Gluconeogenesis

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Here is a complete breakdown of gluconeogenesis, drawn from Lippincott's Illustrated Reviews: Biochemistry (8th ed.) and Basic Medical Biochemistry: A Clinical Approach (6th ed.).

Gluconeogenesis

Overview

Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors. It is the body's primary mechanism for maintaining blood glucose during fasting, starvation, and prolonged exercise. Tissues that absolutely depend on glucose - the brain, erythrocytes, kidney medulla, lens and cornea, testes, and exercising skeletal muscle - cannot synthesize it on their own.

Primary site: Liver (~90% during overnight fast)
Secondary site: Kidney cortex (~10% normally; increases to ~40% after 48+ hours of fasting)
Minor contributor: Small intestine

After ~24 hours of fasting, hepatic glycogen stores are exhausted and gluconeogenesis becomes the sole source of blood glucose.

- Biochemistry, Lippincott Illustrated Reviews 8e, p. 353

Substrates (Gluconeogenic Precursors)

Precursor	Source	Entry Point
Lactate	Anaerobic glycolysis in muscle/RBCs	Converted to pyruvate (Cori cycle)
Alanine & glucogenic amino acids	Muscle protein hydrolysis	Transaminated to pyruvate or TCA intermediates
Glycerol	TAG hydrolysis in adipose tissue	Glycerol 3-phosphate → DHAP
Propionate	Odd-chain fatty acid oxidation	Succinyl-CoA → OAA

Key limitation: Acetyl-CoA and purely ketogenic amino acids (leucine and lysine) cannot serve as gluconeogenic precursors because the pyruvate dehydrogenase complex (PDH) reaction is irreversible - there is no net synthesis of OAA from acetyl-CoA.

The Three Irreversible Bypass Reactions

Gluconeogenesis uses 7 of the 10 glycolytic enzymes (running in reverse), but must bypass the 3 irreversible steps of glycolysis using 4 unique enzymes.

Bypass 1: Pyruvate → PEP (bypasses Pyruvate Kinase)

This is a two-step process spanning the mitochondria and cytosol:

Step 1 - Pyruvate Carboxylase (mitochondria)

Pyruvate + CO₂ + ATP → Oxaloacetate (OAA)
Cofactor: Biotin (covalently bound to enzyme)
Allosterically activated by acetyl-CoA (signals that energy is available but TCA is saturated)

Step 2 - PEPCK - PEP Carboxykinase (cytosol)

OAA + GTP → PEP + CO₂ + GDP
OAA cannot cross the mitochondrial membrane, so it is first reduced to malate (by mitochondrial malate dehydrogenase), transported out, then re-oxidized to OAA in the cytosol before PEPCK acts
This shuttle also transfers NADH (reducing equivalents) from mitochondria to cytosol, which is needed for a later step

Bypass 2: Fructose 1,6-bisphosphate → Fructose 6-phosphate (bypasses PFK-1)

Fructose 1,6-bisphosphatase (FBPase-1)
Fructose 1,6-bisphosphate + H₂O → Fructose 6-phosphate + Pᵢ
Inhibited by: AMP, fructose 2,6-bisphosphate
Activated by: citrate

Bypass 3: Glucose 6-phosphate → Glucose (bypasses Hexokinase/Glucokinase)

Glucose 6-phosphatase (ER membrane enzyme)
Glucose 6-phosphate + H₂O → Glucose + Pᵢ
Present in liver and kidney only (not muscle or brain, which is why they cannot export glucose)

Pathway Diagram

Gluconeogenesis pathway showing the four key enzymes unique to the pathway and entry of substrates

Gluconeogenesis pathway - the 4 unique enzymes (pyruvate carboxylase, PEPCK, FBPase-1, glucose 6-phosphatase) are highlighted in boxes. - Basic Medical Biochemistry, 6e, Fig. 28.3

Energy Cost of Gluconeogenesis

Synthesizing 1 molecule of glucose from 2 pyruvate costs:

4 ATP + 2 GTP + 2 NADH (compared to glycolysis, which yields 2 ATP)

Summary of energy requirements of gluconeogenesis with numbered unique reactions

Numbered reactions (1-4) are unique to gluconeogenesis. Red arrows show energy inputs. - Lippincott Biochemistry 8e, Fig. 10.7

This energy is supplied primarily by beta-oxidation of fatty acids in the liver during fasting.

The Cori Cycle

A key inter-organ relationship:

Exercising muscle/RBCs produce lactate via anaerobic glycolysis
Lactate travels via blood to the liver
Liver converts lactate → pyruvate → glucose
Glucose travels back to muscle/RBCs

This recycles lactate into usable glucose but transfers the metabolic burden (ATP cost) from peripheral tissues to the liver.

