All the chemical reactions constantly occurring in our bodies are called metabolism. These metabolic processes supply the energy we need to move, grow, develop, and reproduce, and are used to create new organic materials. All living organisms produce energy and synthesize materials with the help of enzymes, which are made of proteins. The rate of energy production is called the basal metabolic rate, which varies by sex, race, activity level, diet, age, and diseases like sepsis or cancer. This article covers everything from basic metabolic principles to the metabolism of each nutrient and diseases caused by metabolic disorders.

1. Basic Concepts of Metabolism and the Laws of Thermodynamics

Metabolic processes are chemical reactions that occur nearly identically in all living organisms -- animals, plants, bacteria, and fungi -- regulated by proteins (enzymes) that act as catalysts under specific environmental conditions such as pH and temperature. The information for making these enzymes is stored in our DNA. DNA is composed of four bases -- adenine, guanine, cytosine, and thymine -- located within the nucleus; some organisms use RNA containing ribose and uracil instead of DNA.

In the environment, plants use sunlight to synthesize carbohydrates from water and carbon dioxide, while organisms like us do the opposite -- consuming carbohydrates and other organic materials to produce energy.

Understanding metabolism requires knowing the laws of thermodynamics, especially the first two:

"Energy cannot be created or destroyed, and the result of physical and chemical changes increases the entropy (disorder) of the entire universe."

Here, useful energy, or free energy, is energy that can do work in a state with no temperature difference, while less valuable forms of energy are released as heat.

2. Energy Production at the Cellular Level

The key molecule that transfers energy in our cells is ATP. ATP is synthesized in cellular organelles called mitochondria, which are composed of an outer and inner membrane. The splitting of water into hydrogen ions and hydroxide ions is essential for ATP synthesis.

The catabolic reactions (reactions that break down substances) in our bodies release large amounts of hydrogen ions (protons), most of which are transported to mitochondria for ATP production. These protons are carried through a series of complexes in the inner mitochondrial membrane, using energy released by the electron transport chain to activate ATPase and synthesize ATP.

The food we consume is processed in three main stages:

1. Stage 1: Digestion -- Complex molecules are broken down into simpler forms for absorption. This accounts for about 0.1% of total energy production.
2. Stage 2: Incomplete oxidation of smaller molecules -- The end products are water, carbon dioxide, and three key molecules: acetyl-CoA, oxaloacetate, and alpha-oxoglutarate. Acetyl-CoA is the most common compound.
3. Stage 3: ATP synthesis through the Krebs cycle -- Acetyl-CoA and oxaloacetate combine to form citrate, and protons released during stepwise reactions are transferred to the respiratory chain to ultimately synthesize ATP.

An imbalance between anabolism (synthesis) and catabolism (breakdown) can lead to obesity or cachexia, respectively.

3. Major Organs Involved in Metabolism

Several organs play important roles in metabolism:

• Pancreas: A key metabolic organ that regulates blood carbohydrate levels by releasing insulin to lower blood sugar or glucagon to raise it. The Randle cycle, which governs how the body uses carbohydrates and lipids, is also regulated by insulin.
• Liver: Plays a vital role in processing amino acids and lipids absorbed from the small intestine. It regulates essential metabolic processes including the urea cycle, gluconeogenesis, and glycogen deposition. The liver is essentially the body's metabolic factory.

4. Functions and Metabolic Integration of Three Major Nutrients

The three major energy sources each have unique characteristics, but their metabolism ultimately converges on a single intermediate:

• Carbohydrates: Soluble in water, relatively easy to transport, and non-toxic. They serve as substrates for energy when oxygen levels are low.
• Lipids (Fats): The most energy-dense molecules and the primary energy source for mammals and tissues. However, they don't dissolve in water, can't be used in anaerobic conditions, require more oxygen to extract energy, can't cross the blood-brain barrier, and can't be used by red blood cells or kidney cells.
• Amino acids: Primarily serve as substrates for glucose production only during prolonged starvation when glycogen stores are depleted.

The metabolism of all three converges in the mitochondria on a single molecule: acetyl-CoA.

5. Detailed Metabolism of Carbohydrates, Lipids, and Amino Acids

5.1. Carbohydrate Metabolism

Carbohydrate metabolism focuses mainly on glucose. When a cell takes up a glucose molecule, it is immediately metabolized to glucose-6-phosphate, trapping it inside the cell. This intermediate can be used in nearly all metabolic processes, including glycolysis and glycogenesis.

Carbohydrates are stored as glycogen granules for rapid glucose mobilization. The liver stores nearly 100g of glycogen (24 hours of supply), and skeletal muscles store 350g (60 minutes of muscle contraction). Carbohydrate metabolism is primarily regulated by insulin.

5.2. Lipid Metabolism

Fatty acids serve as energy production sources in oxidative tissues. The intestine absorbs fatty acids in micelle form, which are broken down and reassembled into triglycerides, then combined with proteins to form chylomicrons. The liver processes these and secretes VLDL, which is eventually reduced to LDL (forward cholesterol metabolism). When peripheral tissues have excess fat or cholesterol, HDL carries it back for excretion (reverse cholesterol metabolism). Both processes are regulated by insulin.

5.3. Amino Acid Metabolism

We consume nearly 100g of protein daily, and our bodies contain about 10kg of protein, with 300g metabolized each day. Amino acid metabolism produces ammonium, which is toxic especially to the central nervous system. It is metabolized for excretion through the urea (ornithine) cycle in the liver. Amino acid metabolism occurs through two types of chemical reactions: transamination and deamination. The primary regulators are cortisol and thyroid hormones, which mediate muscle breakdown.

6. Clinical Significance of Metabolism

6.1. Diabetes Mellitus

Insulin deficiency leads to various metabolic changes. Peripheral tissues enter a catabolic state, the liver increases glucose synthesis through gluconeogenesis and glycogenolysis, and adipose tissue increases lipolysis, leading to increased ketone body production.

6.2. Sepsis, Trauma, and Burns

Excessive inflammatory responses can trigger catabolism, characterized by upregulation of pro-inflammatory cytokines like TNF-alpha, IL-6, and IL-1. This process, called Systemic Inflammatory Response Syndrome (SIRS), unfolds in three metabolic phases: the ebb or shock phase, the catabolic phase, and the anabolic phase.

6.3. G6PDH Deficiency

This deficiency is well-distributed in equatorial regions and is an X-linked genetic disorder. It reduces NADPH levels, lowers active glutathione levels, and increases oxidative stress in red blood cells, potentially leading to hemolysis that presents as Heinz bodies and blister cells on peripheral blood smears.

Conclusion

Our body's metabolism is a complex and sophisticated process essential for providing the energy and materials needed for survival. Nutrients like carbohydrates, lipids, and amino acids pass through different pathways to converge as acetyl-CoA for ATP production, with key organs like the pancreas and liver carefully regulating these processes. However, metabolic abnormalities can lead to various diseases including diabetes, sepsis, and G6PDH deficiency. A deep understanding of metabolism is crucial for maintaining health and for preventing and treating disease.