Exam 3 Lecture 1: Gluconeogenesis

Question 1

What happens after you consume carbs?

Answer 1

After consumption of carbohydrates:

• Insulin-dependent glucose transport into adipose tissue and heart and skeletal muscle
• Insulin-independent glucose transport into liver and other tissues
• Active glycolytic pathway
• PDH active in tissues with mitochondria (creating acetyl coA)
• AcCoA metabolized/oxidized in the TCA Cycle

Question 2

In the liver, insulin promotes the expression of which glycolytic enzymes?

Answer 2

Insulin promotes the following enzyme’s expression in the liver:

• Glucokinase
• PFK-1
• Pyruvate Kinase

Question 3

What is the overall effect of glucagon and epi on glycolysis?

FASTED STATE: what enzymes get inhibited and which enzymes are transcribed less

Answer 3

Glucagon and Epi:

• inhibit PFK-2: inhibits PFK-1 and therefore inhibits glycolysis
• Inhibits pyruvate kinase
• ALSO decreases the gene transcription of the following enzmes: Glucokinase, PFK-1, Pyruvate Kinase

Question 4

The fasted states promotes/activates which pathways?

Answer 4

Glucagon and Epi:

• promote glucose synthesis (via gluconeogenesis)
• Increase gene transcription of gluconeogenic enzymes
• Promote mobilization of glucose via glycogen degradation

Question 5

What are the preferred energy sources of the following tissues:

Liver

Adipose

Skeletal Muscle

Heart Muscle

Brain Tissue

Answer 5

Liver: fatty, glucose, AA’s

Adipose Tissue: Fatty Acids

Skeletal Muscle: Fatty Acids (rest), glucose (exertion)

Heart Muscle: fatty acids

Brain: GLUCOSE (fed state), ketone bodies and glucose (starved state)

Question 6

Glucose homeostatis requires two pathways…..?

They both take place in the ______

Answer 6

Glucose homeostatis requires two pathways:

Gluconeogenesis

Glycogen Degradation

Both take place in the liver

Question 7

Explain how glycogen and pyruvate get turned into glucose

Answer 7

Question 8

Gluconeogenesis:

Is the synthesis of glucose from noncarb sources such as:______, _______, ______, and ______

Answer 8

Gluconeogenesis is the synthesis of glucose from non-carb sources such as pyruvate, lactate, glycerol, and glucogenic AA’s

Question 9

Gluconeogenesis:

Is stimulated by what?

Where does gluconeogenesis take place?

How many ATP’s does it require?

Answer 9

Gluconeogenesis:

• Low blood glucose stimulates gluconeogenesis
• Takes place mainly in the liver, and to some extent the kidney
• It is an ATP (6 ATPs) dependent process.

Question 10

Pyruvate is converted to PEP in a two step process via oxaloacetate, which can be viewed as….?

_____ and ____ are involved in this activation, which requires the expenditure of ATP

Answer 10

Pyruvate is converted into PEP in a two step process via oxaloacetate, which can be viewed as the “activated” form of pyruvate

Bicarbonate and the cofactor biotin are involved in this activation, which requires the expenditure of ATP

Question 11

What do the following gluconeogenic precursors come from?

Lactate

Gluconeogenic AA’s like ALANINE

Glycerol

Answer 11

Major Gluconeogenic Precursors:

Lactate: general metabolism, RBC metabolism and muscle metabolism

Gluconeogenic AA’s (Alanine): overnight degradation of muscle AA’s

Glycerol: degradation of adipose tissue triacylglycerols

Question 12

Draw the diagram showing where the various gluconeogenic precursors enter the pathway (lactate, aspartate, glycerol, alanine)

Answer 12

Question 13

Neonate’s brain is very dependent on glucose for glycogen degradation and gluconeogenesis.

It takes a few hours to induce the enzyme _______ which is needed to make glucose from lactate or alanine.

Thus there is a risk of ____ during the first few hours after birth.

Answer 13

Neonates:

Takes a few hours to induce the enzyme PEP Carboxykinase, which is important in turning lactate and alanine into glucose.

