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Its chromaffin cells synthesize and release catecholamines into thebloodstream in response to sympathetic nervous system activation. Whereas sympathetic postganglionic nerves mainlyrelease norepinephrine, 70% to 80% of the catecholaminerelease from chromaffin cells is epinephrine. As is the case forpostganglionic neurons, a number of sympathetic cotransmitters, including neuropeptide Y, are also synthesized andreleased. Release of adrenal catecholamines results in a spectrum of physiological actions throughout the body, witheffects differing somewhat in degree compared with effects ofnorepinephrine released from sympathetic nerves, owing tothe differences in binding affinity of epinephrine and norepinephrine at subtypes of adrenergic receptors (Fig.
28.6).337CLINICAL CORRELATEAddison’s DiseaseAddison’s disease is an uncommon endocrine disease characterized by failure of steroid synthesis by the adrenal gland, due tovarious causes including autoimmune or tubercular destructionof the gland and rare genetic disorders.
As is the case for Cushing’s syndrome, effects of deficiency of adrenal steroids mightbe predicted based on the normal actions of the hormones.Symptoms and signs of adrenal insufficiency include:■■■■■■poor stress tolerancehypoglycemiafatigue and weight losshyperpigmentation of skin (due to ACTH elevation; seeearlier in the chapter)low blood pressuresalt appetiteAn Addisonian crisis, caused by a severe deficiency of adrenalhormones, is a medical emergency, sometimes marking theonset of the disease.
Vomiting and diarrhea, low blood pressure,fainting, loss of consciousness, convulsions, and hypoglycemiaare among the signs and symptoms. Addisonian patients requirelong-term glucocorticoid replacement therapy, and sometimesmineralocorticoid treatment as well.Mucous membranepigmentationSkin pigmentationDarkening of hairFrecklingVitiligoHypotensionPigmentaccentuationat nipples,at frictionareasPigmentconcentrationin skin creasesand in scarsLoss of weightemaciation:anorexiavomitingdiarrheaMuscularweaknessChronic Primary Adrenocortical Insufficiency (Addison’sDisease) In primary adrenocortical insufficiency, adrenocorticalsteroid production is low, due to adrenal atrophy, tubercular destruction of the adrenal, or other causes, and ACTH level is elevated(due to lack of negative feedback).
Symptoms reflect deficiency ofcorticosteroids but also reflect excess of ACTH, which causes pigmentation due to its sequence homology with α-melanocytestimulating hormone (MSH). ACTH, adrenocorticotropic hormone.338Endocrine PhysiologyPreaorticgangliaCH2–CH–COOHNH2srvenichSympathetictrunknplaecnOHSAdrenalmedullaOH++++epin+++++ephEpin++OHCH3OHOHConversionDopamineOHstimulated OHby cortisolCH CH2 NH2EpinephrineOHNor+ephrineCortisol+++++Increasedcardiacoutput++++GlucoseBMRelevation++++GlycogenBronchialdilation;intestinalinhibitionKidneyUrinaryexcretionof metabolitesOHNorepinephrinerine++++BloodpressureelevationCH2 CH2 NH2CH CH2 NHAdrenalcortexT10T11T12L1TyrosineGlycogenolysis;hyperglycemiaFFA(freefattyacids)CNSexcitability+++Lipolysis+++Figure 28.6 Function of the Adrenal Medulla The adrenal medulla releases epinephrine (80%) andnorepinephrine (20%) into the bloodstream during activation of the sympathetic nervous system.
The effectsof epinephrine and norepinephrine, including relative magnitude, are illustrated for various sites. BMR, basalmetabolic rate.339CHAPTER29The Endocrine PancreasThe pancreas has key roles in both gastrointestinal functionand modulation of blood glucose levels. Because the productsof the exocrine pancreas (enzymes and buffers) allow digestion and absorption of carbohydrates into the blood, and theproducts of the endocrine pancreas (insulin, glucagon, andsomatostatin) regulate the blood glucose levels, the pancreascan be viewed as a total processing unit for glucose entry intothe body and the cells.somatostatin inhibits both insulin and glucagon.
This allowsparacrine modulation of the pancreatic response to bloodglucose levels.SYNTHESIS OF INSULIN, GLUCAGON,AND SOMATOSTATINInsulinSTRUCTURE OF THE PANCREASAs noted in Section 6, the exocrine pancreas performs crucialdigestive and buffering functions. The exocrine pancreasmakes up about 99% of the functional cells, with the remainder serving the endocrine function (Fig.
29.1). The primaryendocrine portion is composed of the islet of Langerhans cells,which are made up of three cell types:■■■α-Cells produce glucagon, which mobilizes glucosestores into the blood.β-Cells produce insulin, which stimulates glucose transport into the cells.δ-Cells produce somatostatin, which inhibits bothinsulin and glucagon secretion.In the islets, the cells are organized with the α-cells surrounding the β-cells. There are many more insulin-producing βcells than α and δ cells. There is a fourth cell type (F-cell)within the islets, which produce pancreatic polypeptide, whichinhibits exocrine secretions (buffers and enzymes).The major control of blood glucose levels occurs through theproduction and secretion and action of insulin, which is a 51amino acid peptide hormone formed in the β-cells from aprohormone that contains three peptides: the A and B chainsof the active insulin molecule and the connecting “C”-peptide(Fig.
