Gluconeogenesis- Case-based Multiple-Choice Questions- Set 1

1. A 4-month-old boy is being evaluated for seizures, psychomotor retardation, and hypotonia. Work-up reveals elevated serum levels of lactate, alanine, pyruvate, and ketoacids. Based on the clinical presentation, pyruvate carboxylase activity is measured using fibroblasts from a skin biopsy and is found to be markedly decreased. This enzyme is normally used to directly synthesize which of the following molecules?
A. Acetyl-CoA
B. Malate
C. Oxaloacetate
D. Pyruvate
E. α-Ketoglutarate

Correct Answer: C. Oxaloacetate. Pyruvate carboxylase is a key enzyme involved in gluconeogenesis and anaplerotic reactions. It catalyzes the carboxylation of pyruvate to oxaloacetate using biotin as a cofactor. Oxaloacetate is essential for the replenishment of intermediates in the citric acid cycle and also serves as a precursor for gluconeogenesis. A deficiency of pyruvate carboxylase impairs gluconeogenesis, leading to elevated levels of pyruvate, lactate, and alanine, as seen in this case.
Incorrect Options:
A. Acetyl-CoA
Acetyl-CoA is formed from pyruvate through the action of pyruvate dehydrogenase, not pyruvate carboxylase. It plays a central role in the citric acid cycle and lipid synthesis.
B. Malate
Malate is another intermediate of the citric acid cycle, but it is formed from oxaloacetate through the action of malate dehydrogenase, not pyruvate carboxylase.
D. Pyruvate
Pyruvate is the substrate for pyruvate carboxylase, not its product. It is generated from glycolysis and can be used to form acetyl-CoA or oxaloacetate.
E. α-Ketoglutarate
α-Ketoglutarate is an intermediate in the citric acid cycle, formed from isocitrate by isocitrate dehydrogenase, not pyruvate carboxylase.

2. A 34-year-old woman presents with central obesity, relatively thin extremities, and purple striae on her abdomen. Further work-up reveals excessive serum cortisol levels and a blood sugar level of 258 mg/dl. Which of the following is the most likely cause of her hyperglycemia?
A. A pancreatic adenoma secreting ACTH and glucagon
B. Cortisol-induced inhibition of insulin
C. Excessive consumption of processed carbohydrates
D. Glucocorticoids cause induction of phosphoenolpyruvate carboxykinase gene
E. Increased gluconeogenesis due to increased provision of substrates through fatty acid oxidation

Correct Answer: D. Glucocorticoids cause induction of phosphoenolpyruvate carboxykinase gene. Cortisol is a glucocorticoid that promotes hyperglycemia by increasing gluconeogenesis, which is the generation of glucose from non-carbohydrate precursors. It achieves this effect by inducing the expression of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK). The upregulation of PEPCK enhances the conversion of oxaloacetate to phosphoenolpyruvate, facilitating glucose production in the liver and contributing to elevated blood glucose levels, as seen in this case.
Incorrect Options:
A. A pancreatic adenoma secreting ACTH and glucagon
This is incorrect because pancreatic adenomas generally do not secrete ACTH. ACTH overproduction typically comes from a pituitary tumor (in Cushing’s disease) or ectopic ACTH secretion from other cancers, not pancreatic adenomas.
B. Cortisol-induced inhibition of insulin
While cortisol can reduce insulin sensitivity, the primary mechanism of hyperglycemia is not through direct inhibition of insulin but rather by promoting gluconeogenesis and reducing glucose uptake by tissues.
C. Excessive consumption of processed carbohydrates
Dietary intake can transiently raise blood sugar levels, but it is not the primary driver of chronic hyperglycemia associated with cortisol overproduction.
E. Increased gluconeogenesis due to increased provision of substrates through fatty acid oxidation
While fatty acid oxidation can provide substrates like glycerol and acetyl-CoA, the main driver of hyperglycemia in Cushing’s syndrome is the direct induction of gluconeogenic enzymes by cortisol, such as PEPCK.

