Genetic predisposition – autoimmune disease attacking beta cells
Pancreatic beta cells fail
Environmental factors
Type II diabetes mellitus (adult onset diabetes)
About 95% of all cases
Genetic predisposition (many genes from genome studies)
Body responds poorly to insulin (tissue insulin resistance likely
because of fat)
Eventual pancreatic beta cell “burn-out” - can’t keep up
Biggest culprit: overeating / obesity