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Endocrine Physiology - ALL NOTES (Lecture & Study Guide)

15 Pages
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Department
Physiology
Course Code
Physiology 3120
Professor
Terry Biggs

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Endocrine)Physiology ! Lecture"1"#"Introduction"to"Endocrinology" Introduction" • Endocrine$system$=$tissues$and$cells$capable$of$secreting$and$responding$to$hormones$(chemical$messenger) $ • Nervous$system$vs.$endocrine$system $ o Neural:$functions$mediated$by$electro >chemical$conduction$along$nerves$ o Endocrine:$functions$are$mediated$by$chemic al$messengers$called$hormones$ • Hormone$=$a$chemical$substance,$formed$in$one$organ$or$part$of$the$body,$and$carried$in$the$blood$to$another$organ $ • Depending$on$the$specificity$of$their$effects,$hormones$can$alter$the$functional$activity$of$just$one$organ$or$ various$ numbers$of$organs$(GnRH$vs.$T3) $ • Not$all$hormones$are$the$same $ o Endocrine$=$chemical$mediators$produced$in$one$part$of$the$body$which$act$on$a$distant$part $ o Paracrine$=$chemical$mediators$produced$in$one$cell$that$acts$on$a$neighboring$cell$ $ o Autocrine$=$chemical$mediator$produced$in$one$cell$and$acts$on$itself$ $ • Nervous$system$vs.$endocrine$system $ o Physical$form$of$information$transfer:$Action$potentials$vs.$chemical $ o Speed$of$information$transfer:$Fractions$of$seconds$vs.$minutes,$hours,$days $ o Mechanism$of$gradation:$frequency$vs.$amplitude$modulation$ o Mechanism$to$achieve$specificity:$“Wiring”$vs.$receptors$ $ Classes"of"Hormones" • Peptide/Polypeptide$Hormones$ o Small$monomers$(TRH)$or$large$multimeric$proteins$(TSH,$LH,$FSH )$$ o Water$soluble$>$easily$travel$in$blood$stream$(no$carrier$protein)$ • Steroid$Hormones$ o Derived$from$cholesterol$>$4$hydrocarbon$rings$with$various$side$chains $(testosterone,$estrogen,$vitamin$D)$ o Lipid$soluble$>$requires$carrier$protein$$ • Amino$Acid$Derivatives$ o Derived$from$enzymatic$modifications$of$an$amino$acid$ $ o Examples:$epinephrine,$thyroxine$(T4) $ Regulation"of"Endocrine"Secretion " • Negative$feedback$ o Most$hormone$secretion$is$controlled$through$negative$feedback$mechanisms $ o Classic$example:$ ! Pituitary$gland$produces$TSH$ ! TSH$acts$on$the$thyroid$gland$to$produce$thyroxine $ ! When$the$levels$of$thyroxine$become$too$high,$thyroxine$feedbacks$to$the$pituitary$gland$to$shut$off$ production$of$TSH$ o Negative$feedback$can$also$occur$between$a$hormone$and$a$metabolite $ ! The$parathyroid$gland$produces$PTH$ ! PTH$acts$on$the$osteoclasts$to$increase$levels$of$Calcium $ ! High$calcium$(metabolite)$feedbacks$to$the$parathyroid$gland$to$shut$off$production$of$PTH $ o There$is$also$negative$feedback$between$antagonistic$pairs$of$hormones $ ! If$blood$glucose$gets$too$high,$the$beta$cells$of$the$pancreas$produce$insulin.$Insulin$decreases$blood$ glucose$levels$ ! Meanwhile,$if$blood$glucose$levels$get$too$low,$the$alpha$cells$of$the$pancreas$produce$glucagon.$ Glucagon$increases$blood$glucose$levels$ $ • Positive$feed$forward$ o As$the$oocyte$developments,$it$produces$higher$levels$of$estrogen.