Carbohydrates Metabolism

§ 1 Overview

• Carbohydrates in general are polyhydroxy aldehydes or ketones or compounds which yield these on hydrolysis.

Biosignificance of Carbohydrates

• The major source of carbon atoms and energy for living organisms.

• Supplying a huge array of metabolic intermediates for biosynthetic reactions.

• The structural elements in cell coat or connective tissues.

Glucose Transporters (GLUT)A family of glucose transporters (GLUTs) facilitates transport of D-glucose across the plasma membrane.The gene for the GLUT family are expressed in tissue specific manner.

Glucose transporters designated as GLUT 1-5 all have 12 transmembrane segments with a significant amino acid similarity

• Direction of movement of glucose is usually out to in. Dependent on concentration gradient however, erythrocyte GLUT-1 facilitates transport in both direction

• The three affinity- transporters (GLUT-1, GLUT-3, GLUT-4) function at rates close to maximal velocity because their Km values are below the normal blood sugar level

Isoform Tissue

GLUT1: RBCs, brain - abundant

heart, muscles – low

placenta

GLUT 2: Liver, pancreas, intestines, kidneys

GLUT 3: Brain, kidneys, placenta

GLUT4: Adipose tissue, muscle, heart

GLUT 5: Spermatozoa, intestine

• GLUT 2: catalyzes both glucose influx & efflux in liver cells; it is involved in sensing blood glucose level.

• GLUT 4: is an insulin dependant transporter• GLUT 5: primary transporter of fructose• Activity of some GLUT, in muscles is stimulated

by exercise & hypoxia

The metabolism of glucose

• glycolysis• aerobic oxidation• pentose phosphate pathway• glycogen synthesis and

catabolism• gluconeogenesis

glycogen

Glycogenesis Glycogenolysis

Pentose phosphate pathway

Ribose, NADPH

Glycolysis lactate

H2O+CO2

aerobic oxidation

Digestion absorption

starch

Lactate, amino acids, glycerol

glucose

Gluconeo-

genesis

§2 Glycolysis

Glycolysis• The anaerobic catabolic pathway by

which a molecule of glucose is broken down into two molecules of lactate.

glucose →2lactic acid (lack of O2)

• All of the enzymes of glycolysis locate in cytosol.

1. The procedure of glycolysis

G

pyruvate

lactic acid

glycolytic pathway

1) Glycolytic pathway : G → pyruvate including 10 reactions.

• Phosphorylated G cannot get out of cell • Hexokinase , HK (4 isoenzymes) , glucokinase, GK in liver ;• Irreversible .

(1) G phosphorylated into glucose 6-phosphate

OH

OH

H

OHH

OHH

OH

CH2

H

HOOH

OH

H

OHH

OHH

OH

CH2

H

OPATP ADP

HexokinaseMg2+

G G-6-P

hexokinase glucokinase

occurrence in all tissues only in liverKm value 0.1mmol/L 10mmol/L

Substrate G, fructose, glucose mannose

Regulation G-6-P Insulin

Comparison of hexokinase and glucokinase

(2) G-6-P → fructose 6-phosphate

OH

OH

H

OHH

OHH

OH

CH2

H

OP

G-6-P

isomerase OH

CH2OH

H

CH2

OH H

H OHOOP

F-6-P

(3) F-6-P → fructose 1,6-bisphosphate

• The second phosphorylation • phosphofructokinase-1, PFK-1

OH

CH2OH

H

CH2

OH H

H OHOOP

F-1,6-BP

OH

CH2

H

CH2

OH H

H OHO

OP O P

ATP ADPMg2+

F-6-P

PFK-1

(4) F-1,6-BP → 2 Triose phosphates

• Reversible

F-1,6-BP

CH2C OC HHOC OHHC OHHCH2

O P

O P

CH2C O

O P CHOCHOHCH2 O PCH2OH

+aldolase

dihydroxyacetone phosphate,

DHAP

glyceraldehyde 3-phosphate,

GAP

(5) Triose phosphate isomerization

G→2 molecule glyceraldehyde-3-phosphate, consume 2 ATP .