Regulation

Hormonal

Hormone	Effect	Mechanism
Glucagon	Stimulates ↑	Lowers fructose 2,6-bisphosphate (activates FBPase-1); phosphorylates/inactivates pyruvate kinase; increases PEPCK transcription via CREB
Insulin	Inhibits ↓	Increases fructose 2,6-bisphosphate (inhibits FBPase-1); decreases PEPCK gene expression
Cortisol	Stimulates ↑	Mobilizes amino acids from muscle protein; increases PEPCK gene expression
Epinephrine	Stimulates ↑	Similar cAMP-mediated mechanism to glucagon

Allosteric

Effector	Target	Effect
Acetyl-CoA	Pyruvate carboxylase	Activates (signals excess fatty acid oxidation)
Acetyl-CoA	PDH kinase	Activates → inhibits PDH → diverts pyruvate toward gluconeogenesis
AMP	FBPase-1	Inhibits (reciprocal with PFK-1 activation by AMP)
Fructose 2,6-bisphosphate	FBPase-1	Inhibits
Citrate	FBPase-1	Activates

Substrate Availability

Decreased insulin during fasting promotes muscle protein catabolism, flooding the liver with glucogenic amino acids. Fatty acid oxidation provides the ATP and NADH required for gluconeogenesis to proceed.

Clinical Relevance

Condition	Connection
Type 2 diabetes	Hepatic gluconeogenesis is inappropriately elevated, contributing to fasting hyperglycemia
Metformin (first-line T2DM drug)	Inhibits Complex I of mitochondrial ETC → raises AMP/ATP ratio → activates AMPK → inhibits gluconeogenesis
Biotin deficiency	Impairs pyruvate carboxylase → hypoglycemia
Deficiency of FBPase-1 or glucose 6-phosphatase	Severe fasting hypoglycemia
Glucagonoma	Excess glucagon → uncontrolled gluconeogenesis → hyperglycemia
DKA	Excess glucagon + cortisol drive gluconeogenesis, worsening hyperglycemia alongside ketogenesis
Alcohol intoxication	Ethanol oxidation generates excess NADH → depletes OAA and pyruvate → impairs gluconeogenesis → hypoglycemia

Summary Table: Glycolysis vs. Gluconeogenesis Bypass Points

Glycolysis Enzyme	Direction	Gluconeogenesis Bypass
Pyruvate kinase	PEP → Pyruvate	Pyruvate carboxylase + PEPCK
PFK-1	F6P → F1,6bP	Fructose 1,6-bisphosphatase
Hexokinase/Glucokinase	Glucose → G6P	Glucose 6-phosphatase

Sources: Biochemistry, Lippincott Illustrated Reviews 8e; Basic Medical Biochemistry: A Clinical Approach 6e; Guyton and Hall Textbook of Medical Physiology

Circle of wilis

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Here is a comprehensive overview of the Circle of Willis, sourced from Neuroanatomy through Clinical Cases (3rd ed.), Medical Physiology, and Robbins Pathology.

Circle of Willis (Circulus Arteriosus Cerebri)

Overview

The Circle of Willis is an anastomotic ring of arteries located at the base of the brain, sitting in the subarachnoid space around the optic chiasm and the interpeduncular fossa. It connects the two major arterial systems supplying the brain:

Anterior circulation - from the bilateral internal carotid arteries (ICAs)
Posterior circulation - from the bilateral vertebral arteries (which join to form the basilar artery)

Its primary function is to provide collateral blood flow - if one vessel is occluded, blood can be rerouted through the ring to maintain perfusion. However, a complete, full-caliber ring is present in only approximately 34% of individuals; anatomical variants are the norm rather than the exception.

- Neuroanatomy through Clinical Cases, 3rd ed., p. 417

Diagram: Full Arterial Supply from Aorta to Circle of Willis

Full arterial supply diagram from aorta through vertebral and carotid arteries to the Circle of Willis, showing all named vessels

Vascular anatomy showing origin of anterior and posterior circulations - Medical Physiology

Components of the Circle of Willis

The circle is made up of 7 arteries arranged as an irregular heptagon around the base of the brain:

Anterior Part (from Internal Carotid Arteries)

Vessel	Origin	Contribution
Anterior cerebral arteries (ACA) x2	Terminal branches of ICA	Forms the anterior limbs of the ring
Anterior communicating artery (AComm) x1	Connects the two ACAs	Closes the anterior portion of the ring
Middle cerebral arteries (MCA) x2	Terminal branches of ICA	Not part of the ring itself; arise from the ICA at its bifurcation point
Internal carotid arteries (ICA) x2	Common carotid → ICA	Supply the lateral portions of the ring

Posterior Part (from Vertebrobasilar System)

Vessel	Origin	Contribution
Posterior cerebral arteries (PCA) x2	Terminal branches of basilar artery	Forms the posterior limbs of the ring
Posterior communicating arteries (PComm) x2	Connect ICA to PCA	Bridges the anterior and posterior circulations - the "communicators"

The AComm and the two PComms are the three communicating arteries of the circle - they are the segments that allow collateral flow between the two sides and between the anterior and posterior circulations.

