BIOCHEMISTRY

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BIOCHEMISTRY

• 12-CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER
  AND MUSCLE
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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• INTRODUCTION

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Carbohydrate Storage Synthesis - Introduction

• Most of glucose consumed/day (80) utilized by
  RBCs and brain.
• 200g/day total intake as a requirement.
• Only 10g in plasma and 300g in liver.
• Blood glucose must be replenished constantly.
• Consequences hypoglycemia coma (
• Glucose absorbed from intestine for 2-3 hr post
  meals.

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Carbohydrate Storage Synthesis - Introduction

• Mechanism for maintenance of blood glucose
  between meals.
• Glycogenesis - liver conversion of glucose to
  glycogen for storage.
• Glycogenolysis - liver degradation of glycogen
  stores to glucose.
• Hepatic glycogen not sufficient during 12 hr fast.

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Carbohydrate Storage Synthesis - Introduction

• Mechanism for maintenance of blood glucose
  between meals.
• Glyconeogenesis - during sleep shift from
  glycogenolysis to de novo synthesis of glucose in
  liver essential during fasting or starvation.
• Amino acids form muscle proteins.
• Lactate from glycolysis.
• Glycerol from fat metabolism.
• Lipids from adipose tissue.

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Carbohydrate Storage Synthesis - Introduction

• Mechanism for maintenance of blood glucose
  between meals.
• Muscle glycogen.
• Not available for blood glucose.
• Muscle energy metabolism.
• Primarily from fats.
• Glucose for bursts of physical activity.
• On a tissue mass basis majority of glycogen is
  stored in muscle.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• STRUCTURE OF GLYCOGEN

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Carbohydrate Storage/SynthesisStructure of
Glycogen

• Branched polysaccharide homoglucan.
• Two glycoside linkages.
• Chains of alpha 1- 4-linked glucose residues
  main core chain.
• With alpha 1- 6 branches spaced every 4-6
  residues along the alpha 1- 4 chain.
• Gross structure dendritic, branching from a
  core sequence head of cauliflower.
• Most of glycogenic and glycogenolytic enzymes are
  bound to glycogen granules in cytoplasm assuring
  rapid changes in glycogen metabolism in response
  to
• Allosteric stimuli.
• Hormonal stimuli.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• PATHWAY OF GLYCOGENESIS FROM BLOOD GLUCOSE TO
  LIVER

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Carbohydrate Storage/SynthesisGlycogenesis
Pathway in Liver

• Glycogenesis from blood glucose.
• Glucose transporter (GLUT-2).
• Transporter rich in liver glucose
  permeability of liver cells if high
  concentrations in portal blood.
• Glucokinase (GK), a glucose specific enzyme in
  liver with carbohydrate consumption.
• Catalyzes glucose to G-6-P.
• GK activity as glucose high Km.
• GK not inhibited by G-6-P.

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Carbohydrate Storage/SynthesisGlycogenesis
Pathway in Liver

• Glycogenesis from blood glucose.
• Rapid G-6-P after a meal forces glucose into
  all its major metabolic pathways.
• Glycogenesis.
• Excess G-6-P is channeled in to glycolysis.
• Energy production.
• Or into triglyceride synthesis for storage in
  adipose tissue.

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Carbohydrate Storage/Synthesis Glycogenesis
Pathway in Liver

• Glycogenesis from blood glucose.
• Excess glucose passing through the liver.
• Used by muscles for synthesis and storage of
  glycogen.
• Also stored in adipose tissue for source of
  glycerol and triglyceride synthesis.

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Carbohydrate Storage/Synthesis Glycogenesis
Pathway in Liver

• Steps of glycogenesis 4.
• Step 1 G-6-P to G-1-P.
• Enxyme phosphoglucomutase.
• Step 2 G-1-P activation to sugar nucleotide
  uridine diphosphate UDP-glucose.
• Enzyme UDP-glucose pyrophosphorylase.
• Step 3 Transfer glucose transferred to
  glycogen at alpha 1 - 4 linkage.
• Enzyme glycogen synthase glycerol
  transferase.
• This is the regulating enzyme in glycogenesis.

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Carbohydrate Storage/Synthesis Glycogenesis
Pathway in Liver

• Steps of glycogenesis 4.
• Step 4 Branching if alpha 1 - 4 exceeds 8
  residues in length the enzyme transfers some of
  the alpha 1 - 4-linked residues to an alpha 1 - 6
  branch.
• Enzyme glycogen branching enzyme
  transglycosylase.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• PATHWAY OF GLYCOGENOLYSIS IN LIVER

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Carbohydrate Storage/Synthesis Glycogenolysis
Pathway in Liver

• The breakdown of glycogen in the liver.
• Step 1 Removal of alpha 1 - 4 linkages plus
  branching enzyme activity releases glucose in
  form of G-1-P (cytosolic phosphate as source).
• Enzyme glycogen phosphorylase.
• Step 2 G-1-P to G-6-P.
• Enzyme phosphoglycomutase.
• Step 3 G-6-P to glucose.
• Enzyme glucose-6-phosphatase.
• Step 4 Glucose glucose-2 transporter leads to
  concentration in blood for metabolic
  utilization.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• HORMONAL REGULATION OF HEPATIC GLYCOGENOLYSIS

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Carbohydrate Storage/SynthesisHormonal Control
of Glycogenolysis

• Control switch blood glucose demand.
• utilization
• utilization stress.
• There are 3 hormonal activators of
  glycogenolysis.
• Glucagon.
• Peptide hormone from alpha cells of endocrine
  pancreas.
• Function hepatic glycogenolysis for
  maintenance of normoglycemia.
• Short half life in plasma.
• glucagon levels between meals.
• Glucagon during fasting or low carbohydrate
  diet.

