Glycogen & Gluconeogenesis Review

A comprehensive set of 100 question-and-answer flashcards covering glycogen metabolism, gluconeogenesis, regulation, clinical disorders, and therapeutic drugs.

What is glycogen?

A highly branched polymer of α-D-glucose that serves as the main carbohydrate storage in animals.

What type of glycosidic bonds make up the linear chains in glycogen?

α(1→4) glycosidic bonds.

What type of glycosidic bonds create glycogen branches?

α(1→6) glycosidic bonds.

Approximately how many glucose residues separate glycogen branch points?

About every 8–12 glucose residues.

Which end of a glycogen molecule is enzymatically active for addition or removal of glucose?

The nonreducing end that carries the free 4′-hydroxyl group.

Which enzyme primes new glycogen molecules?

Glycogenin.

Roughly how many glucose residues are contained in a glycogen β-granule?

Approximately 50,000–60,000 glucose residues.

What is the primary function of liver glycogen?

To maintain blood glucose between meals and during fasting.

What is the primary function of skeletal muscle glycogen?

To provide an on-site fuel reserve for muscle contraction.

Name three other tissues that store measurable amounts of glycogen.

Kidneys, red blood cells, and glial cells/neurons (uterus also stores small amounts).

Which hormone predominantly stimulates glycogenesis?

Insulin.

What reaction is catalyzed by phosphoglucomutase during glycogenesis?

Conversion of glucose-6-phosphate to glucose-1-phosphate.

Which enzyme forms UDP-glucose from glucose-1-phosphate and UTP?

UDP-glucose pyrophosphorylase.

Which enzyme elongates the glycogen chain during synthesis?

Glycogen synthase.

What is the role of the branching enzyme in glycogen synthesis?

It transfers a short (6–8-residue) glucose chain to create a new α(1→6) branch.

Why is extensive branching advantageous for glycogen?

Branching increases solubility and provides many non-reducing ends for rapid synthesis or degradation.

Which hormone triggers glycogenolysis in the liver?

Glucagon (epinephrine also promotes it).

Which enzyme cleaves α(1→4) bonds during glycogen breakdown?

Glycogen phosphorylase.

What molecule is released by glycogen phosphorylase activity?

Glucose-1-phosphate.

What two activities does the debranching enzyme possess?

A transferase that moves three glucose residues and an α-1,6-glucosidase that hydrolyzes the branch point.

Which enzyme converts glucose-1-phosphate to glucose-6-phosphate?

Phosphoglucomutase.

Why can muscle glycogen not contribute directly to blood glucose?

Muscle lacks glucose-6-phosphatase, so G6P cannot be dephosphorylated to free glucose.

Do skeletal muscles respond to circulating glucagon?

No; skeletal muscle cells do not possess glucagon receptors.

What type of regulation involves metabolites binding to an enzyme’s regulatory site?

Allosteric regulation.

Which allosteric activator turns on glycogen phosphorylase in muscle?

AMP.

How is glycogen synthase activity generally inhibited?

By covalent phosphorylation through protein kinases.

How does insulin affect the phosphorylation state of glycogen synthase?

Insulin activates protein phosphatase-1, which dephosphorylates and thereby activates glycogen synthase.

How does epinephrine influence glycogen phosphorylase activity?

It raises cAMP, activating PKA, which phosphorylates phosphorylase kinase, which then activates glycogen phosphorylase.

In which two organs does gluconeogenesis mainly occur?

The liver and the renal cortex (kidneys).

List three major carbon sources for gluconeogenesis.

Lactate, alanine, and glycerol.

Can acetyl-CoA from fatty acid oxidation be converted into net glucose?

No; acetyl-CoA cannot provide net carbon for glucose synthesis.

Which two enzymes together bypass the pyruvate kinase step in gluconeogenesis?

Pyruvate carboxylase followed by phosphoenolpyruvate carboxykinase (PEPCK).

Which enzyme bypasses phosphofructokinase-1 during gluconeogenesis?

Fructose-1,6-bisphosphatase.

Which enzyme bypasses hepatic glucokinase/hexokinase in gluconeogenesis?

Glucose-6-phosphatase.

Which hormone suppresses hepatic gluconeogenesis?