CH2C O

O P CHOCHOHCH2 O PCH2OH

DHAP GAP

phosphotriose isomerase

(6) Glyceraldehyde 3-phosphate → glycerate 1,3-bisphosphate

CHOCHOHCH2 O P

NAD+ NADH+H +Pi

glyceraldehyde 3-phosphate

dehydrogenase,GAPDH

CCHOHCH2 O P

O O~ P

glycerate1,3-bisphosphate,

1,3-BPG

glyceraldehyde 3-phosphate

(7) 1,3-BPG → glycerate 3-phosphate

• Substrate level phosphorylation

COO-

CHOHCH2 O P

CCHOHCH2 O P

O O~ PADP ATP

glycerate 1,3-bisphosphate

glycerate3-phosphate

Phosphoglyceratekinase

(8) Glycerate 3-phosphate → glycerate 2-phosphate

COO-

CHOHCH2 O P

COO-

CHCH2OH

O P

glycerate3-phosphate

glycerate 2-phosphate

Mutase

(9) Glycerate 2-phosphate → phosphoenol pyruvate

COO-

CHCH2OH

O P

COO-

C

CH2

O

PEP

~ P + H2Oenolase

glycerate 2-phosphate

(10) PEP →pyruvate

• Second substrate level phosphorylation• irreversible

COO-

C

CH3

ADP ATPCOO-

C

CH2

O

PEP

~ P pyruvate kinaseO

Pyruvate

2) Pyruvate → lactate

COOCCH3

NAD+NADH + H+

O

Pyr

COOCHOHCH3

Lactate dehydrogenase,LDH

Lactic acid

Summary of GlycolysisATP ADP

Mg2+

PFK-1

GAP DHAP

glycerate 1,3-bisphosphate

NADH+H+

glyceraldehyde 3-phosphatedehydrogenase

H3PO4NADH+H+

NAD+

ADPATP

glycerate3-phosphate

glycerate 2-phosphateH2O

PEP

ATP

ADPpyruvate kinase

lactate

pyruvate

G G-6-P F- 6-P F- 1,6-BP

NAD+

Phosphoglyceratekinase

Isomerase Aldolase

MutaseEnolase

LDH

HK

ATP ADPMg2+

Total reaction:

C6H12O6 + 2ADP + 2Pi

2CH3CHOHCOOH + 2ATP + 2H2O

Formation of ATP:

The net yield is 2 ~P or 2 molecules of

ATP per glucose.

2. Regulation of Glycolysis

• Three key enzymes catalyze irreversible reactions : Hexokinase, Phosphofructokinase & Pyruvate Kinase.

1) Hexokinase and glucokinase

• This enzyme is regulated by covalent modification, allosteric regulation and isoenzyme regulation.

• Inhibited by its product G-6-P.

• Insulin induces synthesis of glucokinase.

2) PFK-1

The reaction catalyzed by PFK-1 is usually the rate-limiting step of the Glycolysis pathway.

This enzyme is regulated by covalent modification, allosteric regulation.

bifunctional enzyme

3) Pyruvate kinase

• Allosteric regulation:

F-1,6-BP acts as allosteric activator ； ATP, acetyl-CoA, long chain fatty acids

and Ala in liver act as allosteric inhibitors;

• Covalent modification: phosphorylated by Glucagon through cAMP and PKA and inhibited.

ATP ADP

PKA

Glucagon

Pyruvate Kinase (active)

Pyruvate Kinase- P (inactive)

cAMP

SIGNIFICANCE OF GLYCOLYSIS• Glycolysis, the major pathway for glucose

metabolism, occurs in the cytosol of all cells. It is unique in that it can function either aerobically or anaerobically.

• Glycolysis is both the principal route for glucose metabolism and the main pathway for the metabolism of fructose, galactose, and other carbohydrates derived from the diet.

• The ability of glycolysis to provide ATP in the absence of oxygen is especially important because it allows skeletal muscle to perform at very high levels when oxygen supply is insufficient and because it allows tissues to survive anoxic episodes. However, heart muscle, which is adapted for aerobic performance, has relatively low glycolytic activity and poor survival under conditions of ischemia.