Thus, there is a risk of hypoglycemia during the first few hours after birth.

Question 14

Gluconeogenesis takes place in _______

Glycolysis is active in _______

Answer 14

Gluconeogenesis takes place in liver and kidney

Glycolysis is active in nearly every living cell.

Question 15

Explain the Cori Cycle/Glucose Lactase Cycle

How many ATPs are required?

Answer 15

Cori Cycle/Glucose Lactose Cycle:

Lactate is made in RBCs and skeletal muscles from glycolysis (from pyruvate)

Lactate then enters the blood stream where it goes to the liver

Lactate can then undergo gluconeogenesis in the liver to form glucose (this requires 6 ATPs)

Question 16

Explain the Alanine Cycle/ the glucose alanine cycle

How many ATPs does it require?

Answer 16

Pyruvate gets deaminated to form alanine in muscle cells

Then alanine enters the bloodstream and goes into the liver.

Alanine is deaminated to pyruvate (which can then enter gluconeogenesis and get turned into glucose)

That reaction creates toxic NH2, which undergoes ureagenesis in the liver to create urea, which goes to the kidneys

Note: this cycle uses 10 ATPs total

Question 17

Why does the glucose alanine cycle require additional ATP input?

Answer 17

Alanine cycle requires additional ATP input because ureagenesis is needed to remove NH2 and that process is ATP intensive.

Question 18

Gluconeogenesis from all precursors requires ___

Gluconeogenesis from AA’s requires additional ___ which is used for _____

During an overnight fast _______ is used as the major source of ATPs for gluconeogenesis, not from ___

Answer 18

Gluconeogenesis from all precursors requires ATP

Gluconeogenesis from AA’s requires additional ATPs which is used for ureagenesis

During an overnight fast, oxidation of fatty acids serves as the major source of ATP for gluconeogenesis, not from the source of lactate or alanine-mediated gluconeogenesis.

Question 19

Once acetyl coA is made it can/cannot be used to make glucose; it is commited to either ____ or _______.

Answer 19

Once acetyl coA is made it CANNOT be used to make glucose

Acetyl coA is comitted to either fatty acid synthesis or the Krebs cycle

Question 20

Glycerol is a precursor for synthesis of ________ in the liver and adipose tissue.

Answer 20

Glycerol is a precursor for the synthesis of triaglycerols and of phospholipids in the liver and adipose tissue

Question 21

What happens to glycerol and fatty acids when the body uses stored fat as a source of energy?

Answer 21

When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the blood stream.

Question 22

Glycerol will be converted into its intermediate _____ before entering the pathway of glycolysis or gluconeogenesis (depending on physiological conditions)

Answer 22

Glycerol is converted into glyceraldehyde 3-P before entering glycolysis or gluconeogenesis

This rxn is done by the enzyme glycerol kinase

Question 23

Top Hat Question:

The major source of ATP for gluconeogenesis is from what source?

Answer 23

Major source of ATP for gluconeogenesis comes from fatty acid oxidation

Question 24

Propionyl CoA is a good/bad precursor for gluconeogenesis.

How is propionyl coA formed?

Answer 24

Propionyl CoA is a GOOD precursor for gluconeogenesis (it’s made up of 3 carbons)

Propionyl CoA is formed as a product of beta oxidation of odd chain fatty acids, isoleucine, valine, and alpha-ketobutyric acid.

Question 25

What are the four enzymes that are required to reverse the three irreversible steps of glycolysis?

Answer 25

Mitochondrial: Pyruvate Carboxylase

Cytoplasmic: PEP Carboxykinase

Cytoplasmic: Fructose 1,6-Bisphophatase

Cytoplasmic: Glucose 6-Phosphatase

Question 26

Explain the reaction of Pyruvate Carbosylase

Where does it occur?

What does it need to proceed

Answer 26

To get out of the mitochondria, pyruvate needs to add CO2 to create oxaloacetate

(this rxn is preformed by pyruvate carboxylase)

This reaction needs CO2, ATP, and biotin (a cofactor) to proceed

Question 27

What activates the pyruvate carboxylase reaction?

