L18: Glycogen Metabolism/CHO Metabolism IV

Question 1

What is Pompe’s disease?

Answer 1

• Aka GSD-II: deficiency in alpha-glucosidase (aka acid maltase). It is required for the degradation of glycogen, which with the deficiency, slowly accumulates in the lysosome. Over time, this process eventually kills affected cells. Death occurs by cardiac or respiratory failure.

Question 2

What is Hers disease?

Answer 2

• Aka GSD-VI: deficiency in glycogen phosphorylase in liver. Presents with mild to moderate hypoglycemia, mild ketosis, growth retardation and prominent hepatomegaly.

Question 3

What is GSD-III?

Answer 3

• aka Cori’s disease: deficiency in debranching enzyme. Glycogen granules grow large because only the non-branched, outer layers of the deposits can be degraded. Presents in early childhood or infancy with hepatomegaly, hypoglycemia and growth retardation. Can also present with muscle weakness. Some pts develop cardiomyopathy.

Question 4

How does glucagon regulate glycogen synthesis?

Answer 4

• glucagon inhibits glycogen synthase inhibiting glycogen synthesis

Question 5

What is Cori’s disease?

Answer 5

• Aka GSD-III: deficiency in debranching enzyme. Glycogen granules grow large because only the non-branched, outer layers of the deposits can be degraded. Presents in early childhood or infancy with hepatomegaly, hypoglycemia and growth retardation. Can also present with muscle weakness. Some pts develop cardiomyopathy.

Question 6

Where does glycogen synthesis occur?

Answer 6

• In liver and muscle cells.

Question 6

What is the role of glycogenin vs glycogen synthase?

Answer 6

• Glycogenin: acts as a primer protein and generates short glucose chains via autoglycosylation of glycogenin - Glycogen synthase: takes over from glycogenin and transfers glucose residues from UDP-glucose - Both form alpha-1,4-bonds

Question 6

What are the effects of insulin, glucagon and epinephrine on glycolysis, glycogenolysis and glycogenesis in liver and muscle? Tabulate.

Answer 6

Question 7

How does G6P regulate glycogen synthesis?

Answer 7

• G6P inhibits hexokinase inhibiting glycogen synthesis

Question 7

List the enzymes involved in glycogenolysis. Explain what factors regulate each, ie. what inhibit and stimulate each?

Answer 7

• Glycogen phosphorylase: +: glucagon, epinephrine; -: insulin - Glucose-6-phosphatase: +: glucagon, epinephrine; -: insulin - Debranching enzyme: not regulated

Question 7

What is MEOS? Explain.

Answer 7

• Microsomal ethanol oxidizing system. This is a P450 cytochrome system that is induced in chronic alcohol abuse and has a higher capacity to process alcohol. Activation of this system causes oxidation of NADPH and weakens the cellular antioxidant defense mechanisms.

Question 9

What is GSD-II?

Answer 9

• aka Pompe’s disease: deficiency in alpha-glucosidase (aka acid maltase). It is required for the degradation of glycogen, which with the deficiency, slowly accumulates in the lysosome. Over time, this process eventually kills affected cells. Death occurs by cardiac or respiratory failure.

Question 10

Explain the pattern of diurnal changes of glucose sources and the importance of breakfast.

Answer 10

• A good breakfast will stop the conversion of other sources into glucose (including muscle protein).

Question 11

What is GSD-I?

Answer 11

• aka Von Gierke’s disease: deficiency in G-6-phosphatase. Leads to hypoglycemia and increased glycogen stores in liver. This ez is only found in liver.

Question 12

How does insulin regulate glycogen synthesis?

Answer 12

• insulin stimulates hexokinase activity stimulating glycogen synthesis - insulin stimulates glucokinase activity stimulating glycogen synthesis - insulin stimulates glycogen synthase activity stimulating glycogen synthesis

Question 14

List the enzymes involved in glycogen synthesis. Explain how each is regulated. What are the factors that stimulate and inhibit each.

Answer 14

• Hexokinase: +: insulin; -: G6P - Glucokinase: +: insulin - Phosphoglucomutase: not regulated - UDP-glucose pyrophosphorylase: not regulated - Glycogen synthase: +: insulin; -: glucagon, epinephrine - Branching enzyme: not regulated

Question 15

What is the important of a constant blood glucose level? What is the clinical significance of hypoglycemia and hyperglycemia? Should hypoglycemic events occur in a normal pt?

Answer 15

• The brain depends almost exclusively on glucose to meet its energy need. Hypoglycemia leads to decreased brain function and can lead to tremors, comas and death. - Hyperglycemia can present with vascular disease, neuropathy and hyperglycemic comas - Hypoglycemic events should not occur in a normal patient. Glycogenolysis and gluconeogenesis should prevent this.

Question 16

How does epinephrine regulate glycogen synthesis?

Answer 16

• epinephrine inhibits glycogen synthase inhibiting glycogen synthesis

Question 17

List all the factors (molecules) that regulate glycogen synthesis.