3. A 56-year-old obese man complains of polydipsia, polyuria, and fatigue. A glucose tolerance test confirms the diagnosis of diabetes. He is placed on Metformin, which works by which of the following mechanisms?
A. Increasing cellular responsiveness to circulating insulin
B. Increasing glucagon level
C. Inhibiting hepatic gluconeogenesis
D. Replacing the need for endogenous insulin
E. Stimulating the release of preformed insulin

Correct Answer: C. Inhibiting hepatic gluconeogenesis. Metformin is an oral antidiabetic medication, primarily used for type 2 diabetes, which works by decreasing hepatic gluconeogenesis—the liver’s production of glucose. It enhances the liver’s sensitivity to insulin, reducing glucose output and thereby improving glycemic control. Metformin also improves peripheral glucose uptake and utilization, contributing further to its glucose-lowering effects. Importantly, it does not directly stimulate insulin release, thus posing a lower risk of hypoglycemia compared to other antidiabetic agents like sulfonylureas.
Incorrect Options:
A. Increasing cellular responsiveness to circulating insulin
While Metformin improves insulin sensitivity in peripheral tissues, its primary action is to reduce hepatic glucose production, not to directly increase cellular insulin responsiveness.
B. Increasing glucagon level
Metformin does not increase glucagon levels. In fact, part of its effect is thought to involve reducing hepatic glucose output by modulating the impact of glucagon on the liver.
D. Replacing the need for endogenous insulin
Metformin is not an insulin replacement therapy; it helps the body use insulin more effectively. Insulin replacement is used for type 1 diabetes or advanced cases of type 2 diabetes.
E. Stimulating the release of preformed insulin
Unlike medications like sulfonylureas, Metformin does not promote the release of insulin from pancreatic beta cells. This is why it has a lower risk of causing hypoglycemia.

4. A 28-year-old marathon runner decides to adopt a low-carbohydrate diet to improve endurance by promoting fat metabolism. During intense exercise, his muscles rely on glycolysis for quick energy. However, between workouts, his liver switches to gluconeogenesis to maintain blood glucose levels. Which of the following enzymes is used in both glycolysis and gluconeogenesis?
A. 3-Phosphoglycerate kinase
B. Glucose 6-phosphatase
C. Hexokinase
D. Phosphofructokinase-1
E. Pyruvate kinase

Correct Answer: A. 3-Phosphoglycerate kinase. The 3-phosphoglycerate kinase is a reversible enzyme, catalyzing the conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate in glycolysis, producing ATP. In gluconeogenesis, the same enzyme works in the reverse direction, consuming ATP to convert 3-phosphoglycerate to 1,3-bisphosphoglycerate. This enzyme is one of the few that plays a role in both pathways.
Incorrect Options:
B. Glucose 6-phosphatase
This enzyme is exclusive to gluconeogenesis, converting glucose 6-phosphate to free glucose to maintain blood glucose levels. It is not involved in glycolysis.
C. Hexokinase
Hexokinase catalyzes the phosphorylation of glucose to glucose 6-phosphate in glycolysis but has no role in gluconeogenesis. Instead, gluconeogenesis relies on glucose 6-phosphatase to remove the phosphate group.
D. Phosphofructokinase-1 (PFK-1)
PFK-1 is a glycolytic enzyme that phosphorylates fructose 6-phosphate to fructose 1,6-bisphosphate. Gluconeogenesis uses a different enzyme, fructose 1,6-bisphosphatase, for the reverse reaction.
E. Pyruvate kinase
Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate in glycolysis. In gluconeogenesis, the reverse process requires pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK) to bypass this irreversible step.

5. A 45-year-old individual has been fasting intermittently for 24 hours to maintain metabolic health. As his body transitions from using dietary glucose to generating glucose internally, gluconeogenesis becomes a key metabolic process. Which of the following statements about gluconeogenesis is false?
A. For starting materials, it can use carbon skeletons derived from certain amino acids.
B. It consists entirely of the reactions of glycolysis, operating in the reverse direction.
C. It employs the enzyme glucose 6-phosphatase.
D. It is one of the ways that mammals maintain normal blood glucose levels between meals.
E. It requires metabolic energy (ATP or GTP).

Correct Answer: B. It consists entirely of the reactions of glycolysis, operating in the reverse direction. This statement is false because gluconeogenesis is not a simple reversal of glycolysis. While it shares several reversible reactions with glycolysis, certain steps in glycolysis are irreversible and require bypass reactions with different enzymes in gluconeogenesis. Specifically:
• Pyruvate kinase is bypassed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK).
• Phosphofructokinase-1 is bypassed by fructose 1,6-bisphosphatase.
• Hexokinase or glucokinase is bypassed by glucose 6-phosphatase.

Incorrect Options (Correct Statements):
A. For starting materials, it can use carbon skeletons derived from certain amino acids.
This is correct. Certain amino acids, especially glucogenic ones like alanine and glutamine, can be converted into intermediates of the gluconeogenic pathway.
C. It employs the enzyme glucose 6-phosphatase.
This is correct. Glucose 6-phosphatase is required for the final step of gluconeogenesis, converting glucose 6-phosphate into free glucose, which can be released into the bloodstream.
D. It is one of the ways that mammals maintain normal blood glucose levels between meals.
This is correct. Between meals or during fasting, gluconeogenesis helps to maintain blood glucose levels, which is especially important for tissues like the brain and red blood cells that rely on glucose.
E. It requires metabolic energy (ATP or GTP).
This is correct. Gluconeogenesis is an energy-consuming process, requiring ATP or GTP to drive the conversion of non-carbohydrate precursors into glucose.

