Updated: 12/15/2020

Gluconeogenesis

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Questions
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Evidence
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Overview
  •  Function
    • de novo glucose synthesis
      • effectively glycolysis in reverse
      • can maintain blood glucose when glycogen stores are exhausted
      • must supply brain and RBCs which utilize glucose for energy
        • is NOT a source of energy for the liver
          • hepatocytes use β-oxidation to supply the energy needed for gluconeogenesis
    • potential substrates
      • all amino acids
        • except for leucine and lysine 
      • lactate
        • produced in anaerobic glycolysis
      • glycerol-3-phosphate
        • produced in fat catabolism
      • propionyl-CoA
        • produced in odd-carbon fatty acid catabolism
  • Pathway
    • location 
      • hepatocytes (primary)
      • kidney
      • enterocytes
      • NOT muscle
        • no glucose-6-phosphatase
          • cannot release free glucose
    • enzymes  
      • involves both mitochondrial and cytosolic enzymes
      • several steps of glycolysis are reversible
      • the non-reversible steps must be bypassed with special gluconeogenic enzymes
        • pyruvate carboxylase
          • pyruvate → oxaloacetate
          • requires biotin and ATP
          • activated by acetyl-CoA 
            • oxaloacetate must be converted to malate to exit the mitochondria via the malate-aspartate shuttle
          • in mitochondria
        • PEP carboxykinase (PEPCK)
          • oxaloacetate → phosphoenolpyruvate (PEP)
          • requires GTP
          • activated by glucagon and cortisol
          • in both cytosol and mitochondria
        • fructose-1,6-bisphosphatase 
          • fructose-1,6-bisphosphate → fructose-6-P
          • important control point of gluconeogenesis
          • activated by ATP, inhibited by AMP and fructose-2,6-bisphosphate
          • in cytosol
        • glucose-6-phosphatase (G6P)
          • glucose-6-P → glucose
          • in ER of hepatocytes
          • clinical relevance
            • von Gierke disease = G6P deficiency
              • see Glycogen metabolism
      • other enzymes
        • lactate dehydrogenase
          • lactate → pyruvate
          • requires free NAD+
    • regulation
      • stimulation
        • glucagon
        • acetyl CoA
        • citrate
      • inhibition
        • high NADH/NAD+ ratio
          • alcohol may cause elevated NADH/NAD+ ratio leading to hypoglycemia  
 
 

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Questions (6)
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(M1.BC.15.74) The balance between glycolysis and gluconeogenesis is regulated at several steps, and accumulation of one or more products/chemicals can either promote or inhibit one or more enzymes in either pathway. Which of the following molecules if increased in concentration can promote gluconeogenesis? Tested Concept

QID: 106607
1

AMP

12%

(14/118)

2

ADP

19%

(22/118)

3

Insulin

5%

(6/118)

4

Fructose-2,6-biphosphate

23%

(27/118)

5

Acetyl-CoA

41%

(48/118)

M 1 D

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(M1.BC.14.1) To prepare for an endoscopy, a 27-year-old male was asked by the gastroenterologist to fast overnight for his 12 p.m. appointment the next day. Therefore, his last meal was dinner at 5 p.m. the day before the appointment. By 12 p.m. the day of the appointment, his primary source of glucose was being generated from gluconeogenesis, which occurs via the reversal of glycolysis with extra enzymes to bypass the irreversible steps in glycolysis. Which of the following irreversible steps of gluconeogenesis occurs in the mitochondria? Tested Concept

QID: 106291
1

Glucose-6-phosphate to glucose

2%

(1/48)

2

Fructose-1,6-biphosphate to fructose-6-phosphate

15%

(7/48)

3

Pyruvate to oxaloacetate

65%

(31/48)

4

Phosphoenolypyruvate to pyruvate

12%

(6/48)

5

Glucose-6-phosphate to 6-phosphogluconolactone

2%

(1/48)

M 1 E

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(M1.BC.13.2) A 65-year-old homeless man with a history of hospitalization for alcohol intoxication is brought in confused. His serum glucose is 39mg/dl. Which of the following is likely true? Tested Concept

QID: 100067
1

He has also been using cocaine

1%

(2/330)

2

He has decreased activity of alcohol dehydrogenase

9%

(30/330)

3

Hepatic gluconeogenesis is elevated

7%

(23/330)

4

The next step in management is glucose repletion

21%

(68/330)

5

His hepatic NADH/NAD+ ratio is high

62%

(203/330)

M 1 E

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Evidence (2)
Topic COMMENTS (16)
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