Insulin.

Which two hormones stimulate gluconeogenesis during stress or fasting?

Glucagon and epinephrine.

What enzyme converts lactate to pyruvate in the liver (Cori cycle)?

Lactate dehydrogenase.

How many high-energy phosphate equivalents are required to synthesize one glucose from two pyruvate?

4 ATP, 2 GTP, and 2 NADH per glucose.

From what metabolic process is the ATP for gluconeogenesis largely derived?

Fatty acid β-oxidation.

State four conditions that can cause hypoglycemia due to impaired gluconeogenesis.

Alcohol intake, insulin overdose, cortisol (adrenal) deficiency, and hypothyroidism.

What is the first-line treatment for a conscious patient with acute hypoglycemia?

Ingest 15–20 g of fast-acting carbohydrate such as glucose tablets or fruit juice.

What injectable drug is given to an unconscious hypoglycemic patient?

Glucagon.

Give three disease states that can cause hyperglycemia by promoting gluconeogenesis.

Diabetes mellitus, Cushing syndrome (excess cortisol), and hyperthyroidism.

How does metformin lower blood glucose?

It inhibits hepatic gluconeogenesis, primarily via activation of AMP-activated protein kinase (AMPK).

What is the mechanism of SGLT-2 inhibitor drugs?

They block renal glucose reabsorption, promoting glucose excretion in urine.

How do GLP-1 or GIP receptor agonists lower glucose levels?

By mimicking incretins to stimulate glucose-dependent insulin secretion.

What digestive enzyme is inhibited by acarbose?

Intestinal α-glucosidase, slowing carbohydrate absorption.

In glycogenesis, what is Step 1?

Glucose-6-phosphate is converted to glucose-1-phosphate by phosphoglucomutase.

In glycogenesis, what is Step 2?

Glucose-1-phosphate reacts with UTP to form UDP-glucose via UDP-glucose pyrophosphorylase.

In glycogenesis, what is Step 3?

Glycogenin autoglucosylates to create a short primer chain (≈8 residues).

In glycogenesis, what is Step 4?

Glycogen synthase elongates the chain with α(1→4) linkages.

In glycogenesis, what is Step 5?

The branching enzyme forms α(1→6) branches every 8–12 residues.

During glycogenolysis, what is Step 1?

Glycogen phosphorylase cleaves α(1→4) bonds, releasing glucose-1-phosphate.

During glycogenolysis, what is Step 2?

Debranching enzyme transfers three residues and hydrolyzes the α(1→6) branch point.

During glycogenolysis, what is Step 3?

Phosphoglucomutase converts glucose-1-phosphate to glucose-6-phosphate.

What is Step 4 of glycogenolysis, and in which organ does it occur?

Glucose-6-phosphatase converts G6P to free glucose in the liver (and kidney).

Outline Step 1 of gluconeogenesis starting from pyruvate.

Pyruvate is carboxylated to oxaloacetate by pyruvate carboxylase (biotin-dependent).

What enzyme catalyzes Step 2 of gluconeogenesis (OAA to PEP)?

Phosphoenolpyruvate carboxykinase (PEPCK).

Which reactions constitute Step 3 of gluconeogenesis?

The reversible glycolytic reactions that convert PEP to fructose-1,6-bisphosphate.

Which enzyme catalyzes Step 4 of gluconeogenesis (F-1,6-bisP to F6P)?

Fructose-1,6-bisphosphatase.

Which enzyme performs Step 5 of gluconeogenesis (G6P to glucose) and where?

Glucose-6-phosphatase in the endoplasmic reticulum of liver and kidney cells.

How frequent are branches in muscle glycogen compared with liver glycogen?

Both have branches roughly every 8–12 residues.

Which functional group at the nonreducing end of glycogen allows enzyme access?

The free 4′-hydroxyl group of the terminal glucose.

What small molecule generated during ATP depletion in muscle allosterically activates phosphorylase?

AMP.

Which protein autoglucosylates to create a primer of about eight glucose residues?

Glycogenin.

What pyrophosphate-releasing reaction activates glucose for incorporation into glycogen?

Formation of UDP-glucose from glucose-1-phosphate and UTP, releasing PPi.

