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GLUCONEOGENESISGLUCONEOGENESIS

The process of forming sugar from nonThe process of forming sugar from noncarbohydrate moleculescarbohydrate molecules

Protects the body (especially the brain) ofProtects the body (especially the brain) of

hypoglycemiahypoglycemiaduring prolonged fast , liver glycogen stores areduring prolonged fast , liver glycogen stores aredepleteddepleted

Substrates :Substrates : the glucogenic amino acids, lactate,the glucogenic amino acids, lactate,

glycerol and propionateglycerol and propionateOccurs inOccurs in the cytosol and mitochondriathe cytosol and mitochondria at theat theliver (90 ), !idney ("0 )liver (90 ), !idney ("0 )

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GLUCONEOGENESISGLUCONEOGENESIS

Three irreversible reactions in glycolysisThree irreversible reactions in glycolysiscircumvented by four alternate :circumvented by four alternate :

# $arbo%ylation of pyruvate to o%aloacetate by# $arbo%ylation of pyruvate to o%aloacetate by

pyruvate carbo%ylasepyruvate carbo%ylase, converted to P&P by, converted to P&P by P&PP&P

carbo%y!inasecarbo%y!inase

O%aloacetateO%aloacetate reduced to malate,reduced to malate, transported totransported to

cytosolcytosol reo%idi'ed to o%aloacetatereo%idi'ed to o%aloacetate

# ephosphorylation of fructose ", bisphosphate# ephosphorylation of fructose ", bisphosphatebyby fructose ", bisphosphatasefructose ", bisphosphatase

# ephosphorylation of glucose phosphate by# ephosphorylation of glucose phosphate by

glucose phosphataseglucose phosphatase

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REGULATION OF GLUCONEOGENESISREGULATION OF GLUCONEOGENESIS

*y substrate availability, en'ymes (*y substrate availability, en'ymes (allostericallostericeffectors) and hormoneseffectors) and hormones

Substrate availabilitySubstrate availability a high fat diet, starvation anda high fat diet, starvation and

prolonged fastingprolonged fastingThe four !ey en'yme are affected by +P, +TP,The four !ey en'yme are affected by +P, +TP,$itrate, +cetyl co +, -ructose ., *P,$itrate, +cetyl co +, -ructose ., *P,

-ructose ", *P-ructose ", *P

/ormones : insulin, glucagon, cortisol/ormones : insulin, glucagon, cortisol

altering concentration of allosteric effectorsaltering concentration of allosteric effectors

altering en'ymes synthesisaltering en'ymes synthesis

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GLUCONEOGENESIS SUBSTRATESGLUCONEOGENESIS SUBSTRATES

lucose synthesis fromlucose synthesis from lactatelactate

# 1actate is released by cells have lo2 o%ygen# 1actate is released by cells have lo2 o%ygenconcentrationsconcentrations

# 3n the# 3n the cori cyclecori cycle ::lactate is released by s!eletal muscle duringlactate is released by s!eletal muscle duringe%ercisee%ercise transferred to the livertransferred to the liver pyruvatepyruvate glucoseglucose gluconeogenesisgluconeogenesis

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LACTIC ACID (CORI) CYCLELACTIC ACID (CORI) CYCLE

glucose

glucose glucose glucose-6-P glucose-6-P

glycogen glycogen

ATP ATP NAD Bloo! NAD

"y#u$%&e "y#u$%&e

l%c&%&e l%c&%&e l%c&%&e

L'$e# uscle

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GLUCONEOGENESIS SUBSTRATESGLUCONEOGENESIS SUBSTRATES

lucose synthesis fromlucose synthesis from lycerollycerol

# lycerol, a product of fat metabolism in# lycerol, a product of fat metabolism in

adipose tissueadipose tissue transported to thetransported to theliverliverconverted to glycerol 4 phosphate byconverted to glycerol 4 phosphate by

glycerol !inaseglycerol !inase ((only in liver and !idneyonly in liver and !idney))

1iver and !idney are able to convert glycerol1iver and !idney are able to convert glycerol

glucoseglucose

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GLUCONEOGENESIS SUBSTRATESGLUCONEOGENESIS SUBSTRATES

lucose synthesis from thelucose synthesis from the glucogenic aminoglucogenic amino

acidsacids

##+lanin+lanin the most important asthe most important as glucogenic aminoglucogenic amino

acidsacids

# 5hen e%ercising muscle produces large# 5hen e%ercising muscle produces large

6uantities of pyruvate6uantities of pyruvatealaninealanine transported totransported to

the liverthe liver

reconverted to pyruvate and then toreconverted to pyruvate and then to

glucoseglucose

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+lanine $ycle+lanine $ycle

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F#c-*6-+'sP e,,ec&s 'n l'$e#F#c-*6-+'sP e,,ec&s 'n l'$e#

-rc#., bisP : allosteric effector of P-7 " and-rc#., bisP : allosteric effector of P-7 " andfructose ", bisphosphatase in liverfructose ", bisphosphatase in liver

-ormed by phosphorylation of fructose phosphate-ormed by phosphorylation of fructose phosphate

by P-7 .by P-7 .

5hen blood 8lc is lo2,5hen blood 8lc is lo2, glucagonglucagonis released,is released,

resulting in increased intracellular 8c+P in liverresulting in increased intracellular 8c+P in liver

; -rc#.,#bisP decreases, stimulates-rc#.,#bisP decreases, stimulates

gluconeogenesisgluconeogenesis

5hen blood 8lc is high, -rc#.,#bisP increases5hen blood 8lc is high, -rc#.,#bisP increases

; 3nhibiting -ructose ", bisphosphatase, inhibiting3nhibiting -ructose ", bisphosphatase, inhibiting

gluconeogenesisgluconeogenesis

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$13 # >,>

mmol?1mmol?1

5hen the blood glucose rise to relatively high5hen the blood glucose rise to relatively high

level, the !idney e%erts a regulatory effectlevel, the !idney e%erts a regulatory effect

The glomerular filtrate may contain moreThe glomerular filtrate may contain moreglucose than can be reabsorbedglucose than can be reabsorbed

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$13