1. JonathanJeffrey
FSHN 470 Integrative Metabolism
Exam 1 Questions
Fall 2015
1. AfterGlucose passesthroughthe enterocyte,itisentersthe hepaticportal veinwherethe liver
getsthe “firstpass” at glucose absorption.The liverabsorbsasmuchglucose asit can, and the
restmovesthroughthe bloodstreamwhere itisrecognizedbythe pancreas.The pancreatic
betacellsrecognize the presence of glucose andreleaseinsulinintothe bloodstream.The
insulinandglucose travel throughthe bloodandthe insulinsignalsthe Glut4 transportersin
skeletal musclecytosol tomove tothe cell membrane throughthe insulin-mediated
phosphatidyl-inositol-3kinase pathwayandletsglucose intothe cell.The glucose movesinto
the skeletal muscle cellsthroughthe glut4channel,where itcanbe usedforglycolysisor
glycogenesis. Atthispoint, post-prandial, the levelsof glucose andinsulininthe bloodwill be
highand glucagonwill be low. The bloodglucose concentration immediatelyafterahighcarb
meal inthe portal veincanbe as highas 15 mM. There will be an immediatespike ininsulinand
glucose about15 minutesafterthe meal andafterabout45 minutesto an hour,those levelswill
start to fall.Atthispoint,as insulinandglucose levelsstarttofall,glucagonwill begintorise.
The levelsof insulinglucose andglucagonshouldbe normal about4hoursafter a meal,andinto
the post absorptive state,whereglucagonwill continue torise andinsulinwill continue tofall,
but glucose levelswill not fall asfastas insulinanymore because of the regulationbyglucagon.
Under fastingconditions,bloodglucose levelsshouldbe around70-100 mg/dl.Inthe post
prandial period,theymayreachas highas 140 mg/dl.Underfastingconditions,bloodinsulin
levelsshouldbe between1.4-14µIU/ml,whichisverylow,andglucagonlevelswouldbe high.
Normal glucagonlevelscanbe between50-100 pg/ml and maybe higherwhen fastedfor
longer.
2. Glucose crossesthe sarcolemmabywayof a transportercalledglut4 that isinsulinmediated.
Insulinbindstoitsreceptorinthe cell membrane,andkicksoff acascade of reactionsthatis
referredtoas the phosphatidyl-inositol-3kinase pathway. Throughthiscascade of events,the
glut4 transporterwhichlivesinthe cytosol of the cell issignaledbythe cascade of reactions and
movesfromthe cytosol to the membrane of the cell,intothe lipidbilayer,creatingachannel
that glucose canmove through.Glucose can thenenterthe cell throughthe glut4 transporters
by wayof facilitateddiffusion,drivenbythe concentrationgradient of glucose outside the cell.
3. In skeletal muscle cells,glucoseisphosphorylatedduringthe firststepof glycolysistocreate a
molecule of glucose-6-phosphate. Thisphosphorylationservesafew keypurposes.First,a
phosphorylated moleculecannotpassback throughthe cell membrane,soittrapsthe
compoundinthe cell where itisneeded.Second,itallowsforenzymaticrecognitionof the
compound.Third,itchangesthe concentration gradientof glucose byreducingthe amountof
glucose inthe cell,once itisphosphorylated itdoesn’tcounttowardsthe concentration

2. gradientanylongersoit allowsmore glucose toenterthe cell. Thisphosphorylationiscatalyzed
by HexokinasesIand II.Theyhave a low Km( ~ .1) and a highaffinityforsubstrate.The
phosphorylationof glucose isanendergonicreactionmeaningitrequiresenergytogoforward.
Thismeansthe reactionisnot favorable.Inorderto overcome thispositive change infree
energy, the reactioniscoupledwiththe hydrolysisof ATPto ADP.The conversionof glucose to
G-6-P costs3.3Kcal/mol (endergonic).The hydrolysisof ATPtoADP releases7.3Kcal/mol
(exergonic).Bycouplingthesetworeactions,the total change in free energyis –4.0 Kcal/mol.
The reactionbecomesexergonicoverallandisable tomove forward. Thisenzyme is
allostericallyinhibitedbyhighlevelsof G-6-P.Allostericinhibitionof Phosphofructokinase by
highATP levelswouldalsoinhibithexokinase because of the downstreambackupof G-6-P.
