Biochemistry: Carbohydrate Metabolism

Carbohydrate metabolism sits at the center of human biochemistry because it links energy production, biosynthesis, and blood glucose control. Several interconnected pathways manage the flow of carbon from dietary glucose into ATP, glycogen stores, and reducing power for anabolic reactions. These pathways are tightly regulated by hormones and by cellular energy status. When regulation fails, as in diabetes mellitus, the clinical consequences are often first seen in altered carbohydrate handling.

The central role of glucose and metabolic flexibility

Glucose is a universal fuel, but its importance goes beyond energy. It is a precursor for nucleotides, amino sugars, and lipids, and it supports redox balance through NADPH generation. Cells differ in how they use glucose. Red blood cells depend on it almost exclusively because they lack mitochondria. The brain uses glucose as a primary fuel under most conditions, though it can adapt to ketone bodies during prolonged fasting. Skeletal muscle shifts between glucose and fatty acids depending on activity and hormonal signals.

At the whole-body level, carbohydrate metabolism must balance two competing goals:

• Maintain plasma glucose in a narrow range to supply glucose-dependent tissues
• Store excess energy after meals and mobilize it during fasting and exercise

Insulin and glucagon are the dominant hormonal regulators of this balance.

Glycolysis: extracting energy from glucose

Glycolysis converts one molecule of glucose into two molecules of pyruvate in the cytosol. It provides ATP quickly and supplies intermediates for other pathways. Under aerobic conditions, pyruvate is typically converted to acetyl-CoA and enters the citric acid cycle. Under anaerobic conditions, pyruvate is reduced to lactate to regenerate NAD${}^{+}$ and keep glycolysis running.

Key control points and energetics

Glycolysis has three essentially irreversible steps that serve as regulatory checkpoints:

1. Hexokinase (or glucokinase in the liver): glucose to glucose-6-phosphate (G6P)

This traps glucose inside the cell. Hexokinase is inhibited by G6P, which prevents unnecessary phosphorylation when downstream pathways are backed up. Hepatic glucokinase has different kinetics that favor glucose uptake after meals.

1. Phosphofructokinase-1 (PFK-1): fructose-6-phosphate to fructose-1,6-bisphosphate

This is the main rate-limiting step. PFK-1 is activated by AMP and fructose-2,6-bisphosphate and inhibited by ATP and citrate, allowing the pathway to respond to both energy status and fuel abundance.

1. Pyruvate kinase: phosphoenolpyruvate to pyruvate

This step yields ATP and is regulated by energy signals and, in the liver, by hormonal control through phosphorylation.

The net yield per glucose is 2 ATP and 2 NADH (in glycolysis itself). The ultimate ATP yield depends on mitochondrial oxidation of NADH and pyruvate, which ties glycolysis to oxidative metabolism.

Clinical correlation: lactate and hypoxia

During hypoxia or intense exercise, lactate production increases because cells need to regenerate NAD${}^{+}$. Elevated lactate can also occur when oxidative metabolism is impaired. Clinically, lactate is a useful marker of tissue hypoperfusion and metabolic stress.

Gluconeogenesis: making glucose when supply is low

Gluconeogenesis synthesizes glucose primarily in the liver (and in the kidney to a lesser extent), especially during fasting. It prevents hypoglycemia by providing glucose for the brain and red blood cells.

This pathway is not simply “reverse glycolysis.” Glycolysis includes irreversible steps, so gluconeogenesis uses bypass reactions:

• Pyruvate carboxylase converts pyruvate to oxaloacetate (requires ATP and biotin).
• PEP carboxykinase (PEPCK) converts oxaloacetate to phosphoenolpyruvate (uses GTP).
• Fructose-1,6-bisphosphatase bypasses PFK-1.
• Glucose-6-phosphatase produces free glucose from G6P, a step available in liver and kidney but not in muscle, which explains why muscle glycogen cannot directly maintain blood glucose.