6. Which of the following enzymes is not involved both in the flow of carbon from glucose to lactate (glycolysis) and in the reversal of this flow from lactate to glucose (gluconeogenesis)?
A. 3-Phosphoglycerate kinase
B. Aldolase
C. Enolase
D. Glucose 6-phosphatase
E. Phosphohexose isomerase

Correct Answer: D. Glucose 6-phosphatase. Glucose 6-phosphatase is an enzyme involved only in gluconeogenesis and not in glycolysis. It catalyzes the final step of gluconeogenesis, converting glucose 6-phosphate into free glucose, which can be released into the bloodstream. Glycolysis does not use this enzyme. Instead, glycolysis starts with the phosphorylation of glucose by hexokinase or glucokinase to form glucose 6-phosphate.
Incorrect Options (Correct Statements):
A. 3-Phosphoglycerate kinase
This enzyme is involved in both glycolysis and gluconeogenesis. It catalyzes the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate, producing or consuming ATP depending on the pathway.
B. Aldolase
Aldolase catalyzes the reversible cleavage of fructose 1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate. It plays a role in both glycolysis and gluconeogenesis.
C. Enolase
Enolase catalyzes the reversible conversion of 2-phosphoglycerate to phosphoenolpyruvate (PEP) and functions in both glycolysis and gluconeogenesis.
E. Phosphohexose isomerase
This enzyme, also known as glucose 6-phosphate isomerase, catalyzes the reversible conversion between glucose 6-phosphate and fructose 6-phosphate. It functions in both glycolysis and gluconeogenesis.

7. Which of the following substrates cannot contribute to net gluconeogenesis in mammalian liver?
A. Alanine
B. Glutamate
C. Stearate
D. Pyruvate
E. α-Ketoglutarate

Correct Answer: C. Stearate. Stearate is a long-chain saturated fatty acid. When fatty acids like stearate undergo β-oxidation, they generate acetyl-CoA. However, acetyl-CoA cannot serve as a substrate for net gluconeogenesis because its carbons are fully oxidized to CO₂ in the citric acid cycle. No net carbon is available to contribute to glucose synthesis.
In mammals, only odd-chain fatty acids (rare) can produce small amounts of glucose via propionyl-CoA, which can be converted into succinyl-CoA and enter the gluconeogenic pathway.
Incorrect Options (Correct Substrates for Gluconeogenesis):
A. Alanine
Alanine is a glucogenic amino acid that can be converted into pyruvate, which enters the gluconeogenic pathway.
B. Glutamate
Glutamate is converted into α-ketoglutarate, an intermediate of the citric acid cycle, which can be used for gluconeogenesis.
D. Pyruvate
Pyruvate is a key precursor for gluconeogenesis, easily converted into oxaloacetate by pyruvate carboxylase.
E. α-Ketoglutarate
α-Ketoglutarate is a citric acid cycle intermediate that can be converted into oxaloacetate, feeding into gluconeogenesis.

8. A 6-year-old boy begins playing soccer in a community league. After his first game, he experiences severe muscle cramps and blood in his urine. His pediatrician evaluates him and finds that he has a deficiency of lactate dehydrogenase (LDH). Lactate dehydrogenase is important in which of the following conversions?
A. Pyruvate to Acetyl-CoA
B. Pyruvate to Alanine
C. Pyruvate to Lactate
D. Pyruvate to Oxaloacetate
E. Pyruvate to Phosphoenolpyruvate

Correct Answer: C. Pyruvate to Lactate. Lactate dehydrogenase (LDH) catalyzes the reversible conversion of pyruvate to lactate, especially during anaerobic conditions (such as intense exercise). This reaction allows for the regeneration of NAD⁺, which is essential for maintaining glycolysis when oxygen levels are low. Without functional LDH, the boy’s muscles are unable to effectively convert pyruvate into lactate, causing a buildup of pyruvate and disruption of energy metabolism. This explains his muscle cramps during exercise and myoglobinuria (blood in urine) from muscle breakdown.
Incorrect Options:
A. Pyruvate to Acetyl-CoA
This conversion is catalyzed by pyruvate dehydrogenase and is the first step in the entry of pyruvate into the citric acid cycle, not by LDH.
B. Pyruvate to Alanine
This reaction is catalyzed by alanine aminotransferase (ALT), which transfers an amino group from glutamate to pyruvate, forming alanine.
D. Pyruvate to Oxaloacetate
This step is catalyzed by pyruvate carboxylase, not LDH. It plays a role in gluconeogenesis and the citric acid cycle.
E. Pyruvate to Phosphoenolpyruvate
This conversion is catalyzed by phosphoenolpyruvate carboxykinase (PEPCK) during gluconeogenesis, not by LDH.

