A scientist is trying to design a drug to modulate cellular metabolism in the treatment of obesity. Specifically, he is interested in understanding how fats are processed in adipocytes in response to different energy states. His target is a protein within these cells that catalyzes catabolism of an energy source. The products of this reaction are subsequently used in gluconeogenesis or β-oxidation. Which of the following is true of the most likely protein that is being studied by this scientist?

It is stimulated by epinephrine

It is inhibited by acetylcholine

A 10-month-old boy with a seizure disorder is brought to the physician by his mother because of a 2-day history of vomiting and lethargy. Laboratory studies show a decreased serum glucose concentration with low ketones. Further testing confirms a deficiency in an enzyme involved in fatty acid oxidation. Which of the following enzymes is most likely deficient in this patient?

Glycerol-3-phosphate dehydrogenase

You have been asked to deliver a lecture to medical students about the effects of various body hormones and neurotransmitters on the metabolism of glucose. Which of the following statements best describes the effects of sympathetic stimulation on glucose metabolism?

Epinephrine increases liver glycogenolysis.

Norepinephrine causes increased glucose absorption within the intestines.

Without epinephrine, insulin cannot act on the liver.

Peripheral tissues require epinephrine to take up glucose.

Sympathetic stimulation to alpha receptors of the pancreas increases insulin release.

A 36-year-old woman is fasting prior to a religious ceremony. Her only oral intake in the last 36 hours has been small amounts of water. The metabolic enzyme that is primarily responsible for maintaining normal blood glucose in this patient is located exclusively within the mitochondria. An increase in which of the following substances is most likely to increase the activity of this enzyme?

Oxidized nicotinamide adenine dinucleotide

Gluconeogenesis | Metabolism - OnCourse NEET-PG

Overview - The Sugar Factory

Gluconeogenesis (GNG) is the metabolic pathway that synthesizes new glucose from non-carbohydrate precursors, crucial for maintaining glucose homeostasis during fasting.
Primary Sites: Liver (major, ~90%) and kidney cortex (minor, ~10%).
Cellular Locations: Occurs in both the mitochondria and cytosol, requiring transport of intermediates between compartments.

⭐ Gluconeogenesis is NOT the simple reversal of glycolysis; it bypasses three irreversible glycolytic steps with four unique enzymes.

Substrates - The Starting Lineup

Key molecules that can be converted to pyruvate or TCA cycle intermediates:

Lactate: From anaerobic glycolysis in RBCs & muscle (Cori cycle).
Alanine: From muscle protein breakdown (Alanine-Cahill cycle).
Glycerol-3-Phosphate: From triacylglycerol (TAG) breakdown in adipose tissue.
Propionyl-CoA: From odd-chain fatty acids & certain amino acids (Val, Ile, Met, Thr).

Gluconeogenesis pathway with key enzymes and substrates

⭐ Even-chain fatty acids CANNOT yield net glucose because they are metabolized to acetyl-CoA, and the PDH complex reaction is irreversible.

Key Enzymes - The Bypass Crew

Gluconeogenesis circumvents the irreversible steps of glycolysis using four unique enzymes. These enzymes effectively "bypass" the roadblocks set by glucokinase/hexokinase, PFK-1, and pyruvate kinase.

📌 Pathway Produces Fresh Glucose

Pyruvate Carboxylase
- Location: Mitochondria
- Action: Converts pyruvate to oxaloacetate.
- $Pyruvate + CO_2 + ATP \rightarrow Oxaloacetate + ADP + P_i$
- Requires: Biotin (Vitamin B7).
PEPCK (Phosphoenolpyruvate carboxykinase)
- Location: Cytosol / Mitochondria
- Action: Converts oxaloacetate to phosphoenolpyrate (PEP).
Fructose-1,6-bisphosphatase
- Location: Cytosol
- Action: Dephosphorylates fructose-1,6-bisphosphate to fructose-6-phosphate.
Glucose-6-phosphatase
- Location: Endoplasmic Reticulum
- Action: Dephosphorylates glucose-6-phosphate to free glucose.

⭐ Glucose-6-phosphatase is only found in the endoplasmic reticulum of the liver and kidneys, allowing them to release free glucose into the blood.

Regulation - Traffic Control

Gluconeogenesis and glycolysis are reciprocally regulated. Key control points prevent wasteful futile cycles.

