Glycogen

Overview

•  Structure
  • glycogen
    • polymer of glucose
      • straight chain with α-1,4-bond
      • branches with α-1,6-bond
  • glycogen granule
    • core
      • glycogenin
• Function
  • energy reserves that can provide glucose during a fast or ↑ energy demand
    • supplies exhausted in < 24 hrs
  • stored mainly in the liver and muscle
    • muscle does not have glucose-6-phosphatase so it cannot release free glucose
      • stores for its own consumption
    • liver does have glucose-6-phosphatase so it can release free glucose
• can use supplies to maintain blood glucose levels

Glycogenesis

• Glycogen synthesis 
• Pathway
  • glucose-6-phosphate converted to glucose-1-phosphate
  • UDP group added to form UDP-glucose
  • UDP-glucose added to polymer in an α-1,4 linkage
    • catalyzed by glycogen synthase
      • rate limiting step of glycogen synthesis
  • polymer rearranged to create α-1,6 linked branches
    • catalyzed by branching enzyme
      • deficiency = Anderson disease
• Regulation
  • glycogen synthase
    • in liver
      • activated by insulin
      • inhibited by glucagon, epinephrine
    • in muscle
      • activated by insulin
• inhibited by epinephrine

Glycogenolysis

• Glycogen catabolism
• Pathway
  • glucose-glucose bond broken by addition of a phosphate
    • catalyzed by glycogen phosphorylase
      • rate limiting step of glycogenolysis
        • hepatic deficiency = Hers disease (type VI)
        • muscle deficiency = McArdle disease (type V)
  • glucose-1-phosphate freed
    • converted to glucose-6-phosphate
  • debranching enzymes removes α-1,6 linked branches
    • deficiency = Cori’s disease (type III) 
  • liver converts glucose-6-phosphate to glucose
    • catalyzed by glucose-6-phosphatase
      • deficiency = von Gierke disease (type I)
  • muscle puts glucose-6-phosphate into glycolysis
• Regulation
  • glycogen phosphorylase
    • in liver
      • activated by epinephrine, glucagon
        • via cAMP/protein kinase A
      • inhibited by insulin
      • remember: exact opposite of glycogen synthase
        • hepatic glycogen regulatory processes both turn on forward direction and turn off reverse
    • in skeletal muscle
      • activated by epinephrine, AMP, Ca²⁺
      • inhibited by insulin, ATP
• remember: since muscular glycogen can only supply itself, it is regulated by its own energy supply (AMP/ATP ratio); while liver must supply energy to many other tissues, it functions independently of AMP/ATP ratio in hepatocytes

Glycogen Storage Diseases (Glycogenolyses)

• Overview 
  • all disorders have abnormal glycogen metabolism
    • leads to an accumulation of glycogen within cells
    • organ dysfunction
  • remember: disorders numbered in order of pathway from end (glucose release) to beginning (breakdown of glycogen polymer)
• Glucose release
  • Type I: von Gierke 
    • lacks glucose-6-phosphatase
    • presentation
      • liver cannot release stored glucose
        • hepatomegaly
        • severe hypoglycemia
      • body must rely on fat/protein catabolism for energy
        • hyperlipidemia
        • hyperuricemia
        • lactic acidosis
      • normal glycogen structure
    • tests 
      • stimulation test with glucagon, fructose, galactose
      • does not ↑ serum glucose
• Lysosomal pathway
  • Type II: Pompe “trashes the Pump (heart)” 
    • lacks lysosomal α1,4-glucosidase
      • degrades glycogen-resembling material in endosomes
    • presentation
      • buildup of glycogen in cardiac muscle
        • electron dense granules inside lysosomes
        • cardiomegaly
        • hypertrophic cardiomyopathy
• Branching/debranching
  • Type III: Cori 
    • lacks debranching enzyme
      • remember:
        • Cori = can’t Catabolize branches
        • 6-pack core – alpha 1,6 glucosidase defective
    • presentation
      • liver cannot break down glycogen past a branch point
        • hepatomegaly
        • hypoglycemia
        • abnormal glycogen structure
          • short outer glycogen chains
  • Type IV: Anderson
    • lacks branching enzyme
      • remember: Anderson = can’t Add branches
    • presentation
      • liver cannot form branched glycogen granules
        • hypotonia
        • cirrhosis
• Phosphorylase
  • Type V: McArdles 
    • lacks muscle phosphorylase 
      • remember: McArdles = Muscle
      • can’t breakdown glycogen to glucose-1-phosphate 
      • accumulation of glycogen in muscle tissue
    • presentation 
      • muscle weakness/cramps upon exertion
      • myoglobinuria
      • normal glycogen structure
  • Type VI: Hers
    • lacks hepatic phosphorylase
      • remember: Hers = Hepatic
    • presentation
      • hepatomegaly
      • fasting hypoglycemia
• can be mild due to gluconeogenic compensation