Regulation: reciprocal control with glycolysis

Cells avoid futile cycling by regulating glycolysis and gluconeogenesis in opposite directions. A pivotal signal is fructose-2,6-bisphosphate, which stimulates PFK-1 (promoting glycolysis) and inhibits fructose-1,6-bisphosphatase (suppressing gluconeogenesis). Hormones tune its level: insulin favors glycolysis in the fed state; glucagon favors gluconeogenesis during fasting.

Glycogen metabolism: rapid storage and mobilization

Glycogen is a branched polymer of glucose that provides a rapid-access energy reserve. The liver uses glycogen to stabilize blood glucose between meals. Skeletal muscle uses glycogen locally to support contraction.

Glycogenesis (glycogen synthesis)

When glucose is abundant, G6P is converted to glucose-1-phosphate and then activated to UDP-glucose. Glycogen synthase adds glucose units to glycogen, and a branching enzyme creates branches that increase solubility and allow rapid mobilization.

Insulin promotes glycogenesis, in part by activating glycogen synthase through dephosphorylation and by increasing glucose uptake in insulin-sensitive tissues.

Glycogenolysis (glycogen breakdown)

Glycogen phosphorylase releases glucose-1-phosphate from glycogen. Debranching enzymes handle branch points. In the liver, glucose-6-phosphatase can convert G6P to free glucose for release into the bloodstream. Muscle lacks this enzyme, so its glycogen supports only its own energy needs.

Hormonal regulation is tissue-specific:

• Glucagon stimulates hepatic glycogenolysis during fasting.
• Epinephrine stimulates glycogenolysis in both liver and muscle during stress or exercise.
• Insulin suppresses glycogen breakdown and favors storage.

The pentose phosphate pathway: NADPH and ribose production

The pentose phosphate pathway (PPP) branches from G6P and serves two primary functions:

• Generate NADPH, required for reductive biosynthesis and antioxidant defense
• Produce ribose-5-phosphate for nucleotide synthesis

The oxidative phase yields NADPH. The non-oxidative phase interconverts sugars, allowing cells to match ribose needs with glycolytic flux. NADPH is particularly important in red blood cells, where it helps maintain reduced glutathione to protect against oxidative damage.

Integrated regulation: hormones, energy charge, and tissue roles

Carbohydrate pathways are coordinated through:

• Energy charge: High ATP and citrate signal energy abundance and downregulate glycolysis; high AMP signals demand and activates glycolysis.
• Hormonal signaling: Insulin shifts metabolism toward glucose uptake, glycolysis, glycogen synthesis, and storage. Glucagon shifts metabolism toward glucose production via glycogenolysis and gluconeogenesis.
• Substrate availability: After meals, glucose flux rises; during fasting, lactate, glycerol, and amino acids become important gluconeogenic substrates.

This coordination allows the body to transition smoothly from fed to fasting states, preserving glucose for tissues that need it most.

Clinical correlations: diabetes and disrupted carbohydrate control

Diabetes mellitus is defined by chronic hyperglycemia due to impaired insulin secretion, impaired insulin action, or both. Its metabolic effects can be understood through pathway regulation:

• Reduced effective insulin signaling limits glucose uptake in insulin-sensitive tissues and reduces glycogen synthesis.
• The liver continues glucose production through glycogenolysis and gluconeogenesis when it should be suppressing output after meals.
• Persistent hyperglycemia increases osmotic load and promotes non-enzymatic glycation of proteins, contributing to long-term complications.

From a biochemical perspective, diabetes highlights why carbohydrate metabolism is as much about regulation as it is about chemistry. The same pathways that keep blood glucose stable and energy available can, when misregulated, drive disease.

Putting it into practice: thinking in pathways, not isolated reactions

A useful way to approach carbohydrate metabolism is to ask three questions in any physiologic state:

1. Is the body trying to use glucose now, store it, or make it?
2. What do insulin and glucagon signaling imply for liver versus muscle?
3. Which regulatory steps are being pushed or restrained (PFK-1, fructose-1,6-bisphosphatase, glycogen synthase, glycogen phosphorylase)?

Answering these ties glycolysis, gluconeogenesis, glycogen metabolism, and the pentose phosphate pathway into a coherent framework, and it connects the biochemistry directly to clinical patterns seen in disorders like diabetes.