9. A newborn infant presents with persistent hypoglycemia despite frequent feedings. The child is irritable and has moderate hepatomegaly. Upon further testing, the infant is found to have normal muscle fructose 1,6-bisphosphatase levels but a decreased level of the liver isoform. This condition suggests an impaired gluconeogenic response, given the importance of liver fructose 1,6-bisphosphatase in glucose production. Which of the following statements is true of fructose 1,6-bisphosphatase?
A. It is induced by adenosine monophosphate (AMP)
B. It is induced by insulin
C. It is inhibited by fructose 2,6-bisphosphate
D. It is induced in the fed state
E. It is inhibited during fasting

Correct Answer: C. It is inhibited by fructose 2,6-bisphosphate. Fructose 1,6-bisphosphatase is a key regulatory enzyme in gluconeogenesis. It catalyzes the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, a crucial step in the pathway that allows the liver to produce glucose from non-carbohydrate sources.
• Fructose 2,6-bisphosphate is a potent inhibitor of fructose 1,6-bisphosphatase, favoring glycolysis by activating phosphofructokinase-1 (PFK-1) and inhibiting gluconeogenesis.
• This balance between glycolysis and gluconeogenesis is tightly regulated by the fed-fast cycle and hormonal signals such as insulin and glucagon.
Incorrect Options:
A. It is induced by adenosine monophosphate (AMP):
This is incorrect. AMP is an indicator of low energy levels and inhibits fructose 1,6-bisphosphatase to reduce gluconeogenesis. This shifts metabolism towards energy-saving processes.
B. It is induced by insulin:
This is incorrect. Insulin favors glycolysis and inhibits gluconeogenesis by reducing the expression of enzymes like fructose 1,6-bisphosphatase.
D. It is induced in the fed state:
This is incorrect. During the fed state, insulin levels are high, suppressing gluconeogenesis and promoting glycolysis instead.
E. It is inhibited during fasting:
This is incorrect. During fasting, glucagon stimulates gluconeogenesis to maintain blood glucose levels, upregulating fructose 1,6-bisphosphatase activity.
10. A 32-year-old bodybuilder switches to a strict diet of egg whites, focusing on protein intake to enhance muscle growth. After a few weeks, he experiences decreased energy and is found to be hypoglycemic. The nutritionist suspects a biotin deficiency, which can occur with excessive consumption of raw egg whites due to the presence of avidin, a protein that binds biotin and prevents its absorption.
Which of the following enzymes is unable to catalyze its step in synthesizing glucose from pyruvate due to biotin deficiency?
A. Fructose 1,6-bisphosphatase
B. Glucose-6-phosphatase
C. Phosphoenolpyruvate carboxykinase (PEPCK)
D. Phosphoglycerate kinase
E. Pyruvate carboxylase

Correct Answer: E. Pyruvate carboxylase. Pyruvate carboxylase is a biotin-dependent enzyme that plays a key role in gluconeogenesis by catalyzing the conversion of pyruvate to oxaloacetate in the mitochondria. This step is essential for initiating gluconeogenesis, allowing the liver to produce glucose from non-carbohydrate sources. In the absence of biotin, this reaction is impaired, leading to reduced gluconeogenic capacity and hypoglycemia. Biotin serves as a cofactor that carries activated carbon dioxide in carboxylation reactions, including the one catalyzed by pyruvate carboxylase.
Incorrect Options:
A. Fructose 1,6-bisphosphatase
This enzyme catalyzes the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis. It does not require biotin for its activity.
B. Glucose-6-phosphatase
This enzyme catalyzes the final step of gluconeogenesis, converting glucose 6-phosphate to free glucose. It is not biotin-dependent.
C. Phosphoenolpyruvate carboxykinase (PEPCK)
PEPCK catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in gluconeogenesis, but it does not require biotin. Instead, it requires GTP as a cofactor.
D. Phosphoglycerate kinase
This enzyme participates in both glycolysis and gluconeogenesis, catalyzing the conversion of 3-phosphoglycerate to 1,3-bisphosphoglycerate. It uses ATP but does not depend on biotin.

 

 

error: Content is protected !!