4. The keyenzyme inglycogenesisisglycogensynthase.Itcatalyzesthe reactionthatformsa
glycosidicbondbetweenactivatedUDP-glucose andterminal glycogenresidue.Glycogen
synthase isactive whenitisnot phosphorylated.Insulinaffectsthisenzyme inacouple ways.
1. Throughthe phosphatidyl-inositol-3kinase pathway;Glycogensynthase Kinase 3isan
enzyme downstreaminthe P-I-3Kpathwaythat phosphorylatesGlycogenSynthase. When
insulinbindsto itsreceptoronthe cell membrane itcausesthe cascade of reactions knownas
the PI-3 K pathwaywhichincludes the phosphorylationof GSK-3.GSK-3is inactive when
phosphorylated.Thismeansitwill notgoonto phosphorylate glycogensynthase,leaving
glycogensynthase initsactive form, andglycogenesiscontinues.
2. The otherway insulinstimulatesglycogensynthase isbyreducingthe amountof cyclicAMP.
Wheninsulinisactive,cAMPisnotbeing producedbyadenylate cyclase throughG-protein
coupledreceptors.cAMPactivatescAMPdependentproteinkinase (PKA).PKA stimulatesthe
phosphorylationof PPI-1,whichdecreasesthe activityof phosphoproteinphosphatase,an
enzyme thathelpsdephosphorylate glycogensynthase (active).Soif cAMPreducesthe Active
glycogensynthase,andinsulininhibitscAMP,InsulinupregulatesGlycogensynthase.
5. Glycogenolyisisincreasedby the onsetof exercise bythe presence of the hormones
epinephrine orglucagon.The keyenzyme inglycogenolysisisglycogenphosphorylase,which
removesglucose fromglycogen. WhenglucagonbindstoaG-proteincoupledreceptorinthe
cell membrane, the alphasubunitmovesovertoactivate adenylyl cyclase whichcatalyzesthe
synthesisof cAMPfromATP.CAMP activatesPKA,which actson phosphorylase kinase,changing
it fromitsinactive formtoits phosphorylatedactive form. PKA alsoactson PPI-1,andinhibitor
of phosphoproteinphosphorylase(PP),whichremovesthe phosphatefromglycogen
phosphorylase.Bydown-regulatingthe activityof PP,more glycogenphosphorylaseremainsin
itsactive phosphorylatedstate.Ona side note,PPalsodephosphorylatesGlycogensynthase
leavingitinactive.Thisisaperfectexampleof the body avoidingfutilecyclingbyavoiding
simultaneousglycogenesisandglycogenolysis.Duringthe onsetof exercise,epinephrine also
comesintoplay,due to stimulationof the sympatheticnervoussystem. Andthisalsohasan
effectonupregulatingglycogenphosphorylase.When epinephrine bindstoanalpha-1
adrenergicreceptoronthe cell membrane of the myocyte,itstimulatesag proteintoactivate
Phospholipase C- gammatohydrolyze phosphatidylinositol-4-5-bisphosphate (PIP2) toinositol
1,4,5 triphosphate (IP3).IP3 acta as a signalingmoleculetothe sarcoplasmicreticulumtorelease
calcium.Calciumbindstocalmodulin,whichstimulatesphosphorylase kinasetophosphorylate

3. phosphorylase.Alsothe mechanical contractionof the myocyte willresultinextracalciumbeing
releasedfromthe sarcoplasmicreticulum.The alphaadrenergicpathwaydescribedaboveisa
fastacting pathway,allowingfor fastaccessto storedenergy.Glycolysisisstimulatedbyan
increase inglycogenolysisbecauseglycogenolysis resultsinthe conversionof glycogento
glucose-1-Pbyglycogenphosphorylase, thenthe conversionof G-6-P,byphosphoglucomutase.
G-6-P, is the strongeststimulatorof Phosphofructokinase (PFK),the keyenzyme inglycolysis.
Thisrelationshipallowsthe cellstocontinue tocreate energythroughthe glycolyticpathway.
Thisthe bloodisnotdepletedof glucose foruse bythe brainandCNS,because inthiscase,
insulinwillnotbe active,therefore glut4transporterswill be lessactive, andthe glucose will
not be absorbedthe myocytes,andtheirhighaffinityforglucose (Hexokinase1and 2). The
compartmentationof glycolysisandglycogenolysishappeninginthe myocyte allowsthe cells to
use energytheyproduce intheirowncell,sothere isnoneedto drainthe bloodstreamof
glucose.