Glycogen/GSD - Abali 3/8/16 Flashcards Preview

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Flashcards in Glycogen/GSD - Abali 3/8/16 Deck (35):

glycogen basics

storage form of glucose

glucose molecules attached in numerous chains to a core protein, glycogenin - base for elongating/degrading chains


glycogenolysis: first means of maintaining blood sugar

next step: gluconeogenesis (*remember: always running in the background to clear lactate from RBCs)


fuel sources within the body

  • where do you find glycogen?

RBCs (exclusive) and brain (gl + ketones in starvation) NEED GLUCOSE as fuel at all times

1. proteins : breakdown of sk muscle → fuel gluconeogenesis

2. fats : useful for ATP production, not for gluconeogenesis

3. glycogen (small store)

  • liver - used to regulate blood glucose levels
  • skeletal muscle - used as fuel for muscles only (no G6Pase = can't form, secrete glucose for use by other tissues)


maintenance of blood glucose

carried out by hepatic glycogen

  • as post-prandial glucose levels drop, glycogenolysis and background gluconeogenesis pick up to compensate and maintain blood glucose


cardiac muscle and glycogen

cardiac muscle has v little glycogen

  • uses primarily FA beta ox for energy
  • doesn't get much benefit from glycolysis

consequence: anything that interrupts flow of oxygenated blood to heart leads to serious damage/death


lactic acidosis and uric acid

in lactic acidosis, body will try to get rid of buildup via URAT1 transporter (organic anions - lactate - out, urate in) in kidneys


consequence: buildup of uric acid


*can also happen in ketoacidosis!


glucose polymers

starch: least branched, alpha 1:4 glycosidic bonds

cellulose: beta 1:4 glycosidic bonds

glycogen: most branched, alpha 1:4 glycosidic bonds


*glycogen and amylopectin (form of starch) also contain occasional alpha 1:6 bonds at branch points holding two chains together


why is glycogen a good source of energy?


why is it a better fuel reserve than fats?

  • can be rapidly broken down into glucose
    • enzymes of glycogen metab are bound to the surface
    • many terminal glucoses particles = lots of potential to release glucose
  • don't need oxygen to generate energy (can take glucose through anaerobic resp)

why glycogen > fats for rapid energy?

  • fats need oxygen for beta ox
  • fats have to be mobilized from adipose tissue to wherever you need energy
  • brain needs glucose → animals can't turn fats into glucose


steps of glycogenesis

1. trap glucose: glucose → glucose-6-P

  • glucokinase [liver], hexokinase [everywhere else]

2. transitions: G6P → G1P → UDP-glucose

  • phosphoglucomutase; G1P uridyl transferase

3. glycogen synthase goes to work: strips glucose from UDP-glucose, adds it to an alpha 1:4 chain on glycogen (seeded on glycogenin core)

  • glycogen synthase

4. branching: if alpha1:4 chain is at least 11 residues long, at least 6 of those residues can be shifted and made into a new branch

  • branching enzyme



steps of glycogenolysis

1. 4trimming: glycogen branches stripped down to branches of 4 units each. released as G1P → isomerized into G6P → glucose [via G6Pase]

  • glycogen phosphorylase

2. debranching-step1: blocks of 3 residues are shifted from one terminal branch to another

  • debranching enzyme

3. debranching-step2: the single remaining residue on the cut branch (the alpha 1:6 moiety) is removed → linear chain of alpha 1:4 linkages. released as glucose

  • debranching enzyme


implication: wayyyy more alpha 1:4 linkages than alpha 1:6s → much more glucose will be released through glycogen phosphorylase activity (90%) than debranching enzyme activity (10%)


glycogenolysis: fate of glycogen in the liver

the liver expresses G6Pase 

  • can modify G6P → glucose for release into bloodstream for brain/RBCs
  • allows liver to regulate blood sugar levels


glycogenolysis: fate of glycogen in the skeletal muscle

skeletal muscle DOES NOT EXPRESS G6Pase 

  • G6P is stuck in cells and sent into glycolysis → pyruvate
    • if anaerobic: pyruvate → lactate [lactate DH]
    • if aerobic: pyruvate → acetyl CoA [PDH] → TCA cycle


glycogen metabolism regulation: basics

1. allosteric regulation

2. hormonal regulation

  • glucagon, epinephrine : activate glycogenolysis
  • insulin
    • shuts down glycogenolysis (dephosphorylates/deactivates glycogen phosphorylase)
    • triggers glycogenesis (dephosphorylates/activates glycogen synthase)

3. neuronal regulation


allosteric regulation of glycogen metabolism

+ = glycogenesis: G1P → glycogen

[via glycogen synthase]

- = glycogenolysis: glycogen → G1P

 [via glycogen phosphorylase]



+ : G6P [buildup from import, leftover from glycolysis]

- : glucose, ATP, G6P ["endpdts" of glycogen phosphorylase]

*general rule: high energy inhibits buildup


+ : G6P [buildup from import, leftover from glycolysis]