Answer 17

• G6P, insulin, glucagon, epinephrine

Question 19

Describe/draw the reactions of glycogen degradation (glycogenolysis).

Answer 19

Question 20

Explain how ethanol is metabolized? What is its impact on CHO metabolism?

Answer 20

• Alcohol metabolism occurs in the liver by two mechanisms: 1.) two DH reactions (main pathway) and 2.) MEOS: microsomal ethanol oxidizing system: induced by chronic alcohol abuse. - Both DH reactions reduce NAD to NADH, which interferes with CHO metabolism and utilization. - When NADH is high in the cytoplasm, pyruvate and oxaloacetate are converted into lactate and malate respectively via lactate dehydrogenase and malate dehydrogenase respectively. Pyruvate and oxaloacetate are both intermediates in gluconeogenesis and glycolysis. - Lactate levels rise (more than normally) and cannot be processed in the Cori cycle, causing accumulation in blood, leading to metabolic acidosis. Body responds by increasing respiration in order to attempt restoral of acid/base balance. - Failure to complete Cori cycle also leads to epinephrine and glucagon release, which induces a stress response. - NADH inhibits key enzymes of TCA and shunts acetyl-CoA into FA/ketone body biosynthesis leading to a fatty liver over time.

Question 21

What is Von Gierke’s disease?

Answer 21

• aka GSD-I: deficiency in G-6-phosphatase. Leads to hypoglycemia and increased glycogen stores in liver. This ez is only found in liver.

Question 22

Explain why NADH concentration increases while NADPH concentration decreases in alcohol-metabolizing cells.

Answer 22

• The main step to handling ethanol in the liver is through two dehydrogenases (alcohol DH and aldehyde DH), both, which produce NADH. - The other way to handle ethanol is through the higher capacity MEOS system, which as a means to process the alcohol, also oxidizes NADPH.

Question 23

What is the main difference between storage of CHOs in liver and muscle?

Answer 23

• Liver stores glycogen for use by itself and the entire body. - Muscle stores glycogen for use by itself only.

Question 25

What do the branching enzymes do in glycogen synthesis?

Answer 25

• They branch chains using alpha-1,6-bonds, which allows for easier access to the glycogen molecule when degradation needs to occur.

Question 26

What is GSD-VI?

Answer 26

• aka Hers disease: deficiency in glycogen phosphorylase in liver. Presents with mild to moderate hypoglycemia, mild ketosis, growth retardation and prominent hepatomegaly.

Question 27

What is GSD-V?

Answer 27

• aka McArdle’s disease: deficiency in glycogen phosphorylase in muscle. Muscle is unable to use glycogen. Leads to greater than normal glycogen stores in muscles. During periods of high glucose demand, ie. exercise, patients experience muscle cramps.

Question 28

List and describe the glycogen storage diseases (GSD). What is occurring in each and what is the clinical presentation?

Answer 28

• GSD-I: aka Von Gierke’s disease: deficiency in G-6-phosphatase. Leads to hypoglycemia and increased glycogen stores in liver. This ez is only found in liver. - GSD-II: aka Pompe’s disease: deficiency in alpha-glucosidase (aka acid maltase). It is required for the degradation of glycogen, which with the deficiency, slowly accumulates in the lysosome. Over time, this process eventually kills affected cells. Death occurs by cardiac or respiratory failure. - GSD-III: aka Cori’s disease: deficiency in debranching enzyme. Glycogen granules grow large because only the non-branched, outer layers of the deposits can be degraded. Presents in early childhood or infancy with hepatomegaly, hypoglycemia and growth retardation. Can also present with muscle weakness. Some pts develop cardiomyopathy. - GSD-V: aka McArdle’s disease: deficiency in glycogen phosphorylase in muscle. Muscle is unable to use glycogen. Leads to greater than normal glycogen stores in muscles. During periods of high glucose demand, ie. exercise, patients experience muscle cramps. - GSD-VI: aka Hers disease: deficiency in glycogen phosphorylase in liver. Presents with mild to moderate hypoglycemia, mild ketosis, growth retardation and prominent hepatomegaly.

Question 29

Describe/draw the reactions of glycogen formation (glycogenesis)

Answer 29

Question 30

What is McArdle’s disease?

Answer 30

• Aka GSD-V: deficiency in glycogen phosphorylase in muscle. Muscle is unable to use glycogen. Leads to greater than normal glycogen stores in muscles. During periods of high glucose demand, ie. exercise, patients experience muscle cramps.

Question 31

Explain the effect of insulin-induced dephosphorylation on glycogen phosphorylase and glycogen synthase.

Answer 31

• Glycogen phosphorylase is inactivated - Glycogen synthase is activated

Question 32

Explain the effect of glucagon-induced phosphorylation on glycogen phosphorylase and glycogen synthase.

Answer 32

• Glycogen phosphorylase is activated - Glycogen synthase is inactivated.