A 51-amino-acid peptide hormone consisting of two chains (A: 21aa, B: 30aa) linked by 3 disulfide bonds. The first protein ever sequenced (Sanger, 1951), first genetically engineered drug (1978), and the most important hormone in metabolic medicine.
Insulin is a peptide hormone produced by the beta cells of the pancreatic islets of Langerhans. It is the body's primary anabolic hormone, responsible for facilitating glucose uptake from the blood into cells, promoting glycogen synthesis, stimulating protein synthesis, and inhibiting lipolysis (fat breakdown).
Insulin's discovery in 1921 by Banting and Best (Nobel Prize 1923) transformed Type 1 diabetes from a death sentence into a manageable condition. Frederick Sanger's complete sequencing of insulin's amino acid structure (Nobel Prize 1958) was a landmark in biochemistry — it proved that proteins have defined sequences, not random arrangements.
Insulin binds to the insulin receptor, a receptor tyrosine kinase (RTK) — one of only a few peptide hormones that signal through RTKs rather than GPCRs. Binding to the α-subunit triggers autophosphorylation of the β-subunit, recruiting IRS proteins that activate the PI3K-Akt pathway. Akt phosphorylates multiple targets, most importantly triggering GLUT4 vesicle translocation to the cell membrane, allowing glucose to enter muscle and fat cells.
| Pathway | Effect | Significance |
|---|---|---|
| GLUT4 translocation | Akt → AS160 → GLUT4 vesicle fusion with membrane | Primary mechanism for glucose uptake in muscle/adipose |
| Glycogen synthesis | Akt → GSK3 inhibition → glycogen synthase activation | Stores glucose as glycogen in liver and muscle |
| Protein synthesis | Akt → mTOR activation → ribosomal protein translation | Anabolic effect — promotes muscle protein synthesis |
| Lipogenesis | Activates SREBP-1c → fatty acid synthesis genes | Promotes fat storage; inhibits lipolysis |
| Gene expression | MAPK pathway activation → cell growth and differentiation | Long-term metabolic programming |
| Study | Design | Findings | Level |
|---|---|---|---|
| Type 1 diabetes | 100+ years clinical use | Exogenous insulin is essential for survival in T1D; multiple analogs optimize pharmacokinetics | Level I (standard of care) |
| Type 2 diabetes | Extensive RCTs | Insulin therapy when oral agents insufficient; basal-bolus regimens optimize control | Level I |
| Diabetic ketoacidosis | Standard of care | IV insulin is the definitive treatment for DKA | Level I |
| Insulin analogs | RNCT comparisons | Rapid (lispro, aspart), long-acting (glargine, detemir, degludec) improve glycemic control vs regular insulin | Level I |
Hypoglycemia: The most common and dangerous side effect. Occurs when insulin dose exceeds glucose needs. Can cause confusion, seizures, coma, and death. Requires glucose monitoring.
Weight gain: Insulin promotes fat storage. Patients starting insulin therapy often gain weight, which can worsen insulin resistance in T2D.
Lipodystrophy: Repeated injection at the same site can cause lipoatrophy (fat loss) or lipohypertrophy (fat accumulation). Injection site rotation is essential.
Hypokalemia: Insulin drives potassium into cells. In DKA treatment, potassium supplementation is critical to prevent cardiac arrhythmias.
| Jurisdiction | Status |
|---|---|
| FDA | Approved: Multiple analogs (Humalog, NovoLog, Lantus, Levemir, Tresiba, Fiasp, etc.) |
| WHO | Essential Medicine |
| History | First genetically engineered drug (recombinant human insulin, Humulin, 1982) |