1. ANPS Anatomy & Physiology
Endocrinology III

2. Stress - anything that perturbs homeostasis Bad
Emotional – exams, bills, bad job
Physical – drugs, hard labor, wound
Metabolic – starvation, cold, heat
Combination – car accident, combat, rape
Good
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
Both types of stressors turn on same systems
Epinephrine binds to GPCRs on B1, B2, A1 receptors

3. ACTH and Hypothalamic- Pituitary-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

4. Pro-opiomelanocortin (POMC)
Precursor to adrenocorticotropin (ACTH) and -endorphin
ACTH
-endorphin
Anterior
pituitary
Not on test*
Hypothalamus
brain
(anorexic peptide
suppresses appetite)

5. Adrenal gland cortex – 3 contiguous layers medulla – sympathetic
Aldosterone
Cortisol
Androgens
Epinephrine
(adrenalin)
cortex – 3 contiguous layers
medulla – sympathetic
-chromaffin cells (E)
Adrenal glands
Adrenal gland sits on top of kidneys in posterior wall, buried in fat
Medulla composed of adrenal cells that produce epinephrine

6. Cholesterol ACTH Cortisol Corticosterone Glucocorticoids
zona glomerulosa
zona fasciculata
zona reticularis
All 3 zones use Cholesterol
ACTH activates zona fasciulata that produces Coritsol (humans), Corticosterone (other species)
Glucocorticoids: lipophilic
Aldosterone
Cortisol
Corticosterone
Androgen
Glucocorticoids

7. glucocorticoid receptor
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)
(+)

8. 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)
Cortisol increases level of glucose available to use (kidneys: glucose production, fat/muscle: breakdown to fuel)
**raise blood glucose levels
Vascular:
enhances epinephrine function to
maintain vascular tone and pressure

9. 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
Stress increases inflammatory mediators  tissue damage
Our body was never made to maintain stress response, used to turn on/off
Increase of glucose in body = increase in body fat in trunk (chest to belly)
Coritsol activates the breaking down of CT, matrix, tissue  muscle wasting, loss of calcium

10. Glucocorticoids: the good vs bad in therapeutics
the anti-inflammatory/immunosuppressive effects
of glucocorticoids (hydrocortisone, dexamethasone)
are used therapeutically to blunt severe inflammation,
allergic reactions, autoimmune responses and
transplant rejections
The bad:
long term use can lead to immunosuppression
(bad for infections), muscle wasting,
osteoporosis, hyperglycemia, obesity,
neural/psychiatric disorders
Good for short term, bad for long term

11. Pancreas, Islets and Glucose Homeostasis
Insulin is the key regulator of blood glucose
Insulin actions are opposed and balanced by glucagon
β-islet cells – insulin (green)
α-islet cells – glucagon (red)
exocrine/endocrine pancreas
endocrine Islets of Langerhans
High glucose in blood would coat rbc and everything in blood stream, damages capillaries (retna, kidneys)
90g of glucose in blood from a normal meal
5 gram: amount body tries to keep of glucose in blood
How to get rid of all the glucose in blood? Store in muscle or fat
Pancreas- mostly exocrine (amylase, tripsin), produce Islet cells
Most cells produced by pancreas are Beta Islet cells: more insulin that glucagon from pancreas

12. Glucose transporters (GLUT): the other key players
, brain
Know GLUT 2, 4
GLUT 2: brain! (20% glucose used by brain), beta islet cells
GLUT4: insulin dependent, muscle/fat

13. 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
Net positive charge in islet cells
Opens up calcium channels, allows insulin release from B islet cells
depolarization

14. 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

15. 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 P
IRS
PI3K
Sos
Ras
Raf
Akt
MEK
ERK
increase cell survival/proliferation
decrease gluconeogenesis
increase GLUT4
translocation into membrane
(muscle/fat)
glucose entry
insulin receptor
dimerization α β
Shc
Grb2
*insulin receptor translocation of GLUT4 to allow glucose entry to muscle/fat

16. **study this slide GLUT2 GLUT4 Triglycerides (muscle / liver
(fat storage)
(muscle / liver
storage)

17. 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)
Body tries to maintain 100 mg/dL
If <100mg, glucagon released from alpha cells
If>100 mg, insulin released

18. 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

19. 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
Type 1: people are dependent on insulin for metabolism
Type 2: excess fat inhibits role of Insulin receptors, beta cells constantly turned on