$Estrogen$has$a$positive$effect$on$LH$and$FSH$ secretion$(induces$ovulation)$ o Conversely,$a$negative$feedback$control$occurs$with$progesterone$after$ovulation$occurs.$High$levels $of$ progesterone$negatively$impacts$secretion$of$LH$and$FSH $ Characteristics"Shared"by"All"Hormones " • Receptor$Specificity$ o Only$certain$cells$respond$to$a$given$hormone$ >$this$is$because$only$certain$cells$express$the$appropriate$ receptor$for$the$particular$hormone$$ o In$addition,$some$cells$are$targets$for$more$than$one$hormone$(=$they$express$more$than$1$receptor) $ • A$single$hormone$may$elicit$different$responses$in$each$target$tissue $ o Testosterone$enters$its$target$cell$and$can$either$bind$to$its$androgen$ receptor$and$elicit$particular$effects,$or$it$ can$be$converted$to$DHT$and$elicit$more$potent$androgen$effects $ • Single$processes$can$be$altered$by$multiple$hormones $ o Serum$glucose$levels$can$be$altered$by$catecholamines,$cortisol,$glucagon,$and$insulin $ • Signal$amplification$ o Each$hormone/receptor$complex$produces$multiple$second$messenger$molecules$(e.g$cAMP,$PKC,$Ca ++)$ o Each$second$messenger$molecule$activates$different$signaling$cascades$(protein$phosphorylation) $ o End$result$is$generation$of$multiple$copies$of$an$mRNA,$functional$phosphorylated$protein ,$hormone,$etc.$ Factors"Affecting"Hormone"Action " • Hormone$Production/Release$Rate $ o Regulation$of$gene$transcription,$translation,$and$modification$(golgi)$ o Availability$of$necessary$substrates,$enzymes,$and$energy $ o In$certain$tissues,$the$nervous$tissue$needs$to$innervate$the$tissue$in$order$for$the$tissue$to$make$hormones $ o More$hormone$present$at$a$given$target$cell$will$lead$to$the$activation$of$more$receptors$(at$least$until$receptors$ are$saturated)$ o However,$constant$exposure$to$high$levels$of$hormone$may$eventually$lead$to$down >regulation$of$the$receptor$ in$the$target$cell(s)$ o Variability$of$release$rate$into$the$blood $ ! Ultradian,$diurnal,$circadian$secretion$ $ • Serum$Carrier$Proteins$can$affect$hormone$transportation$ o Solubility$in$blood$ o Stability$ o Prevention$of$metabolic$clearance$ o Bioavailability$>$hormone$is$not$biologically$active$until$released$by$carrier$protein $ • Converting/Deactivating$Enzymes$(in$plasma$and$target$cells) $ • Metabolic$clearance$ o As$hormones$circulate$in$the$blood,$they$can$be$picked$up$and$cleared$by$the$kidneys$or$the$liver;$if$this$ happens,$than$the$hormone$obviously$cannot$affect$its$target$organ $ • Hormone$Receptors$$ o Hormone$action$is$achieved$through$receptor$expression$and$availability$of$signaling$ pathway(s)$ Hormone"Receptors" • Cell,surface,(membrane),receptors $>$for$water>soluble$ligands$and$large$ligands$that$cannot$passively$travel$into$the$ cell$(peptides/polypeptides,$cytokines,$amino$acid$derivatives,$ions) $ o G>protein$coupled$receptor$ o Tyrosine$kinase>associated$receptor$ o Tyrosine$kinase$receptor$ o Receptor>mediated$ion$channel$ • Intracellular,receptors$>$for$lipid>soluble$ligands$(steroids,$thyroid$hormones,$vitamin$D) $ o Cytosolic$receptor$ ! HSPs$regulation$the$activation$of$cytosolic$nuclear$receptors,$all owing$them$to$translocate$into$the$ nucleus$and$elicit$downstream$effects$(typically$alter$transcription$ >$activate$or$repress)$ o Nuclear$receptor$$ Lecture"2"#"Neuroendocrinology"(Hypothalamus,"Pituitary)" Introduction" • The$hypothalamus$is$the$primary$region$of $integration$between$the$central$nervous$and$endocrine$systems$ • Input$from$a$vast$array$of$neural,$humoral$and$endocrine$sources$are$processes,$coordinated,$and$then$related$into$action:$ the$secretion$of$factors$which$stimulate$or$inhibit$anterior$pituitary $function;$the$release$of$neurohypophysial$hormones;$ as$well$as$efferent$output$to$the$CNS $ Functional"Anatomy" • Parvicellcular$cells$ o Produce$hormones$which$are$transported$to$the$ anterior$pituitary$via$the$hypophyseal$portal$system$$ o The$hormones$stimulated$for$release$in$the$anterior$pituitary$travel$via$the$blood$to$act$on$target$tissues/organs $ • Magnocellular$cells$ o $These$cells$have$long$neurons$that$travel$all$the$way$to$the$ posterior$pituitary$and$terminate$within$the$ posterior$pituitary$near$a$capillary$network $ • Posterior$pituitary$>$oxytocin,$vasopressin$(ADH)$ o Targets$on$the$kidney,$uterus,$and$mammary$gland $ • Anterior$pituitary$>$trophic$hormones$(ACTH,$TSH,$GH,$LH,$FSH,$Prolactin) $ o Stimulated$for$release$by$TRH,$CRH,$GHRH,$GnRH,$Dopamine,$Somatostatin $ o Targets$the$adrenals,$thyroid,$liver,$ovary $ • There$are$also$Hypothalamic$Projection$Neurons:$ordinary$neuron$that$communicate$with$other$neurons $(not$tissues)$ Episodic"Endocrine"System" • Hormones$are$be$triggered$for$release$via:$ o Circadian$rhythm>$around$24$hours$(influenced$by$sleep$patterns)$ o Diurnal$rhythm$>$exactly$24$hours$(GHRH,$CRH,$cortisol) $ ! Example:$cortisol$peaks$at$4am $ o Ultradian$>$minutes$or$hours$(GnRH,$LH) $ ! Example:$GnRH$peaks$every$couple$o f$hours$(role$in$reproduction)$ • Most$hormones$display$more$than$1$pattern$of$secretion$ $ o GH$hormones$peaks$every$day$at$the$same$time$(diurnal);$but$it$also$fluctuates$during$the$day$(ultradian) $ • How$is$circadian$rhythm$regulated?$ $ o The$SCN$(suprachiasmatic$nucleus)$of$the$hypothalamus$has$intrinsic$circadian$pattern$of$secretion$and$ neuronal$activity$involves$the$coordinated$expression$of$“clock”$genes$(Cry,$Per)$depending$on$the$light$signal$ $ o Utilizes$direct$input$from$the$retina$(non >visual)$ o Light$detected$by$the$retina$resets$the$pattern$to$correspond$to$day/night$cycle$ $ • Pineal$gland$ o Produces$melatonin$during$dark$peri ods$from$metabolism$of$serotonin $ o Non>$Visual$signal$from$retina$"$SCN$"$Spinal$Cord$"$Pineal$Gland$",Melatonin,"$Reset$the$clock$ ! Turns$off$“clock”$genes$$ Hypothalamic#Pituitary#Adrenal"Axis"(HPA)" • Senses$system$stress$(cold,$hypoglycemia,$fear)$ • Releases$CRH$(Corticotropic$releasing$hormone)$ Hypothalamu• Parvicellular$Hypophysiotropic$neuron$>>>$hypophyseal$portal$system$$ Anterior$• Releases$ACTH$ Pituitary$ • Release$cortisol$ • Increase$blood$glucose$(gluconeogenesis,$muscle$catabolism$(amino$acids),$inhibition$of$ Adrenal$CorteGLUT4$activity$ Fasciulata$and$ Reticularis)$egative$feedback$to$hypothalamus$and$anterior$pituitary$ • How$is$ACTH$produced?