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Carbohydrate Storage/SynthesisHormonal Control
of Glycogenolysis

• There are 3 hormonal activators of
  glycogenolysis.
• Epinephrine.
• Catecholamine hormone.
• Released from adrenal medulla due to stress
  (physiologic, pathologic and psychologic)
  glycogenolysis.
• Cortisol.
• Adrenocorticoid steroid hormone.
• cortisol glycogenolysis.
• stress cortisol glycogenolysis.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• MECHANISM OF ACTION OF GLUCAGON

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Mechanism of action of glucagon.
• Serves as general model for hormone actions
  through cell surface receptors.
• Steps.
• 1 Glucagon binds to its hepatic receptor
  initiates a cascade of reactions within cell.
• 2 Receptor linked to G-Protein on inside of
  cell membrane signal transduction protein
  activation.
• 3 G-protein-GDP configuration in resting
  state.

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Mechanism of action of glucagon.
• Steps.
• 4 Glucagon causes exchange of G-protein GDP for
  GTP initiated by phosphorylation by a kinase
  conformational change release of alpha subunit
  GTP activation of plasma membrane enzyme
  adenyl cyclase.
• 5 Adenyl cyclase converts ATP to
  cyclic-3,5-AMP (cAMP).

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Mechanism of action of glucagon.
• Steps.
• 6 cAMP soluble mediator or second messenger
  as a result of glucagon activity (and other
  hormones).
• 7 cAMP binds to protein kinase A (PKA) and
  disinhibits it.
• Causes dissociation of inhibitory subunits
  (regulatory subunits) from the catalytic subunits
  of the enzyme PKA activity.

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Mechanism of action of glucagon.
• Steps.
• 8 PKA initiates protein-phosphorylation
  reactions.
• 9 PKA activation of glycogen phosphorylase
  which involves a cascading phenomenon of the
  posphorylation of many molecules of phosphorylase
  kinase by PKA which leads to formation of many
  glycogen phosphorylase molecules.

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Mechanism of action of glucagon.
• Steps.
• 10 Results cascade amplification system
  signal strength within seconds of glucagon
  binding.
• 11 Phosphorylation of phosphorylase
  glycogenolysys G-6-P in liver which is
  hydrolyzed to glucose.

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Mechanism of action of glucagon.
• Steps.
• 12 PKA inhibitor-1, protein phosphatase
  inhibitor protein activated by phosphorylation
  
• This prevents the reverse of phosphorylation of
  enzymes which would quench the glucagon response
  
  glycogenolysis.

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Carbohydrate Storage/SynthesisGlucagon Control
of Glycogenolysis

• Activation of glycogenolysis coordinated with
  inactivation of glycogenesis along with other
  hepatic pathways.
• For example, PKA inactivates glycogen synthase.
• There is also a rapid termination of glucagon
  response by multiple redundant pathways.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• MOBILIZATION OF HEPATIC GLYCOGEN BY EPINEPHRINE

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Carbohydrate Storage/SynthesisEpinephrine
Control of Glycogenolysis

• Receptors alpha and beta adrenergic receptors.
• Glucagon and epinephrine can work together in
  severe hypoglycemia.
• Flight or fight response stress
  epinephrine blood glucose.
• Tea and coffee blood glucose alertness and
  responsiveness.
• Cafeine (coffee) and theophyline (tea) active
  ingredients.
• Both are inhibitors of phosphodiesterase and
  cAMP glucose levels in blood.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• GLYCOGENOLYSIS IN MUSCLE

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Carbohydrate Storage/SynthesisGlycogenloysis in
Muscle

• No glucagon receptors or G-6-Pases are in the
  muscle tissue.
• Muscle cannot mobilize glycogen for blood
  glucose.
• Glucose is used by muscle internally.
• Flight of fight stress.
• Prolonged exercise.
• Activation of glycogenolysis in muscle.
• Hormonal mechanism epinephrine, beta-adrenergic
  receptor.
• G-protein.
• cAMP system.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• REGULATION OF GLYCOGENESIS

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Carbohydrate Storage/SynthesisRegulation of
Glucogenesis

• Introduction.
• Glucogenesis occurs after meals.
• Glucose plus other carbohydrates enter liver by
  portal circulation and trapped there for
  glycogenesis.
• Glucose that makes it through the liver is taken
  up by muscle and adipose tissue for energy
  reserves and storage.

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Carbohydrate Storage/SynthesisRegulation of
Glucogenesis

• Storage control in liver by insulin.
• Mechanisms.
• Direct stimulation of liver glucogenesis by
  glucose levels.
• Allosteric inhibition of phosphorylase by
  glucose.
• protein phsophatase activity.