- : ATP, G6P; Ca, AMP

*general rule: high energy inhibits buildup


covalent regulation of glycogen metabolism: epinephrine

receptors in liver and muscle

activates cAMP → PKA pathway → phosphorylates target

  • P's glycogen synthase: deactivates it
  • P's glycogen phosphorylase: activates it


covalent regulation of glycogen metabolism: glucagon

receptors in liver ONLY

activates cAMP → PKA pathway → phosphorylates target

  • P's glycogen synthase: deactivates it
  • P's glycogen phosphorylase: activates it



regulation of glycogen metabolism: Ca

Ca is elevated in active muscle

activates phosphorylase kinase

  • P's glycogen phosphorylase: activates it


takeaway: high Ca leads to glycogenolysis



what causes upregulation of glycogenolysis?

acute and chronic stress trigger glycogenolysis

1. physiologic (increased use of blood glucose during exercise)

2. pathologic (blood loss/shock)

3. psychological (acute/chronic threats)


4 hormones [sources] : triggers → effect on glycogenolysis

acute and chronic stress trigger glycogenolysis


1. glucagon [pancreatic alpha cells] : hypoglycemia → rapid activation

2. epinephrine [adrenal medulla] : acute stress, hypoglycemia → rapid activation

3. cortisol [adrenal cortex] : chronic stress → chronic activation

4. insulin [pancreatic beta cells] : hyperglycemia → inhibition



fasting state

[blood] → tissue response

[glucagon high, insulin low]

glycogenolysis high,

glycogenesis low



carb meal

[blood] → tissue response

[glucose high: insulin high, glucagon low]

glycogenolysis low,

glycogenesis high




[blood] → tissue response

[glucose high, epi high]

glycogenolysis high




[blood] → tissue response

[insulin low]

glucose transport low

glycogenesis low




carb meal

[blood] → tissue response

[insulin high]

glucose transport high

glycogenesis high





[blood] → tissue response

[epi high; tissue levels of AMP high]

glycogenesis low

glycogenolysis high

glycolysis high



key enzymes in glycogen metabolism

1. glucose 6 phosphatase : converts G6P → glucose for export

2. alpha 1,6 glucosidase (aka debranching enzyme)

3. glycogen phosphorylase : breaking down alpha 1:4 glycosidic linkages

4. branching enzyme


PAS-D staining

periodic acid-Schiff-diastase


PAS stains glycogen

diastase = alpha amylase, which breaks glycogen down


PAS-diastase staining allows you to see glycogen stores by showing you a before/after of degradation


von Gierke disease

type I

glucose 6 phosphatase deficiency 

enzyme affected : G6Pase

glycogen : normal

tissues affected : liver, kidney

  • inability to export glucose from gluconeogenesis or glycogenolysis → severe hypoglycemia


tx : frequent feeding with carbs (uncooked starch), possibly nasogastric tube to feed while sleeping


Pompes disease

type II

alpha 1,4 glucosidase deficiency 

enzyme affected : alpha 1,4 glucosidase (aka acid maltase)

glycogen : accumulates in lysosome due to inability to degrade

tissues affected : heart

  • accumulation of glycogen in cardiac tissue leads to LVH, cardiomegaly
  • typically, death before 2
  • might also see accumulation/weakness in muscle


tx : recombo alpha 1,4 glucosidase given to pt might help some symptoms


Coris disease

type III

alpha 1,6 glucosidase deficiency 

[debranching enzyme]

enzyme affected : alpha 1,6 glucosidase (aka debranching enzyme)

glycogen : shorter branches, impeded glycogenolysis

tissues affected : liver

  • hepatomegaly
  • hypoglycemia


Andersens disease

type IV

alpha 4,6 glucosidase deficiency 

[branching enzyme]

enzyme affected : alpha 4, 6 glucosidase (aka branching enzyme)

glycogen : no branches : long, insoluble chains

tissues affected : liver

  • hepatomegaly
  • cirrhosis (presents as infantile cirrhosis → failure to thrive, death)


McArdles disease

type V

glycogen phosphorylase (muscle isozyme) deficiency 

enzyme affected : glycogen phosphorylase (muscle)

glycogen : normal, but accumulates

  • can't be broken down for use in anaerobic glycolysis; dependent on circulating glucose or eventual FA beta ox

tissues affected : muscle

  • decreased exercise tolerance w/ muscle cramps
  • myoglobinuria


Hers' disease

type VI

glycogen phosphorylase (liver isozyme) deficiency 

enzyme affected : glycogen phosphorylase (liver)

glycogen : normal, but accumulates

  • can't be broken down for blood glucose regulation

tissues affected : liver

  • hepatomegaly
  • fasting hypoglycemia
    • why only fasting? you still have gluconeogenesis runnning in background!


Taruis disease

type VII

muscle PFK1 deficiency 

enzyme affected : phosphofructokinase (muscle)

glycogen : normal 

tissues affected : muscle

  • decreased exercise tolerance
  • myoglobinuria
  • hemolytic anemia


causes of hyperuricemia

1. increased lactate/other anion being secreted → antiport-ing of urate through URAT-1

2. increased G6P can lead to increase in purine synth through HMP pathway → uric acid

3. decreased hepatic concentration of P (inhibitor of AMP deaminase) → increased purine catabolism, producing uric acid

  • P would typically be released by G6Pase, of which there is none in von Gierkes disease
  • no G6Pase → no P → no inhibition of AMP deaminase (rate limiting enzyme for A nt → uric acid) → more uric acid


von Gierke's disease : buildup of TAGs and cholesterol

lack of G6Pase forces the G6P released through glycogenolysis to go through glycolysis 

→ buildup of acetyl CoA 

→ increase TAG synth 

→ increase synth/secretion of VLDL