• Diseases in which enzymes of glycolysis (eg, pyruvate kinase) are deficient are mainly seen as hemolytic anemias or, if the defect affects skeletal muscle (eg,phosphofructokinase), as fatigue.

• In fast-growing cancer cells, glycolysis proceeds at a higher rate forming large amounts of pyruvate, which is reduced to lactate and exported. This produces a relatively acidic local environment in the tumor which may have implications for cancer therapy.

• The lactate is used for gluconeogenesis in the liver, an energy expensive process which is responsible for much of the hypermetabolism seen in cancer cachexia.

• Lactic acidosis results from several causes including impaired activity of PDH.

3. Significance of glycolysis 1) Glycolysis is the emergency energy-

yielding pathway.

2) Glycolysis is the main way to produce ATP in some tissues, even though the oxygen supply is sufficient, such as red blood cells, retina, testis, skin, medulla of kidney.

• In glycolysis, 1mol G produces 2mol lactic acid and 2mol ATP.

In the erythrocytes of many mammals, the reaction catalyzed by phosphoglycerate kinase may be bypassed by a process that effectively dissipates as heat the free energy associated with the high-energy phosphate of 1,3-bisphosphoglycerate. Bisphosphoglycerate mutase catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate, which is converted to 3-phosphoglycerate by 2,3-bisphosphoglycerate phosphatase

(and possibly also phosphoglycerate mutase). This alternative pathway involves no net yield of ATP from glycolysis. However, it does serve to provide 2,3-bisphosphoglycerate, which binds to hemoglobin, decreasing its affinity for oxygen and so making oxygen more readily available to tissues

§ 3 Aerobic Oxidation of Glucose

• The process of complete

oxidation of glucose to CO2 and water with liberation of energy as the form of ATP is named aerobic oxidation.

• The main pathway of G oxidation.

1. Process of aerobic oxidation

G Pyr

cytosol Mitochodria

glycolyticpathway

secondstage

thirdstage

CO2 + H2O+ATPPyr CH3CO~SCoAfirst

stageTAC

1) Oxidative decarboxylation of Pyruvate to Acetyl CoA

• irreversible;• in mitochodria.

COO-

CCH3

NAD+ NADH + H +

O

pyruvate

CH3CPyruvate

dehydrogenasecomplex Acetyl CoA

O~SCoA+ HSCoA + CO2

Pyruvate dehydrogenase complex: E1 pyruvate dehydrogenase

Es E2 dihydrolipoyl transacetylase

E3 dihydrolipoyl dehydrogenase

thiamine pyrophosphate, TPP (VB1)

HSCoA (pantothenic acid)

cofactors lipoic Acid

NAD+ (Vpp)

FAD (VB2)

HSCoA

NAD+

Pyruvate dehydrogenase complex:

The structure of pyruvate dehydrogenase complex

S S

CH

H2C

H2C (CH2)4 COOH

SH SH

CH

H2C

H2C (CH2)4 COOH+2H

-2H

lipoic acid dihydrolipoic acid

C

C

NH2HC

NCH2

SC

C

NC

NCH

CH3

CH2CH2H3C O P O

O-

O

P

O

O-

O-

+

TPP

HSCoA

HS CH2 CH2 NH C CH2

OCH2 NH C C

O

OH

HC CH2

CH3

CH3

O P O

OH

OP

OH

OO

3'AMP

¦Â-alanine pantoic acid pyrophosphate

pantothenic acid

4'-phosphopantotheine

¦Â-mercapto-ethylamine

CO2

CoASHNAD+

NADH+H+

Regulation of PDH:Two regulatory enzymes (that are part of the complex) activate & inactivate E1

1. The cAMP-independent PDH kinase phosphorylates &, thereby, inhibits E1

ATP, acetyl CoA & NADH are allosteric activators of PDH kinase their presence turns off the PDH complex.Pyruvate is the inhibitor of PDH kinase its presence activates PDH complex

