The adrenal gland
The adrenal gland• Adrenal CortexOuter glandderived from mesodermproduces steroid hormones• Adrenal MedullaInner region of glandproduces epinephrine and norepinephrinederived from neural crest
Adrenal gland•Ad, adjacent to, next to; renal,kidney•First hormone purified from agland, adrenalin- epinephrine(IUPAC)- 1901 by JokichiTakamine purified from the adrenalmedulla•Adrenal medulla- derived fromneural crest•Adrenal cortex- derived fromurogenital mesoderm
3 layers of adrenal cortex• Zona glomerulosa (outer zone)-producesaldosterone• Zona fasciculata (middle zone)- producescortisol• Zona reticularis (inner zone)- produces theweak androgen DHEA
Figure 21—4. Fine structure of2 steroid-secreting cells fromthe zona fasciculata of thehuman adrenal cortex. Thelipid droplets (L) containcholesterol esters. M,mitochondria withcharacteristic tubular andvesicular cristae; SER, smoothendoplasmic reticulum; N,nucleus; G, Golgi complex; Ly,lysosome; P, lipofuscinpigment granule. x25,700.
Acyl CoA+Cholesterol=sterol O-acyltransferase
CoA+ Cholesterol esterhttp://members.aol.com/logan20/acyl.gif
CatecholamineSynthesis-Synthesized from the amino acidtyrosine, which is taken up intomedulla cells by active transport.
Fig. 1. Dr. Dwight J IngleDallman, M. F. Am J Physiol Endocrinol Metab 289: E361-E362 2005;doi:10.1152/classicessays.00033.2005Copyright ©2005 American Physiological Society
Administration of exogenouscortisol or corticosterone willcause atrophy of the adrenalgland due to negativefeedback
Edward Calvin Kendall•1950 shared Nobel prize inphysiology/medicine fordiscovery of adrenal steroids•Grind adrenal cortex,solubilize in sovent•Spot on chromatographypaper•Hormones identified byletters (alphabet soup!)•B, corticosterone•F, cortisol•S, 11-deoxycortisol
Edward C. Kendall (seated) and Philip S. Hench (far right) of the Mayo Clinicwere awarded the Nobel Prize in 1950 for the isolation and first clinical use ofcortisone. By permission of the Mayo Foundation.http://www.mbbnet.umn.edu/firsts/historic.html
Steroidogenic Pathway•Steroids produced fromcholesterol•Synthesized upon demand
Cortisol• Increases blood glucose but spares liverglycogen stores.• Increases conversion of fats and aminoacids into glucose.• Increases liver glycogen.
MuscleAdiposeNon-neural TissueProteinGC (+)AAGlycogenE (+)LactateATPTriglyceridesE (+)MG NEFAsAcetyl CoAATPGC (-)Blood Glucose(to All Tissues)KetonesGluconeogenesisGC, E (+)Glucose GlycogenE (+)LiverBlood ketones(eg. Acetone, acetoacetic acidnormally low)Epinephrine (E):1. Promotes glycogenolysis.2. Promotes gluconeogenesis in liver.3. Promotes triglyceride breakdownin adipose tissue.4. Elevates blood glucose.Glucocorticoids (GC):1. Promote protein catabolism.2. Inhibit glucose uptake by muscle.3. Promote gluconeogenesis in livervia stimulation of PEPCK4. Permissive effect on E actionin adipose tissue.5. Elevate blood glucose.
Aldosterone• Removing the adrenal gland (adrenalectomy)causes death in 2 weeks due to lack ofaldosterone• Aldosterone increases Na+ and waterretention by kidney• Water and Na+ retention are required fornormal blood pressure• Decrease blood volume leads to decreasedcardiac output, decreased blood pressure,and death.