Answer 27

Pyruvate Carboxylase is activated by acetyl coA

remember pyruvate carboxylase takes pyruvate, adds CO2 to create oxaloacetate

(this rxn needs ATP, and biotin which is a cofactor)

Question 28

Explain the Pyruvate Carboxylase Genetic Deficiency:

• Symptoms?
• What accumulates in the blood stream?

Answer 28

Pyruvate Carboxylase Genetic Deficiency:

• Symptoms: failure to thrive, developmental delays, recurrent seizures, metabolic acidosis
• Lack of PC enzyme creates accumulation of pyruvate in the plasma, which gets converted into lactate by LDH, causing elevated lactic acid levels in the plasma also
• Also, high alanine levels are found in serum because pyruvate can also be deaminated into alanine

Question 29

Draw the diagram of the ER and explain the transporter and the glucose-6-phosphatase enzyme

Answer 29

Question 30

Glucose 6-phosphatase requires _____ and ___

Answer 30

Glucose 6 phosphatase requires the enzyme activity and transport of glucose 6-phosphate into the ER.

Question 31

A genetic defect in either the ____ or the ____ interferes with gluconeogenesis, and results in accumulation of glycogen in the liver.

Answer 31

A genetic defect in either the transporter or the phosphatase interferes with gluconeogenesis and results in the accumulation of glycogen in the liver.

Question 32

Glucose 6-Phosphatase Deficiency:

Explain what it is.

What is another name for it

Answer 32

Glucose 6-Phosphatase Defiency aka Von Gierke Disease:

• Group of inherited metabolic diseases
• It is characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver (enlarged), elevated serum uric acid, and elevated serum lactate.

Question 33

Compare the regulation of glucokinase with glucose 6-phosphatase

Answer 33

Question 34

Compare the regulation of PFK-1 and fructose 1,6, bisphosphatase

Answer 34

Question 35

Explain the difference in regulation of pyruvate kinase vs PEPCK and pyruvate carboxylase

Answer 35

Question 36

Explain the overall regulation of the synthesis of key hepatic glycolytic and gluconeogenic enzymes

Answer 36

Question 37

Glycolysis: insulin increases the synthesis of key glycolytic enzymes… list them

Gluconeogenesis: glucagon and epinephrine increases the synthesis of key gluconeogenic enzymes… list them

Answer 37

Glycolysis:

Insulin increases the synthesis of these enzymes: Glucokinase, PFK-1, and Pyruvate Kinase

Gluconeogenesis:

Glucagon and Epi increase the synthesis of these enzymes: Pyruvate Carboxylase, PEPCK, Fructose 1,6-Bisphosphatase, and Glucose 6-Phosphatase

Question 38

Ehtanol metabolism can cause _________; the high ____ opposes gluconeogenesis

Ethanol metabolism (Ethanol Dehydrogenase) increases the ratio of _______

Increased ____ promotes the conversion of two gluconeogenic precursors (_____ & ______) into the conversion to _____ and ______

Why does this cause hypothermia?

Answer 38

Ehtanol metabolism can cause hypothermia: the high NADH level opposes gluconeogenesis.

Ethanol metabolism (Ethanol Dehydrogenase) increases the ratio of NADH/NAD+.

Increased NADH promotes the conversion of two gluconeogenic precursors (pyruvate and oxaloacetate) to lactate and malate.

Thus removing pyruvate and oxaloacetate from the pool of glucose precursors (hypoglycemia)

Question 39

The increased NADH from ethanol metabolism oxidizes/reduces the gluconeogenic precursors pyruvate and OAA to lactate and malate.

Answer 39

Pyruvate and OAA are REDUCED to lactate and malate

Question 40

Increased NADH leads to ______ formation

Decreased NADH leads to _______ formation

Answer 40

Increased NADH leads to increased lactate formation

Decreased NADH leads to decreased lactate formation

Question 41

Pyruvate Carboxylase uses ___ as its energy source and is located in the _______

PEPCK uses ___ as its energy source and is located in the ______

Answer 41

Pyruvate Carboxylase: uses ATP, located in mitochondria

PEPCK: uses GTP, located in cytoplasm