29.2). In the endoplasmic reticulum, disulfide bridgesare formed between the A and B chains of the proinsulin,which are still connected by the C-peptide chain. In the Golgiapparatus, the C-peptide is cleaved from the proinsulin,forming active insulin.
Both the insulin and C-peptide arepackaged in granules for secretion into blood.Glucose (GLUT) TransportersSecretion of insulin is stimulated directly by blood glucoselevels, as well as by gut peptides. The glucose enters cellsthrough a variety of facilitated glucose transporters (GLUT).Although many GLUT transporters have been identified(more than 10), the function of several of the newly discovered isoforms is not clear. Of the main transporters:■There are also important paracrine (cell-to-cell) interactionswithin the islets. Because the blood forms a capillary networkin the islets, insulin (from β-cells) is carried to the glucagonproducing α-cells in a paracrine manner.
Insulin can inhibitits own secretion, as well as glucagon secretion, whereasBecause both insulin and the C-peptide fragments aresecreted when contents of the insulin-containing granules are released, the amount of C-peptide in the blood is areflection of insulin production. Clinically, C-peptide is used todetermine endogenous insulin secretion in diabetic patientsreceiving insulin injections.■GLUT1 is in all adult cell membranes and is responsiblefor allowing enough glucose into cells to maintain cellular respiration and viability. It is also found in highconcentration in the membranes of the blood-brainbarrier, and the transporters are under positive controlby circulating glucose (increased glucose increasesGLUT1 transporters). SGLUT1 are secondary activetransporters, which carry glucose with sodium, andthese are found in apical membranes of renal proximaltubules, choroid plexus, and small intestine along withSGLUT2.GLUT2 is located in the membranes of the small intestine (basolateral side), brain, liver, and pancreas, andthese transporters facilitate easy entry of glucose to thosetissues.
SGLUT2 are secondary active transporters,340Endocrine PhysiologyInferior vena cavaAortaCeliac trunkPortal veinCommon bile ductSpleenStomachAdrenalLesser omentum (free edge)ilTaPancreaslonocoseerse mtransvmnudeHeadtofBodyenDuoRightkidneychAttamJejunumLeftkidneyColonSuperiormesenteric vesselsUncinate processRoot of mesenteryColonCommon bile ductPrincipal pancreatic duct (Wirsung’s)21Accessory pancreatic duct (Santorini’s)223ADB4112Low-power section of pancreas1.
Acini, 2. islet, 3. interlobularseptum, 4. interlobular ductPancreatic islet: A⫽␣,B⫽, and D⫽␦ cells.1. Reticulum, 2. aciniFigure 29.1 Structure of the Endocrine Pancreas The pancreas is a key component of the gastrointestinal (GI) tract because of its exocrine function; it also provides the primary control of blood glucosebecause of its production of endocrine hormones. The vast majority of the pancreas (∼99%) is composedof acinar cells, which produce and secrete the buffers and enzymes through ducts into the GI tract (exocrinefunction) (micrograph on left).
The endocrine pancreas is composed of cells that form the islets of Langerhans. The cells of the islets produce insulin (β-cells), glucagon (α-cells), and somatostatin (δ-cells).■■■which carry glucose with sodium, and these are foundin apical membranes of renal proximal tubules, choroidplexus, and small intestine along with SGLUT1.GLUT3 is mainly in neurons and placenta.GLUT4 is expressed in skeletal and cardiac muscle andadipose tissue and is the insulin-stimulated glucosetransporter.GLUT5 is the fructose transporter.Mechanism of Insulin SecretionWhen blood glucose increases (see Fig. 29.3A):■■■Glucose enters the pancreatic β-cells via GLUT2transporters.Intracellular glucose metabolism increases adenosine triphosphate (ATP), which inhibits K+ efflux.
This depolarizes the β-cells and opens voltage-gated Ca2+ channels.The Ca2+ influx stimulates secretion of the insulin andC-peptide into the blood.In addition to blood glucose, the gut-derived incretins (glucoseinsulinotropic peptide [GIP] and glucagon-like peptide-1[GLP-1]) and increased blood amino acids, fatty acids, andThe Endocrine PancreasA. Proinsulin5556575859Glu54Connectingpeptide53 52Leu AlaLeu AlaGlnGly51 504749 48Leu46Gly Gly Leu Gly45Gly44Gly43Leu42Glu4140 3938Ala Gly Ala GlnVal3736ProAsn35GlnAlaPro34Glu60 Pro33Arg 3261 GlnArg 3162 Lys63341Ala 30ArgGlyS1A chainSCOOH211112 135 620 AsnIle14 15 16 17 18 19Cys Thr Ser Ile CysValSerCysCysGlu GlnLeu TyrTyr273 489 10Gln Leu Glu AsnSLeuHis5GlnAsnVal4SCys67Ser His Leu Val GluGlyAlaGlyGluPro 28Thr27TyrPhe25PheSSLys 29ArgGlyLeu Tyr22Leu Val Cys8 9 10 11 12 13 14212015 1617 18 19B chainB.
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