Stress- Historical Background• Claude Bernard (1813-1878)- the concept of maintaining a constantinternal environment• Walter Cannon (1871-1945)The concept of “homeostasis” and thediscovery of the role of adrenaline• Hans Selye (1907-1982)Introduced the term “stress”
“The constancy of the internalenvironment is the conditionthat life should be free andindependent.... So far fromthe higher animal beingindifferent to the externalworld, it is on the contrary ina precise and informedrelation with it, in such away that its equilibriumresults from a continuousand delicate compensation,established as by the mostsensitive of balances”Claude Bernard
Walter Cannon• The Wisdom of theBody, Walter B.Cannon, 1939.Second edition, W.W. Norton, New York.• First use of the term“homeostasis”
Hans Selye• Canadian physician, studied the effects ofovarian extracts on rats• Found that many different treatmentsresult in the same effects:Enlargement of the adrenal glandReduction in thymus sizeDevelopment of GI ulcers
The “Pharmacology of Dirt”The early experiments of Hans SelyeFormalin, toxinsStress
controlstressThe triadLarger AdrenalsSmaller ThymusSmaller Lymph nodesPeptic ulcersFrom Selye, H. “The Stress of Life”
General adaptation syndrome• Alarm phase• Adaptation phase• Exhaustion
Diversity of Stressors“Systemic Stressor”(interoceptive or visceralstressors) Reflexive,visceral sensorypathways•Ether•Hemorrhage•Formalin•Cholecystokinin•Surgery•Bacteria (LPS), “immunestress”“Neurogenic Stressor”Higher brain processing• Restraint• Confinement• Novelty• Unpredictability• Social status• Grief
STRESSORBehavioralResponsesEndocrineResponsesVisceromotorResponses•Feeding behavior•Reproductive behavior•Locomotor activity•Learning and memoryHypothalamusCRHPituitary glandSpinal cordAdrenal medullaNEPupillarydilatationInc HeartrateACTHAdrenal cortexCortEReduced GIfunctionPromotesexualorgasmFat Muscle LiverIncrease Blood Glucose
Pancreas• Exocrine and Endocrine organ• Endocrine cells:Islets of Langerhans (several cell types)• Beta cells (70%)- insulin• Alpha cells –glucagon• Delta cells-somatostatin
Figure 21—10.Photomicrograph of an isletof Langerhansshowing alpha(A) cells andbeta (B) cells.Gomori’strichromestain. Highmagnification.
PC, prohormone convertase
History of diabetes• Clinicians have reported for years the presence ofglucose in the urine (glucosuria). The Indian physicianSushruta in 400 B.C. described the sweet taste of urinefrom affected individuals.• In 250 B.C., the name "diabetes" was first used. It is aGreek word that means "to syphon", The complete term"diabetes mellitus" was coined in 1674 by Thomas Willis,physician to King Charles II. Mellitus is Latin for honey.• Up until the mid-1800s, the most successful treatmentswere starvation diets in which caloric intake was severelyreduced.
History• 1869, Paul Langerhans,discovered islets• 1860s Miring and Minkowski Removing pancreas causesdiabetes Tie off pancreatic duct in dogs,the exocrine pancreas digestsitself, but the islets are left intact. These dogs did not developdiabetesPaul Langerhans(1847-1888)
History• Islets were required for blood glucoseregulation and that diabetes involvedloss of the islets.• Early 1920s. Fred Banting M.D. andCharles Best (Grad student) use dogsto develop first insulin preparation• Worked in the laboratory of JohnMcLeod, University of Toronto
Dr. J. Collip
Teddy Ryder, 5 yr old, receivedinsulin July 10, 1922Contract with Eli Lilly, 1922
The thyroid gland• Lays over the larynx• Accumulates tyrosine and iodide• Hollow, soccer-ball shaped structurescalled follicles
Thyroid hormones• Act on intracellular receptors• T3 is 10x more potent than T4• Increase metabolic rate by increasingoxygen consumption• Increase heat production by “uncoupling”oxidative phosphorylation, ie. Make lessATP, more heat