Which sub-activity of the debranching enzyme is termed “transferase”?

The activity that shifts a trisaccharide from the limit branch to another chain.

Which sub-activity of the debranching enzyme is termed “α-1,6-glucosidase”?

The activity that hydrolyzes the single glucose remaining at the branch point.

What second-messenger pathway does epinephrine use in muscle to activate glycogenolysis?

The cAMP-dependent protein kinase A (PKA) pathway.

What enzyme removes phosphate groups from glycogen synthase in response to insulin?

Protein phosphatase-1 (PP1).

How does elevated intracellular calcium during muscle contraction influence glycogen breakdown?

Calcium binds calmodulin in phosphorylase kinase, activating it to turn on glycogen phosphorylase.

What is the approximate total mass of glycogen stored in a well-fed adult liver?

About 100–120 g (≈400 kcal).

What is the approximate total mass of glycogen stored in skeletal muscle of a well-trained adult?

Up to about 400 g.

During prolonged fasting, after about how many hours is liver glycogen nearly depleted?

Roughly 24 hours.

Which vitamin-derived cofactor is required by pyruvate carboxylase?

Biotin.

In what cellular compartment does pyruvate carboxylase operate?

The mitochondrial matrix.

Where inside the cell is glucose-6-phosphatase located?

In the endoplasmic reticulum membrane/lumen.

Which transport protein carries G6P into the ER lumen for dephosphorylation?

G6P translocase (T1).

Which isoenzyme of glycogen synthase is found predominantly in liver?

GYS2 (Liver Glycogen Synthase)

Which isoenzyme of glycogen phosphorylase is found predominantly in skeletal muscle?

PYGM.

What is the effect of phosphorylation on glycogen phosphorylase activity?

Phosphorylation converts it to the active a-form.

Name the kinase that phosphorylates and activates glycogen phosphorylase.

Phosphorylase kinase.

Name the phosphatase that dephosphorylates and activates glycogen synthase.

Protein phosphatase-1 (PP1).

What compound produced during epinephrine signaling activates protein kinase A?

Cyclic AMP (cAMP).

Which metabolic pathway supplies glycerol for gluconeogenesis during prolonged fasting?

Adipose tissue lipolysis of triglycerides.

What effect does cortisol have on gluconeogenesis?

It up-regulates gluconeogenic enzymes, increasing hepatic glucose production.

Which form of glycogen synthase (a or b) is the active dephosphorylated state?

The a-form (dephosphorylated) is active.

Which form of glycogen phosphorylase (a or b) is the active phosphorylated state?

The a-form (phosphorylated) is active.

What is the consequence of a glycogen branching enzyme deficiency (Andersen disease)?

Poorly branched, insoluble glycogen accumulates, causing hepatosplenomegaly and cirrhosis (GSD Type IV).

What disease is caused by glucose-6-phosphatase deficiency?

Von Gierke disease (Glycogen Storage Disease Type I).

Which enzyme deficiency leads to McArdle disease?

Muscle glycogen phosphorylase deficiency (PYGM, GSD Type V).

How is hepatic glycogen phosphorylase deficiency (Hers disease) designated?

Glycogen Storage Disease Type VI.

What analytical stain is commonly used in histology to visualize glycogen?

Periodic acid–Schiff (PAS) stain.

Which transport pathway delivers lactate from muscle to liver for gluconeogenesis?

The Cori cycle.

Which amino acid is the major donor of carbon and nitrogen to gluconeogenesis?

Alanine.

What enzyme converts glycerol to glycerol-3-phosphate?

Glycerol kinase.

Which enzyme converts glycerol-3-phosphate to dihydroxyacetone phosphate?

Glycerol-3-phosphate dehydrogenase.

How does alcohol intake inhibit gluconeogenesis?

Ethanol increases the NADH/NAD⁺ ratio, diverting pyruvate and oxaloacetate to lactate and malate, depleting gluconeogenic substrates.

What is the normal fasting range for blood glucose in mg/dL?

Approximately 70–100 mg/dL (3.9–5.6 mmol/L).

At about what blood glucose concentration do neuroglycopenic symptoms of hypoglycemia typically begin?

Around 50 mg/dL (≈2.8 mmol/L).