C₂₅₇H₃₈₃N₆₅O₇₇S₆ — Insulin

Insulin is a vital peptide hormone produced by the beta cells of the islets of Langerhans in the pancreas. It plays a central role in regulating carbohydrate, fat, and protein metabolism by facilitating the uptake of glucose into cells, thus maintaining blood sugar homeostasis. The molecular formula of insulin is \(C_{257}H_{383}N_{65}O_{77}S_6\), and it is a small protein consisting of 51 amino acids arranged in two polypeptide chains (A and B) linked by disulfide bonds.

Discovered by Frederick Banting and Charles Best in 1921, insulin revolutionized the treatment of diabetes mellitus. It is now produced synthetically using recombinant DNA technology, ensuring purity and effectiveness in clinical applications.

The insulin molecule consists of two peptide chains:

• A-chain: Contains 21 amino acids.
• B-chain: Contains 30 amino acids.

The two chains are connected by two interchain disulfide bonds between cysteine residues (A7–B7 and A20–B19) and one intrachain disulfide bond within the A-chain (A6–A11).

These disulfide bonds stabilize the three-dimensional structure of the hormone, which is essential for its biological activity. The overall chemical structure can be represented as:

The presence of sulfur atoms from cysteine residues makes insulin one of the earliest studied sulfur-containing proteins.

Insulin is synthesized in the pancreatic β-cells as a single polypeptide precursor called preproinsulin. The process of biosynthesis involves several stages:

1. Preproinsulin formation: A 110-amino acid precursor synthesized in the rough endoplasmic reticulum. It includes a signal peptide, B-chain, C-peptide, and A-chain.
2. Conversion to proinsulin: The signal peptide is cleaved, forming proinsulin, which folds to form disulfide bonds.
3. Formation of mature insulin: The connecting C-peptide is enzymatically removed in the Golgi apparatus, yielding mature insulin (A and B chains) and free C-peptide, both of which are secreted into the bloodstream.

The biosynthetic process ensures precise folding and proper bond formation, crucial for biological activity.

Insulin acts through the insulin receptor (IR), a transmembrane receptor with intrinsic tyrosine kinase activity. The sequence of events is as follows:

• Insulin binds to the extracellular α-subunit of the receptor.
• This triggers autophosphorylation of the intracellular β-subunit.
• Phosphorylated receptor activates signaling cascades such as the PI3K/Akt pathway and the MAPK pathway.
• These pathways lead to increased glucose uptake via GLUT4 transporters in muscle and adipose tissues, and enhanced glycogen synthesis in the liver.

Through these actions, insulin lowers blood glucose levels and promotes anabolic processes such as lipid synthesis and protein formation.

• Carbohydrate Metabolism: Promotes glucose uptake, glycolysis, and glycogen synthesis while inhibiting gluconeogenesis.
• Lipid Metabolism: Stimulates fatty acid synthesis and storage as triglycerides; inhibits lipolysis and ketogenesis.
• Protein Metabolism: Enhances amino acid uptake and protein synthesis, reducing proteolysis.
• Cellular Growth: Supports DNA synthesis and cell proliferation by activating growth-related pathways.

Insulin thus acts as a master regulator of energy balance in the body, ensuring that nutrients are properly stored and utilized.

Therapeutic insulin preparations vary based on onset and duration of action:

• Rapid-acting insulin: Begins working within 15 minutes (e.g., insulin lispro, aspart).
• Short-acting insulin: Regular insulin with onset in 30–60 minutes.
• Intermediate-acting insulin: (e.g., NPH insulin) effective for 12–18 hours.
• Long-acting insulin: Provides steady basal levels for up to 24 hours (e.g., insulin glargine, detemir).

These synthetic analogs mimic natural insulin secretion patterns, providing flexibility in diabetes management.

• Nature: Peptide hormone with a defined tertiary structure.
• Stability: Sensitive to temperature, pH, and enzymatic degradation.
• Solubility: Soluble in aqueous solutions but precipitates under extreme conditions.
• Reactivity: Reacts with strong acids or bases, leading to denaturation.
• Isoelectric point (pI): Around 5.4, meaning it is least soluble at this pH.

In pharmaceutical formulations, stabilizers like zinc or protamine are added to control solubility and release rate.

Modern insulin used in medicine is produced through recombinant DNA technology. The process includes:

1. Inserting human insulin gene into Escherichia coli or yeast cells.
2. Allowing the microorganisms to express the insulin protein.
3. Purifying and refolding the protein to form biologically active insulin.

Earlier, insulin was extracted from bovine or porcine pancreas, but recombinant human insulin is preferred for its identical structure and reduced immunogenicity.

Disruption in insulin secretion or function leads to diabetes mellitus, classified into:

• Type 1 Diabetes: Autoimmune destruction of pancreatic β-cells leading to insulin deficiency.
• Type 2 Diabetes: Insulin resistance at the receptor or post-receptor level.
• Gestational Diabetes: Temporary insulin resistance during pregnancy.

Therapeutic administration of insulin is crucial in Type 1 diabetes and in advanced stages of Type 2 diabetes. Continuous glucose monitoring and insulin pumps are modern advancements enhancing treatment precision.