Download ANPS 020 Black 03-16

ANPS 020
ENDOCRINOLOGY III
MARCH 16, 2012
(Cont’d from endo. II)
PARATHYROID HORMONE/CALICUM HOMEOSTASIS
Calcium importance
-bone maintenance
-nervous signaling
-muscle contraction, skeletal, smooth, cardiac
-blood clotting
-others…
All cells need calcium
Three regulators:
-parathyroid hormone
-vitamin D
-calcitonin (important during development held in equilibrium)
Here integrated sites of action:
-bone: largest reservoir of body calcium
-GI calcium absorption
-kidney calcium excretion
PARATHYROID HORMONE (PTH)
-Produced by parathyroid gland – located on the posterior thyroid
-activates G protein coupled receptors on target tissues (bone, kidney)
VITAMIN D
-not one but class of compounds
-synthesis in 3 tissues (skin, liver, kidney)
-PTH important in final synthesis of active vitamin D in kidney
Slide 33 chart is important
BODY CALCIUM HOMEOSTASIS (does not have to go to hypothalamus)
Free (ionized) calcium is active (50% free and 50% bound)
PTH and blood calcium levels are tightly balanced
Drop in blood calcium leads to increased PTH releases
PTH FUNCTIONS
PTH increases kidney calcium reabsorption (fast)
PTH increases bone resporption to free calcium (slow)
PTH stimulates kidney vit D synthesis – 1, 25 – (OH) 2D
1, 25 (OH)2D binds to GI steroid – type receptors to stimulate calcium absorption
All mechanisms will increase calcium in blood
CLACITONIN
Peptide produced by thyroid C cells
Decreases blood calcium, opposite effects of PTH and vitamin D
Blood calcium so tightly coupled with PTH/vit D that calcitonin is more important during development
than in adults
ENDOCRINOLOGY III
Hypothalamic – Pituitary – Adrenal Axis (HPA)
Stress, pain, circadian drive activate hypothalamic corticotropin releasing hormone (CRH) release
CRH binds to G protein coupled receptors on anterior pituitary corticotroph cells
Cortciotrophs release POMC product ACTH
ACTH binds to adrenal cortex G protein coupled receptors for cortisol release for adaptive responses
Cortisol binds to steroid receptors
Cortisol has long feedback to hypothalamus and pituitary gland
ADRENAL GLAND
Cortex – 3 contiguous layers
Medulla – sympathetic in nature
CORTISOL
Cortisol is lipophilic and enters cells
Cortisol binds to cytosolic glucocorticoid (steroid) receptors (GR) associated with chaperone heat-shock
protein (HSP90)
Bound to GR complex translocate in nucleus
Complex acts as transcription factor to activate or repress genes on a variety of tissues
HPA axis hormone response
CRH-ACTH- Cortisol response is tightly coupled
Peak cortisol response lags slightly but more persistent
CORTISOL ACTIONS: PERMISSIVE MAKES THINGS WORK
-metabolic
-anti-inflammatory
-immunosuppressive
-vascular
Metabolic responses:
“gluco” in glucocorticoids implies increased blood glucose levels
Liver – stimulates gluconeogenesis
Muscle- stimulates protein catabolism for amino acids as substrates for gluconeogenesis, inhibits
glucose uptake
Fat- stimulate lipolysis, inhibits glucose uptake
Net effect- disbetogenic
In excess- cortisol leads to muscle wasting and thin skin from connective tissue loss
Bone resorption/loss – osteoporosis
Centripetal (trunk) obesity
Sodium retention and potassium loss from binding to mineralocorticoid receptors
ANTI-INFLAMMATRY/IMMUNOSUPPRESIVE RESPONSES
Cortisol inhibits inflammatory mediator production in arachidonic pathway (prostaglandins, interleukins,
thromboxane)
Decreases other inflammatory molecules – TNF
Reduces T lymphocytes and interferon production in immune responses
Decrease antibody production (long term)
Vascular:
Facilitates vascular adrenergic function to maintain tone and blood pressure
GLUCOCORTICOIDS: THE GOOD AND BAD
The good:
The anti-inflammatory/immunosuppressive effects of synthetic glucocorticoids (dexamethasone) are
used therapeutically to blunt sever 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, neuronal/psychiatric disorders, adrenal insufficiency (from HPA negative
feedback)
PANCREAS, ISLETS, AND GLUCOSE HOMEOSTASIS
Exocrine/endocrine pancreas
Endocrine islets of Langerhans:
Beta islets cells – insulin (green)
Alpha islet cells – glucagon (red)
Sigma islets cells – somatostatin (not shown)
INSULINAND INSULIN SIGNALING: are key regulators of blood glucose (after dinner hormone)
-insulin actions are opposed and balanced by glucagon
-both insulin and glucagon are modulated in inhibitory somatostatin actions
INSULIN: TRIGGERING ITS RELEASE
Increase in blood glucose (after a meal) result in glucose entry into beta cells via GLT2
Cellular glucose metabolism result in increased ATP
Increase in ATP inhibit intracellular K+ efflux
Increase in cellular K+ results in cell depolarization and calcium entry
Increased calcium stimulates insulin release from secretory granules
ISLET BETA CELL INSULIN PRODUCTION
Synthesized as 21 amino acid chain
3 disulfide bonds
Intervening connecting peptide (also called C-peptide) is removed by dibasic RR/KR cleavage
INSULIN REPCEPTOR SIGNALING
Insulin binds to tyrosine receptors kinases in target cells
Different signaling pathways from scaffold increase cell survival/proliferation, decrease glucose
synthesis, and increase GLUT transporter insertion to enhance cell glucose entry
Slide 53-important chart
IN BRIEF, ELEVATED GLUCOSE LEVELS WILL:
Increase GLUT4 insertion into tissues for glucose entry
Increase tissue glycogen production and storage (from excess glucose) in liver and muscle
Increase amino acid into tissues for protein synthesis
Inhibit glycogenesis (glycogen breakdown)
Inhibit gluconeogenesis (glucose synthesis)
Inhibit lipolysis and reduce circulating free fatty acids
Inhibit free fatty acid oxidation ( esp. in liver) and keto acid formation
Net result is glycogen and triglyceride storage (i.e. fuel storage)
FROM DECREASED IN BLOOD GLUCOSE LEVELS 9BETWEEN MEALS, FASTING)
Glucagon I released from islet alpha 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 protein breakdown to amino acids
Increased lipid catabolism to free fatty acids and keto acids
Net effect is fuel mobilization to serve metabolic demands
DIABETES – 2 TYPES
INSULIN DEPENDENT DIABETES MELLUTUS (IDDM)
Type 1
About 5% of all cases
Genetic predisposition
Pancreatic beta cells fail
Environmental factors
NON INSULIN DEPENDENT DIABETES MELLITUS (NIDDM)
Type II
About 95% of all cases
Genetic predisposition
Body responds poorly to insulin
Pancreatic beta cells can’t keep up
The biggest culprit: overeating/obesity