2. PDH phosphatase activates E1 by dephosphorylationCa2+ is a strong activator of phosphatase, stimulating E1 activity

Deficiency of PDH is the most common biochemical cause of congenital lactic acidosis

(1) Pyruvate dehydrogenase complex

Pyruvate dehydrogenase(active form)

allosteric inhibitors:ATP, acetyl CoA,NADH, FA

allosteric activators:AMP, CoA, NAD+,Ca2+

pyruvate dehydrogenase (inactive form)

P

pyruvate dehydrogenase kinase

pyruvate dehydrogenase phosphatase

ATP

ADPH2O

Pi

Ca2+,insulin acetyl CoA,NADH

ADP,NAD+

2) Tricarboxylic acid cycle, TCAC

• The cycle comprises the combination of a molecule of acetyl-CoA with oxaloacetate, resulting in the formation of a six-carbon tricarboxylic acid, citrate. There follows a series of reactions in the course of which two molecules of CO2 are released and oxaloacetate is regenerated.

• Also called citrate cycle or Krebs cycle.

(1) Process of reactions

fumarase

Citrate cycle

CO

CH2

COO

COO

CH3CO~SCoA

C

CH2

COO

COO

CH2

HO

COO

C

CH

COO

COO

CH2 COO

CH

CH

COO

COO

CH2 COO

H2O

H2O

HO

CO2

CH2

CH2

COCOO

COOCH2

CH2

COO

CO~ SCoA CO2

NAD+NADH+H+

CH2

CH2

COO

COO GDP+PiGTP

CH

CH2

COO

COO

OOC CH

C COOH

HONAD+

NADH+H+

FAD

FADH2

H2O

acetyl CoA

H2Ooxaloacetatecitrate synthase

citrate

aconitase

cis-aconitate

aconitase

isocitrate

NAD+

NADH+H+

isocitrate dehydrogenase

¦Á-keto-glutarate

¦Á-ketoglutaratedehydrogenase

complex

succinyl-CoAADP ATP

CoASH

succinyl CoA syntetase

succinate dehydrogenase

fumarate

succinate

fumarase

malate

malate dehydrogenase

HSCoA

HSCoA

Summary of Krebs Cycle ①

Reducing equivalents

Bio-significance of TCA1.Acts as the final common pathway for the

oxidation of carbohydrates, lipids, and proteins.

2.Serves as the crossroad for the interconversion among carbohydrates, lipids, and non-essential amino acids, and as a source of biosynthetic intermediates.

3. Takes part in gluconeogenesisAll the intermediates of TCA are potential glucogenic

4. Amino acid synthesisThe cycle serves as a source of carbon skeleton for the synthesis of non essential amino acids by transamination reactions e.g. Alanine from pyruvate, aspartate from oxaloacetate & glutamate from α-ketoglutarate

5. Takes part in fatty acid synthesisAcetyl CoA formed from pyruvate dehydrogenase, is the major substrate for long chain fatty acids synthesis

Krebs Cycle is at the hinge of metabolism.

ATP produced in the aerobic oxidation of glucose

• 1 G → 2 pyruvate : 2 (NADH+H+) → 6 or 8 ATP

• pyruvate →acetyl CoA: NADH+H+ → 3 ATP

• acetyl CoA → TCAC : 3 (NADH+H+) + FADH2 + 1GTP → 12 ATP

• 1mol G ： 36 or 38mol ATP

（ 12 ＋ 3 ） ×2 ＋ 6 （ 8 ）＝ 36 （ 38 ）

3. The regulation of aerobic oxidation

• The Key Enzymes of aerobic oxidation The Key Enzymes of glycolysis Pyruvate Dehydrogenase Complex Citrate synthase Isocitrate dehydrogenase (rate-limiting ) -Ketoglutarate dehydrogenase