$ o Anterior$pituitary$produced$(POMC),$which$undergoes$post >translational$processing$to$release$ACTH$ o ACTH$can$be$broken$down$into$MSH$and$CLIP $ ! MSH$causes$increases$in$pi gmentation$>>$causes$you$to$tan$ o In$Addison’s$disease,$you$do$not$produce$enough$cortisol$from$the$adrenal$gland$(hypothalamus$and$pituitary$ continue$to$make$CRH$and$ACTH);$One$symptom$is$pigmentation$(due$to$MSH,$due$to$the$high$levels$of$ACTH) $ Hypothalamic#Pituitary#Thyroid"Axis"(HPT)" • Releases$TRH$(Thyroid$releasing$hormone)$ • Parvicellular$Hypophysiotropic$neuron$>>>$hypophyseal$portal$system$$ Hypothalamus$ • Releases$TSH$ Anterior$ Pituitary$ • Release$T3$and$T4$ • Increase$metabolism$and$heart$rate$(over$days,$weeks,$months)$ Thyroid$ follicles$$ Negative$feedback$to$hypothalamus$and$anterior$pituitary$ • SRIF$(somatotropin$release$inhibiting$peptide)$is$released$by$the$hypothalamus$and$inhibits$the$production$of$T3$and$T4$$ Hypothalamic#Pituitary#Growth"Axis" • Releases$GHRH$(Growth$Hormone$releasing$hormone)$ Hypothalamus$• Parvicellular$Hypophysiotropic$neuron$>>>$hypophyseal$portal$system$$ • Releases$GH$ • GH$can$act$on$and$directly$regaulte$the$growth$of$bones$ Anterior$ Pituitary$ • GH$can$act$on$and$directly$regulate$fat$tissue$(to$produce$leptin)$ • Realease$of$IGF>1$ • Increases$growth$of$our$cells,$tissues,$and$bones$ Liver$ • Negative$feedback$to$hypothalamus$and$anterior$pituitary$ • SRIF$(somatotropin$release$inhibiting$peptide)$is$released$by$the$hypothalamus$and$inhibits$the$production$of$GH$ • Bones,$liver,$and$fat$cells$are$stimulated$by$GH $ o Bones$>$increase$bone$growth$and$repair$ o Liver$>$general$growth$of$cells$and$tissue $ o Fat$>$release$of$leptin$(feed$forward$loop$>$increases$GH$release)$ ! Decreases$food$intake,$decrease$appetite;$increases$energy$output$$ ! Decrease$bone$formation$ Prolactin" • Dopamine$is$produced$by$the$hypothalamus$and$act$to$shut$down$the$release$of$prolactin $ $ • Releases$TRH/PRF$(prolatcin$freleasing$factor)$ " Hypothalamus$• Parvicellular$Hypophysiotropic$neuron$>>>$hypophyseal$portal$system$$ " $ • Releases$prolactin$ Anterior$ Pituitary$ • Increased$milk$production$ • Feed$forward$loop$(caused$by$suckling)$ Breast$ " Hypothalamic#Pituitary#Gonadal"Axis"(HPG)" • Releases$GnRH$(Gonadotropin$releasing$hormone)$ • Parvicellular$Hypophysiotropic$neuron$>>>$hypophyseal$portal$system$$ Hypothalamus$ • Releases$LH$and$FSH$ Pituitary$ • Gametogenesis$and$matration;$steroidogensis$$ • Testosterone,$estrogen,$progesterone,$inhibin,$LH,$FSH:$negative$feedback$to$hypothalamus$ Gonads$ and$anterior$pituitary$ Pituitary"Failure" • There$are$many$reasons$for$why$some$people$have$pituitary$failure $ o Can$have$genetic$mutations$in$the$production$of$the$hormone$ o Can$have$receptor$mutations$$ o Can$have$structural$changes$that$can$occur$to$the$pituitary$and$hypothalamus$(underperformance,$ overperformance)$ o Transcription$factor$defect$$ Neurohypophysis:"Magnocellular"Neurons " • The$neurohypophysis$consists$of$magnocellular$hypothalamic$neurons$which$synthesize$vasopressin$(AVP,$ or$ADH)$and$ oxytocin$and$their$termini$within$the$posterior$pituitary $ • Secretion$of$these$two$hormones$occurs$into$the$capillary$bed$of$the$posterior$pituitary $ Vasopressin ( $ $ $ Oxytocin ( • Oxytocin$secretion$is$stimulated$by$stretch$(uterus)$and$suckling$(breast)$ • Oxytocin$then$initiates$uterine$contraction$and$milk$ejection$ • Oxytocin$may$also$play$a$role$in$maternal$behavior$(?) $ " " " Lecture"3"#"Thyroid"Physiology" Introduction"and"Functional"Anatomy" • Thyroid$gland$ o Found$in$the$neck$ o Largest$endocrine$gland$ o Controls$how$quickly$we$use$energy$(regulates$basal$metabolic$rate) $ o Stores$dietary$iodine$ o Produces$T3,$T4,$and$calcitonin $ • Thyroid$follicles$are$surrounding$by$a$cuboidal$epithelium,$inside$you$will$find$an$accumulation$of$thyroglobulin$(Tg) $ o ***Tg$contains$~330$tyrosine$residues$$ • Parafollicular$cells$are$located$outside$the$thyroid$follicles$ >$produce$calcitonin$$ • Iodide/Iodine$ o We$require$~60$mg$iodine/day $ o Major$sources:$salt,$seafood,$dark$green$vegetables $ o Important$role$in$the$production$of$thyroid$hormones$(T3/T4)$ for$growth,$physical$and$mental$development$ HPT"Axis" • Releases$TRH$(Thyroid$releasing$hormone)$ • Parvicellular$Hypophysiotropic$neuron$>>>$hypophyseal$portal$system$$ Hypothalamus$ • Releases$TSH$ Anterior$ Pituitary$ • Release$T3$and$T4$ • T3$and$T4$increase$metabolism$and$heart$rate$(over$days,$weeks,$months)$ Thyroid$ • Negative$feedback$to$hypothalamus$and$anterior$pituitary$ follicles$$ • SRIF$=$somatostatin$release$inhibitory$factor$ >$inhibits$the$anterior$pituitary$from$producing$TSH$ Production"of"Thyroid"Hormones " • T3$and$T4$are$produced$from$the$amino$acid$tyrosine$ "$therefore$thyroid$hormones$are$amino$acid$derivatives $ • Tyrosine$residues$in$thyroglobulin$are $first$iodinated$and$coupled$to$ultimately$lead$to$T3$and$T4$ o Thyroid$Peroxidase$(TPO)$is$very$important$>$it$iodinates$and$couples$$ o This$iodination$and$coupling$occurs$at$the$apical$surface$of$the$follicular$cells$ $ • TSH$binds$to$TSHR$"$increases$activity$of$NIS$(bring$in$more$iodide),$increases$Tg$production,$increases$TPO$activity $ • Thyroglobulin$is$produced$within$the$follicular$cells$a nd$secreted$into$the$colloid$ • Iodide$is$transported$from$the$blood$into$the$follicular$cells$via$the$ Na+/I>,symporter,(NIS);,pendrin$transports$the$ iodide$into$the$colloid$$ • Tyrosine$can$either$be$iodinated$by$TPO$once$(monoiodotyrosine)$or$twice$(diiodotyro sine)$"$then$TPO$can$couple$ either$two$diiodotyrosines$(to$make$T4),$or$one$monoiodotyrosine$+$one$diiodotyrosein$(to$make$T3) $ T3(vs.(T4 ( • %$Of$hormone$secreted:$10%$vs.$90% $ • %$Free$in$plasma:$1%$vs.$0.1% $ • Relative$activity$(potency):$10$vs.$1$ [T3,is,the,active,form,of,thyroid,hormone;,T4,can,be,converted,to,T3] $ • Half>life:$1$vs.$7$ Thyroid"Hormone"Transport" • Thyroid$hormones$are$hydrophobic$due$to$their$ring$sturcture$(therefore$will$need$carrier$protein) $ • Carrier$proteins:$ o Thyroxine,Binding,Globulin,(TBG) $>$75%$of$T3$and$T4$ o Transthyretin$(TTR)$>$20%$of$T4,$5%$of$T3$ o Human$Serum$Albumin$(HAS)$>$5$%$of$T4,$20%$of$T3$ • TBG$and$TTR$regulate$the$bioavailability$and$half >life$or$T3/T4$$ Thyroid"Hormone"Action" • T4$can$easily$cross$the$cell$membrane,$it$will$then$be$converted$ to$T3$via$the$enzyme$D2$(deiodinase)$ • T3$will$then$translocate$into$the$nucleus,$binds$to$and$activates$it$nuclear$receptor$(thyroid$receptor),$the$receptor$ dimerizes,$binds$thyroid$response$element,$attract$co >activators,$turn$on$transcription$of$genes$$ Role"of"Thyroid"Hormones" • Very$important$in$early$growth$and$development$ o Required$for$GH$secretion$and$action $ o Essential$for$early$neural$development$(via$induction$of$NGF) $ o Maternal$lack$of$3 /T4$#$growth$retardation$and$cretinism $ • Increases$mitochondrial$growth,$replication,$and$activity$ "$increase$basal$metabolic$activity$$ o Increased$heat$production,$O2$demand,$HR$and$SV$$ • Stimulates$Na+/K+>ATPase$activity$&$β>adrenergic$receptors$in$several$tissues$including$the$heart $$ o Increased$metabolic$demand$(e.g.$increased$glucose) $$ • Increases$transcription$of$energy$metabolism$enzymes $$ o Increased$lipolysis,$glycolysis$and$gluconeogenesis $(make$new$glucose)$leads$to$increased$blood$metabolite$ levels$and$cellular$uptake$$ • Recall:$the$actions$of$thyroid$hormone$occur$over$days/weeks/months! $ • T3/T4$is$permissive$to$growth$hormone$action$(aka$induce$GH$receptor$expression) $ • It$is$also$necessary$for$induction$of$prolactin,$surfactant,$and$nerve$growth$factor$expression $ Dysfunctions ( • There$are$many$geographical$areas$with$low$bioavailability$of$iodine$leading$to$endemic$goiter$ –$including$N.$America$ (early$1900s)$ o Goiter$is$caused$by$excessive$TSH$secretion$(no$neg.$feedback)$leading$to$ thyroid$cell$hypertrophy$ o No$iodine$>$do$not$make$T3/T4$properly$>$therefore$they$do$not$feedback$to$the$hypothalamus,$TSH$continues$to$ act$on$the$thyroid$gland$=$hypertrophy $ • Hypothyroidism$$ o Lack$of$energy,$slow$heart$rate,$muscle$cramping,$lack$of$concentration,$poor$memory,$puffy$eyelids,$feeling$cold $ • Hasimoto’s$disease$ o Auto>immune$disease;$Anti>TPO$antibodies$"$no$ability$to$iodinate$thyroglobulin$ $ • Hyperthyroidism$>$treated$by$blocking$actions$of$T3$and$T4$$ o Feeling$hot,$increased$sweating$ o Fast,$strong$or$irregular$heart$beat $ o Nervousness,$trembling$hands $ o Weight$loss$ • Grave’s$Disease$ o Anti>TSH$receptor$antibodies$>>$activating$TSH$receptors$ o Hand$tremor,$insomnia,$hyperactivity,$protrusion$of$eye $(growth$of$optic$nerve),$mood$swings,$dizziness$$ • Mutations/dysfunction$in$any$of$the$thyroid$“players”$gives$rise$to$thyroid$hormone >related$pathology$ o TBG$mutations$ o TSH$receptor$mutations$ o Nuclear$receptor$mutations$ $ Calcitonin" • 34$amino$acid$peptide$ • Produced$in$parafollicular$cells$in$thyroid$gland $ • Inhibits$osteoclast$activity$(long$term)$ • Decreases$calcium$tubular$reabsorption$ $ Lecture"4"#"Glucose"Homeostasis" Overview" • Normal$glucose$level:$5$mmol/L $ • During$and$after$a$meal,$serum$glucose$levels$rise$rapidly$ "$insulin$then$acts$to$decrease$plasma$glucose$levels$ o Two$phases$of$insulin$release$ • In$between$meals$when$serum$glucose$levels$drop$"$glucagon$acts$to$increase$plasma$glucose$levels$ $ ( ( Cellular(Respiration(refresher ( • Glucose$is$the$best$source$for$the$generation$of$cellular$ATP >the$molecule$which$provides$energy$for$all$cellular$processes.