Regulator Type	Activators (↑ Gluconeogenesis)	Inhibitors (↓ Gluconeogenesis)
Hormonal	Glucagon, Epinephrine, Cortisol	Insulin
Allosteric	Acetyl-CoA (activates Pyruvate Carboxylase)	AMP, Fructose-2,6-bisphosphate (inhibit F-1,6-bisphosphatase)
flowchart TD

Glucagon["<b>🍕 Glucagon</b><br><span style='display:block; text-align:left; color:#555'>• Fasting state</span><span style='display:block; text-align:left; color:#555'>• ⬆️ cAMP levels</span>"]
Insulin["<b>💉 Insulin</b><br><span style='display:block; text-align:left; color:#555'>• Fed state</span><span style='display:block; text-align:left; color:#555'>• ⬆️ Tyrosine kinase</span>"]

PKA["<b>⚡ PKA</b><br><span style='display:block; text-align:left; color:#555'>• Protein Kinase A</span><span style='display:block; text-align:left; color:#555'>• Phosphorylation</span>"]
Phosphatase["<b>💧 Phosphatase</b><br><span style='display:block; text-align:left; color:#555'>• Dephosphorylation</span><span style='display:block; text-align:left; color:#555'>• Protein PP-1</span>"]

FBPase2["<b>🧬 FBPase-2</b><br><span style='display:block; text-align:left; color:#555'>• Active if phospho</span><span style='display:block; text-align:left; color:#555'>• ⬇️ F-2,6-BP</span>"]
PFK2["<b>🧬 PFK-2</b><br><span style='display:block; text-align:left; color:#555'>• Active if dephospho</span><span style='display:block; text-align:left; color:#555'>• ⬆️ F-2,6-BP</span>"]

F26BP["<b>🧪 F-2,6-BP</b><br><span style='display:block; text-align:left; color:#555'>• Potent regulator</span><span style='display:block; text-align:left; color:#555'>• Controls flux</span>"]

F16BPase["<b>✂️ F-1,6-BPase</b><br><span style='display:block; text-align:left; color:#555'>• Gluconeogenesis</span><span style='display:block; text-align:left; color:#555'>• Rate-limiting step</span>"]

GlucoNeo["<b>🍞 Gluconeogenesis</b><br><span style='display:block; text-align:left; color:#555'>• Glucose synthesis</span><span style='display:block; text-align:left; color:#555'>• Occurs in liver</span>"]

Glucagon -->|+ | PKA
PKA -->|+ | FBPase2
FBPase2 -->|⬇️| F26BP

Insulin -->|+ | Phosphatase
Phosphatase -->|+ | PFK2
PFK2 -->|⬆️| F26BP

F26BP -->|- | F16BPase
F16BPase -->|+ | GlucoNeo

style Glucagon fill:#F1FCF5, stroke:#BEF4D8, stroke-width:1.5px, rx:12, ry:12, color:#166534
style Insulin fill:#F1FCF5, stroke:#BEF4D8, stroke-width:1.5px, rx:12, ry:12, color:#166534
style PKA fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8
style Phosphatase fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8
style FBPase2 fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8
style PFK2 fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8
style F26BP fill:#FFF7ED, stroke:#FFEED5, stroke-width:1.5px, rx:12, ry:12, color:#C2410C
style F16BPase fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8
style GlucoNeo fill:#F6F5F5, stroke:#E7E6E6, stroke-width:1.5px, rx:12, ry:12, color:#525252


> ⭐ Fructose-2,6-bisphosphate is the most important allosteric regulator. It is a powerful inhibitor of gluconeogenesis (by inhibiting F-1,6-BPase) and a potent activator of glycolysis.

## Clinical Tie-ins - When GNG Fails
*   Impaired GNG manifests as severe **fasting hypoglycemia** and **lactic acidosis**, as pyruvate cannot be converted back to glucose.
*   **Inherited Enzyme Deficiencies**:
    -   **Von Gierke disease** (G6Pase def.): Presents with hepatomegaly, steatosis, and hyperuricemia.
    -   **PEPCK deficiency**: Affects a key rate-limiting step.
    -   **Fructose-1,6-bisphosphatase deficiency**: Impairs the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate.
> ⭐ Chronic alcohol consumption increases the NADH/NAD+ ratio, shunting gluconeogenic precursors (pyruvate to lactate, OAA to malate), thereby inhibiting gluconeogenesis and causing hypoglycemia.

📌 Mnemonic for key enzymes: **V**ery **P**oor **F**armer (Von Gierke, PEPCK, F-1,6-bisphosphatase).

> *   Gluconeogenesis synthesizes **new glucose** from **non-carbohydrate precursors**, mainly in the **liver**.
> *   Key substrates are **lactate** (Cori cycle), **alanine** (Cahill cycle), and **glycerol-3-phosphate**.
> *   Bypasses glycolysis's irreversible steps via **Pyruvate carboxylase**, **PEPCK**, **Fructose-1,6-bisphosphatase**, and **Glucose-6-phosphatase**.
> *   **Even-chain fatty acids cannot** yield new glucose because they produce only **acetyl-CoA**.
> *   Stimulated by **glucagon** and **cortisol**; inhibited by **insulin** and high **AMP**.
> *   **Fructose-2,6-bisphosphate** is a key allosteric **inhibitor**.