(2) Citrate synthase• Allosteric activator: ADP

• Allosteric inhibitor: NADH, succinyl CoA, citrate, ATP

(3) Isocitrate dehydrogenase• Allosteric activator: ADP, Ca2+

• Allosteric inhibitor: ATP

(4) -Ketoglutarate dehydrogenase• Similar with Pyruvate dehydrogenase complex

Pentose Phosphate Pathway

1. The procedure of pentose phosphate pathway/shunt

In cytosolTwo phases

Irreversible oxidative phase Reversible non oxidative phase

1) Oxidative Phase

NADP+ NADPH+H+H2O

CO2

G-6-P

Xylulose 5-P

Ribulose 5-P

Ribose 5-P

G-6-P dehydrogenase

6-Phosphogluconate

6-phosphogluconate dehydrogenase

6-Phosphogluconolactonase

6-phosphogluco-nolactone

Epimerase

Isomerase

NADP+

NADPH+H+

2) Non-Oxidative PhaseRibose 5-p

Xylulose 5-p

Xylulose 5-p

Fructose 6-p

Glyceraldehyde 3-p

Fructose 6-p

• Transketolase: requires TPP• Transaldolase

Glycolysis

The net reation:3G-6-P + 6NADP+ → 2F-6-P + GAP + 6NADPH + H+ + 3CO2

2. Regulation of pentose phosphate pathway Glucose-6-phosphate Dehydrogenase is the

rate-limiting enzyme.

NADPH/NADP+↑, inhibit; NADPH/NADP+↓, activate.

3. Significance of pentose Phosphate pathway

1) To supply ribose 5-phosphate for bio-synthesis of nucleic acid;

2) To supply NADPH as H-donor in metabolism;

NADPH is very important “reducing power” for the synthesis of fatty acids and cholesterol, and amino acids, etc.

NADPH is the coenzyme of glutathione reductase to keep the normal level of reduced glutathione;

So, NADPH, glutathione and glutathione reductase together will preserve the integrity of RBC membrane.

2GSH

G-S-S-G NADPH + H+

glutathione reductaseNADP+H2O2

2H2O

Deficiency of glucose 6-phosphate dehydrogenase results in hemolytic anemia.

favism

NADPH serves as the coenzyme of mixed function oxidases (mono-oxygenases). In liver this enzyme participates in biotransformation.

Glycogen synthesis and catabolism

Glycogen is a polymer of glucose residues linked by (1→4) glycosidic bonds, mainly (1→6) glycosidic bonds, at

branch points

The process of glycogenesis occurs in cytosol of liver and skeletal muscle mainly

1. Glycogen synthesis (Glycogenesis)

Glycogen Synthesis

Glycogen Synthesis• Glycogen is the major storage of glucose in animals and many microorganisms (plants use starch)• Glycogen synthesis can take place in all tissues, but is especially predominant in

liver (100 gm make up10% w, <24 hr) and muscle tissue (400 gm make up 1~2% w, exhausted after <1hr vig activity)

•Fats cannot be converted to glucose in mammals, cannot be catabolized anaerobically.

• Once stored in cytosolic granules, glycogen can be:1. Broken down for distribution to other tissues (liver)2. Broken down for glycolytic fuel to produce ATP

(muscle)

1. First glucose is primed by a) glucokinase (hexokinase IV in liver) or b) hexokinase (hexokinase I or II in muscle)

D-Glucose + ATP D-Glucose-6-phosphate + ADP

2. Next D-Glucose-6-phosphate is isomerized byphosphoglucomutase

glucose-6-phosphate glucose-1-phosphate

Glycogen Synthesis

3. Glucose is charged with UDP byUDP-glucose Pyro-phosphorylase:

Note: it is named for the reverse reactionFigure 15-7

glucose-1-P + UTP UDP-glucose + 2Pi

Helps drive the reaction

4. Glucose is transferred to the non-reducing end of branched glycogen by glycogen synthase:

14linkage

•The free energy change from glucose-1-P to the glycogen polymer is highly favorable

5. A block of residues is transferred to make a 1 6 linkage from the growing 1 4 chain by the

glycogen branching enzyme:

Once 11 residues are built up, 6-7 are transferred to a branch. Branching: solubility , # of nonreducing ends

Glycogenin catalyzes two distinct reactions. Initial attack by the hydroxyl group of Tyr194 on C-1 of the glucosyl moiety of UDP-glucose results in a glucosylated Tyr residue. The C-1 of another UDP-glucose molecule is now attacked by the C-4 hydroxyl group of the terminal glucose, and this sequence repeats to form a nascent glycogen molecule of eight glucose residues attached by (1→4) glycosidic linkages.