$ $ • Energy$is$stored$in$the$third$phosphate$bond$of $ATP$and$most$activities$in$the$cell$are$regu lated$by$phosphorylation$of$ ATP$ • Glucose$is$broken$down$in$3$separate$biochemical,$consecutive$processes: $ o Glycoloysis*converts$glucose$(C6)$to$pyruvate$or$lactate$(C3)$and$produces$2$ATP $ o The$TCA*cycle*(using$acetyl$co>enzyme$A)$produces$2$ATP$ o The$electron*transport*chain*(mitochondrial$membranes)$produces$34$ATP$ o =$38,ATP/molecule,glucose$ Glucose(Transporters ( Name Tissue distribution Important features GLUT 1 Brain, erythrocytes, placenta, fetal tissue Low Km (high affinity, ~1 mM) -constant uptake of glucose *GLUT 2 Liver, kidney, intestine, pancreatic β-cell. High Km (15–20 mM) -glucose equilibration across membrane *GLUT 3 Brain Low Km (<1 mM) -preferential uptake in hypoglycemia *GLUT 4 Muscle and adipose Med Km (medium affinity, 2.5–5 mM) -Insulin-sensitive GLUT 5 Jejunum Med Km (~ 6 mM) -fructose and insulin uptake The"Pancreas" • The$pancreas$is$both$exocrine$(digestive$cells)$and$endocrine$ $ • Endocrine$function$occurs$in$the$Islets$of$ Langerhans$ o Alpha,cells$>$periphery$>$produce$glucagon$ o Beta,cells$>$central$>$produce$insulin$and$amyloid$ o Delta$cells$>$periphery$>$stomatostatin$(suppresses$growth$hormone) $ o D1$cells$>$produce$VIP$(vasoactive$intestinal$peptide) $ o PP$cells$produce$pancreatic$polypeptide$ $ Insulin"Production"and"Secretion" Production ( • Insulin$is$a$classic$polypeptide$hormone$ • It$is$made$through$transcription,$then$undergoes$post >translation$modification$(golgi)$to$produce$mature$hormone $ • Preproinsulin$"$Proinsulin$(A,$B,$and$C$chains)$"$Insulin$(A$and$B$chains)$"$Mature$insulin$into$secretory$vesicles$ Secretion ( • Biphasic$response$ o 1 $peak$within$1>5$minutes$of$glucose$load$(“meal”) ;$2 $peak$within$15>20+$minutes$after$meal$ • Phase$1$ o Increased$plasma$glucose$"$increased$glucose$uptake$by$the$pancreatic$beta$cells$(GLUT2)$ o Increased$cytosolic$glucose$in$the$beta$cells$results$in$increased$cellular$respiration$and$generation$of$ATP $ o ATP$closes$ATP>sensitive$K+$channels$"$build$up$of$positive$charge$in$the$cell$(me mbrane$depolarization) $ o The$wave$of$depolarization$opens$voltage$gated$Ca++$channels,$and$allows$for$the$influx$of$Ca++$ions$into$the$B$ cell$cytoplasm$ o Increased$cytosolic$Ca++$signal$for$the$release$of$insulin$from$stored$secretory$granules $ • Phase$2$ o Increased$cytosolic$Ca++$(from$phase$1)$activates$CaM$kinase$(Ca++/Calmodulin$dependent$protein$kinase) $ o CaM$kinase$activates$transcription$of$the$insulin$gene $ o Secrete$insulin$(from$phase$1)$binds$to$beta$cell$insulin$receptors$ $ o Activated$insulin$receptors$ increase$transcription$of$insulin$gene$via$the$PI>3$kinase$pathway$ o This$pathway$also$activates$the$translocation$of$GLUT4$transporters$from$the$cytoplasm$and$into$the$cell$ membrane$ o These$3$mechanisms$decrease$the$amount$of$glucose$in$the$blood $ Tyrosine CKin ase(Receptors( ( • The$insulin$receptor$is$a$membrane$of$the$tyrosine$kinase$family$of$receptors $ • Ligand$binding$induces$dimerization$of$the$receptors$ "$receptor$activation$(phosphorylation)$"$down$stream$signaling$ events$(
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