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Carbohydrate Storage/SynthesisRegulation of
Glucogenesis

• Storage control in liver by insulin.
• Produced in the beta cells in islets of
  Langerhans within the pancreas.
• Steps
• Meal insulin release into the blood.
• Actions
• Turns off glucagon phosphorylase enzyme activity.
• activation of glycogen synthase glucose
  storage as glycogen.
• Gene expression - insulin causes synthesis of
  enzymes involved with glucose metabolism and
  storage.

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Carbohydrate Storage/SynthesisRegulation of
Glucogenesis

• Storage control in muscle/adipose tissue by
  insulin.
• Insulin action of glucose transporters.
• Low concentration of cell surface glucose
  transporters
  lipids for energy metabolism.
• insulin receptor tyrosine kinase activity
  movement of GLUT-4 transporter from
  intracellular vacuoles to the cell surface
  glucose transport into the cell glycogenesis.
• Muscle glycogen.
• Adipose tissue triglycerides.

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CARBOHYDRATE STORAGE AND SYNTHESIS IN LIVER AND
MUSCLE

• GLYCONEOGENESIS

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Carbohydrate Storage/SynthesisGluconeogenesis

• Need when hepatic glycogen is depleted and
  blood glucose homeostasis is compromised.
• Muscle protein major blood glucose precursors
  by proteolysis amino acids converted to
  glucose.
• Adipose tissue provides general body and
  gluconeogenesis energy needs.

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Carbohydrate Storage/SynthesisGluconeogenesis

• Carbon skeleton sources for glycogenesis.
• Lactate anaerobic metabolism product of
  glycolysis.
• Uses same glycolytic enzymes involved in
  glycolysis.
• Reverses the glycolytic cycle by bypassing the
  key regulatory kinase enzymes by action of the
  Cori or lactate cycle.
• Amino acids from muscle protein major source.
• Adipose tissue glycerol from lipids.
• Control of gluconeogenesis.
• By phosphorylation/dephosphorylation of enzymes
  by glucagon and insulin.

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Children born of
• Diabetic
• Malnourished mothers.
• Glycogen storage diseases.
• vonGierkes disease.

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Children born of diabetic mothers are usually
  very large. Why?
• Baby born of a poorly controlled diabetic mother.
• Large and chubby.
• Rapid decline into hypoglycemia after birth.
• What has happened?

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Children born of diabetic mothers.
• In utero hyperglycemia insulin production
  body size due to growth-hormone-like insulin
  activities.
• At birth maternal glucose ceases but has
  adequate blood glucose levels and hepatic supply
  of glycogen.
• insulin glucose uptake into muscle and
  adipose tissue hypoglycemia stress.
• Responds well to glucose infusion and good
  prospects for gluconeogenesis from muscle protein
  (1-2 days later).

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Children born of malnourished mother may have
  hypoglycemia. Why?
• Weak signs of distress heart rate and
  respiration.
• Blood glucose 63 mg/dL which drops to 27 mg/dL
  (normal
  unresponsive and comatose.
• Improvement with glucose infusion followed by
  carbohydrate-rich diet.
• What has happened?

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Children born of malnourished mother may have
  hypoglycemia. Why?
• In utero glucose from maternal circulation.
• After birth glucose source from hepatic
  glycogen none available in child.
• Not much chance for glyconeogenesis because of muscle mass
• Therefore - hypoglycemia.

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Glycogen storage disease von Gierkes disease.
• Baby cranky, irritable, sweaty and lethargic,
  demands food frequently.
• Swollen abdomen/enlarged liver.
• Blood glucose 70 mg/dL (100 mg/dL normal)
  hypoglycemic.
• heart rate sweating periods blood glucose
  40 mg/dL.
• Corrected by feeding.
• Liver biopsy massive glycogen particles in
  liver cell cytosol.
• Whats the problem?

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Carbohydrate Storage Synthesis

• Clinical considerations.
• Whats the problem?
• Glycogen mobilization deficiency severe
  hypoglycemia.
• G-6-Pase mutation affecting

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Carbohydrate Storage/SynthesisLearning Objectives

• Be familiar with the structure of glycogen.
• Know the pathway of glycogenesis from blood
  glucose in liver.
• Outline the pathway of glycogenolysis in liver.
• Understand the hormonal regulation of hepatic
  glycogenolysis.

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Carbohydrate Storage/SynthesisLearning Objectives

• How does glycogenolysis in muscle differ from
  that in the liver?
• Describe the regulation of glycogenesis.
• What is meant by glyconeogenesis.
• Outline glyconeogenesis from lactate.
• Outline glyconeogenesis from amino acids and
  glycerol.
• Identify the steps in the regulation of
  glyconeogenesis.

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Carbohydrate Storage/SynthesisLearning Objectives

• How can alcohol excess lead to hypoglycemia?
• Why can a large child be born of a diabetic
  mother?
• Under what maternal conditions can a newborn
  child have hypoglycemia?
• How can a glycogen storage disease reduce ones
  capacity to exercise?