Branching enzyme

Branching enzyme

• Amylo-α (1-4) α(1-6)-transglucosidase transfers a chain of 6-8 glycosyl residues from the non-reducing end of the glycogen chain, and attaches it by an α(1-6) linkage, thus functioning as 4:6 transferase.

Phosphorylase: key E;

The end products: 85% of G-1-P and 15% of free G;

There is no activity of glucose 6-phosphatase (G-6-Pase) in skeletal muscle.

GnPi Gn-1

G-1-P G-6-P G-6-Pase

H2O PiG

Phosphorylase

2. Glycogen catabolism (glycogenolysis)

Glycogen Breakdown by phosphorolysis• Glycogen is broken down by glycogen phosphorylase using Pi to form glucose-1-phosphate ( glucose-6-P)

• A debranching enzyme (oligo (14) to (16) glucantransferase) catalyzes two other reactions to transfer the branches (left)

• Finally, phophoglucomutase converts glucose-1-phosphate to glucose-6-phosphate that can then enter glycolysis (muscle).

• In liver, the glucose-6-phosphate is converted to glucose by glucose-6-phosphatase for release to the blood

Debranching enzyme: glucan transferase -1,6-glucosidase

Nonreducing ends(1→6) linkage

Glycogen phosphorylase

(1→6) glucosidase activity of debranching enzyme Glucose

Transferase activity of debranching enzyme

3. Regulation of glycogenesis and

glycogenolysis1) Allosteric regulationIn liver: G phosphorylase

glycogenolysisIn muscle:AMP phosphorylase-b

ATPG-6-P

phosphorylase-aglycogenolysis

Ca2+

2) Covalent modification

Glucagonepinephrine

Adenylyl cyclase

cAMP

G proteinreceptor

PKA

glycogenolysis

Phosphorylase

Glycogen synthase

glycogenesisBlood sugar

glucagon, epinephrine

inactiveadenylate cyclase

activeadenylate cyclase

ATP cAMP

inactivePKA

activePKA

phosphorylase bkinase

phosphorylase bkinase

P

ATP

ADP

H2O

Pi

phosphorylase b

P

P

ATP ADP

Pi

H2OATP ADP

glycogen synthase

glycogen synthase

P

H2OPi protein phosphatase-1

(active) (inactive)

inhibitor-1 (active)

inhibitor-1 (inactive)

phosphorylase a

ATP

§6 Gluconeogenesis

• Concept:

The process of transformation of non-carbohydrates to glucose or glycogen is termed as gluconeogenesis.

• Substrates: lactate, glycerol, pyruvate and glucogenic amino acid.

• Site: mainly liver

kidney

http://en.wikipedia.org/wiki/File:Amino_acid_catabolism.png

⑤ Anaplerotic reaction of oxaloacetate

pyruvate carboxylase

BiotinATP ADP + Pi

+ CO2C

CH3

COOH

OC

C

COOH

COOH

O

H2

NAD+ NADH+H+

malic acid DH+ CO2

malic enzymeC

CH3

COOH

O

NADPH+H+ NADP+

CHOH

C

COOH

COOH

C

C

COOH

COOH

O

H2H2

1. Gluconeogenic pathway

• The main pathway for gluconeogenesis is essentially a reversal of glycolysis, but there are three energy barriers obstructing a simple reversal of glycolysis.

1) The shunt of carboxylation of Pyruvate

PEPADP

ATP

oxaloacetic acid

Pyr carboxylase

ADP+Pi ATP CO2Biotin

GTP

GDP CO2

PEP carboxykinase

Pyr kinase

COO-

CCH3

COO-

CH

CH2

O~ P

O

pyruvate

COO-

CCH2

O

COOH £¨ Mt.£©

£¨ 1/3Mt. 2/3cytosal£©.