Detailed Anatomy Diagram (Inferior View)

Circle of Willis and its main branches as seen from below the brain, with all vessels labeled including ACA, MCA, PCA, PComm, AComm, basilar artery, vertebral arteries, and cranial nerves III and VI

Circle of Willis and its main branches - inferior view of the brain. Note the relationship of CN III to the posterior communicating artery - Neuroanatomy through Clinical Cases, 3rd ed., Fig. 10.3

Feeding Vessels

Anterior circulation pathway: Aorta → Brachiocephalic/Common carotid → Internal carotid artery → bifurcates into ACA + MCA

Posterior circulation pathway: Aorta → Subclavian → Vertebral arteries (ascend through foramina transversaria of C1-C6) → enter foramen magnum → converge to form basilar artery → bifurcates at the pontomesencephalic junction into bilateral PCAs

Vascular Territories of the Three Main Cerebral Arteries

Three views of the brain showing vascular territories in color - blue for ACA, yellow for MCA, pink for PCA; lateral, medial, and inferior views

Cortical territories of ACA (blue), MCA (yellow/gold), and PCA (pink) - Neuroanatomy through Clinical Cases, 3rd ed., Fig. 10.5

Artery	Territory	Key Clinical Deficit if Occluded
ACA	Medial frontal & parietal cortex, anterior corpus callosum	Contralateral leg weakness/sensory loss (medial homunculus)
MCA	Lateral cortex (frontal, parietal, temporal), internal capsule via lenticulostriate branches	Contralateral face + arm weakness, aphasia (dominant), neglect (non-dominant)
PCA	Occipital lobe, medial temporal lobe, thalamus	Contralateral homonymous hemianopia, memory deficits

Deep Penetrating Branches

Arising near the circle of Willis are small perforating arteries that supply deep structures:

Lenticulostriate arteries (from MCA) - supply basal ganglia, putamen, internal capsule
Anterior choroidal artery (from ICA) - supplies posterior limb of internal capsule, hippocampus, choroid plexus
Thalamoperforating arteries (from PCA/PComm) - supply thalamus

These small vessels are prone to hypertensive lacunar strokes.

Clinical Significance

1. Berry (Saccular) Aneurysms

The branch points of the Circle of Willis are the most common sites for intracranial saccular aneurysms, due to congenital deficiency of the elastic lamina at arterial bifurcations.

Common locations (in order of frequency):

AComm / ACA junction (most common, ~35%)
ICA / PComm junction (~30%) - classically causes CN III palsy due to compression of the nerve running adjacent to PComm
MCA bifurcation in the Sylvian fissure (~20%)
Basilar tip (~5-10%)

Rupture → subarachnoid hemorrhage (SAH) → "worst headache of life," meningismus, xanthochromia on LP

2. Stroke and Occlusion Syndromes

Occlusion at or near the circle produces predictable deficits based on the territory involved (see table above). The completeness of the circle determines how much collateral compensation is possible.

3. CN III Palsy - "Surgical Third Nerve Palsy"

A PComm aneurysm expands and compresses CN III as it runs parallel to it. This produces:

Ptosis
"Down and out" eye position
Dilated, unreactive (blown) pupil - the hallmark that distinguishes compressive (surgical) from ischemic (medical) CN III palsy

4. Anatomical Variations

Only ~34% of people have a complete ring. Common variants:

Hypoplastic or absent PComm (most common, ~20%) - reduces posterior-anterior collateral capacity
Fetal-type PCA - PCA arises directly from ICA rather than basilar (present in ~20-30%) - means PCA territory becomes vulnerable if ICA is occluded

5. Collateral Flow

If the ICA is gradually occluded (e.g., atherosclerosis), a complete Circle of Willis allows the contralateral ICA or the vertebrobasilar system to compensate via the communicating arteries, potentially preventing stroke.

Sources: Neuroanatomy through Clinical Cases 3rd ed.; Medical Physiology (Boron & Boulpaep); Robbins Pathologic Basis of Disease

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