2) F-1, 6-BP →F-6-P

F-6-P F-1,6-BP

ATP ADP

Pi H2O

PFK-1

Fructose-bisphosphatase

3) G-6-P →G

G G-6-P

ATP ADP

Pi H2O

Glucose-6-phosphatase

HK

gluconeogenesisglucose

G-6-P

glycogen

F-1,6BP

glyceral-dehyde 3-P

glycerol1.3-bisphospho- glycerate

glycerate 3-P

glycerate 2-P

lactate

G-1-P

malic acid

phosphoenol pyruvate

pyruvate

GTP

GDPCO2

2/3

malic acid

pyruvate

phosphoenol pyruvate

GTP

GDPCO2 1/3

CO2

CYTOSOL MITOCHONDRIA

NAD+ NADH+H+

NAD+

NADH+H+

NAD+

NADH+H+

glutamate¦Á-ketoglutarate ¦Á-ketoglutarate

glutamate

OAAAspAspOAADHAP

ATP

ADP

ATPADP

PKADP

ATP

F-6-P

Biotin

Key enzymes of gluconeogenesis

Pyr carboxylase

PEP carboxykinase

Fructose-bisphosphatase

Glucose-6-phosphatase

F-1,6-BP

ATP

ADP

Pi

H2O

PFK-1FBPase-1

F-6-P

F-2,6-BP

AMP

glycolysis

gluconeogenesis:

F-1,6-BP

ATP

ADPF-2,6-BP

PEP

Pyr

acetyl CoA

glucagon

insulin glucagonAla in liverOAA

3. Significance of gluconeogenesis(1) Replenishment of Glucose by

Gluconeogenesis and Maintaining Normal Blood Sugar Level.

(2) Replenishment of Liver Glycogen.

(3) Regulation of Acid-base Balance.

Lactic acid (Cori) cycle• Lactate, formed by the oxidation of

glucose in skeletal muscle and by blood, is transported to the liver where it re-forms glucose, which again becomes available via the circulation for oxidation in the tissues. This process is known as the lactic acid cycle or Cori cycle.

• prevent acidosis ； reused lactate

muscle

glucose

pyruvate

lactate

glucose

blood

pyruvate

lactate

glycolytic pathway

glucose

liver

lactate

NAD+

NADH+H+

NADH+H+

NAD+

gluconeo-genesis

Lactic acid cycle

§6 Blood Sugar and Its Regulation

1. The source and fate of blood sugar

blood sugar3.89¡« 6.11mmol/L

dietary supply

liver glycogen

(gluconeogenesis)

other saccharides

CO2 + H2O + energy

glycogen

other saccharides

non-carbohydrates

>8.89¡«10.00mmol/L(threshold of kidney)

non-carbohydrate

(lipids and some amino acids)

urine glucose

origin (income) fate (outcome)

Blood sugar level must be maintained within a limited range to ensure the supply of glucose to brain.

The blood glucose concentration is 3.89 ～ 6.11mmol/L normally.

2. Regulation of blood sugar level1 ） insulin ： for decreasing blood sugar

levels.

2 ） glucagon ： for increasing blood sugar levels.

3 ） glucocorticoid: for increasing blood sugar levels.

4 ） adrenaline ： for increasing blood sugar levels.

3. Abnormal Blood Sugar Level

• Hyperglycemia: > 7.22 ～ 7.78 mmol/L

• The renal threshold for glucose: 8.89

～ 10.00mmol/L

• Hypoglycemia: < 3.33 ～ 3.89mmol/L

Stage 1 – postparandial All tissues utilize glucose

Stage 2 – postabsorptive KEY – Maintain blood glucoseGlycogenolysisGlucogneogenesisLactatePyruvateGlycerolAAPropionateSpare glucose by metabolizing fat

Stage 3- Early starvationGluconeogenesis

Stave 4 – Intermediate starvationgluconeogenesisKetone bodies

Stage 5 – Starvation

Pyruvate as a junction point