Chemical Identity

Property	Value
Name	Insulin
Source	Pancreatic β-cells (islets of Langerhans)
Structure	Heterodimer: A-chain (21 aa) + B-chain (30 aa)
A-chain sequence	GIVEQCCTSICSLYQLENYCN
B-chain sequence	FVNQHLCGSHLVEALYLVCGERGFFYTPKT
Chemical Formula	C₂₅₇H₃₈₃N₆₅O₇₇S₆
Molecular Weight	5808 Da
Disulfide Bonds	2 intra-chain (A6-A11, A7-B7), 1 inter-chain (A20-B19)
PDB Structures	4INS (hexamer), 1ZNI (T6 state)
Isoelectric Point	5.4 (A-chain), 6.9 (B-chain)

Discovery

Insulin was discovered by Frederick Banting and Charles Best in 1921, purified by James Collip, and first administered to a human patient in 1922. Banting and Macleod received the Nobel Prize in Physiology or Medicine in 1923.

The amino acid sequence was determined by Frederick Sanger in 1951 (Nobel Prize 1958), and the 3D structure was solved by Dorothy Hodgkin in 1969 (Nobel Prize 1964).

Biosynthesis

Pathway

1. Preproinsulin (110 aa) → Signal peptide cleavage → Proinsulin
2. Proinsulin (86 aa) → Prohormone convertases (PC1/3, PC2) → Insulin + C-peptide
3. Storage: Zinc-coordinated hexamers in secretory granules
4. Secretion: Glucose-stimulated exocytosis

Regulation

• Stimulators: Glucose, amino acids, GLP-1, GIP, acetylcholine
• Inhibitors: Somatostatin, epinephrine, norepinephrine, GABA

Receptor and Signaling

Insulin Receptor (IR)

• Type: Receptor tyrosine kinase (RTK)
• Structure: Heterotetramer (α₂β₂)
• Isoforms: IR-A (fetal), IR-B (metabolic)
• Ligands: Insulin (Kd ~0.1 nM), IGF-1 (Kd ~1 nM)

Signal Transduction

Insulin → IR autophosphorylation → IRS-1/2 phosphorylation
                                    ↓
                    PI3K → PIP₃ → PDK1 → AKT
                                    ↓
                              GLUT4 translocation
                              Glycogen synthesis
                              Lipogenesis
                              Protein synthesis

Physiological Effects

Carbohydrate Metabolism

• Glucose uptake: Translocates GLUT4 to cell surface (muscle, adipose)
• Glycogenesis: Activates glycogen synthase
• Gluconeogenesis: Inhibits hepatic glucose production
• Glycolysis: Stimulates glucose oxidation

Lipid Metabolism

• Lipogenesis: Stimulates fatty acid synthesis
• Lipolysis: Inhibits hormone-sensitive lipase
• Ketogenesis: Inhibits ketone body production

Protein Metabolism

• Amino acid uptake: Increases membrane transport
• Protein synthesis: Activates mTOR/S6K pathway
• Proteolysis: Inhibits protein degradation

Clinical Applications

Diabetes Mellitus

Type	Mechanism	Insulin Deficiency
Type 1	Autoimmune β-cell destruction	Absolute
Type 2	Insulin resistance + progressive β-cell failure	Relative
Gestational	Placental hormones cause resistance	Variable
Monogenic	Single gene mutations (MODY)	Variable

Insulin Analogs

Analog	Modification	Onset	Peak	Duration
Lispro (Humalog)	Lys(B28), Pro(B29)	15 min	1-2 h	3-4 h
Aspart (NovoLog)	Asp(B28)	10 min	1-2 h	3-4 h
Glulisine (Apidra)	Lys(B3), Glu(B29)	15 min	1-2 h	3-4 h
Glargine (Lantus)	Gly(A21), 2×Arg(B31-32)	1-2 h	Flat	24 h
Detemir (Levemir)	Lys(B29)-C12 fatty acid	1-2 h	6-8 h	18-24 h
Degludec (Tresiba)	Lys(B29)-C16 fatty acid + γGlu spacer	1-2 h	Flat	>42 h

Formulations

• Rapid-acting: Lispro, Aspart, Glulisine (prandial)
• Long-acting: Glargine, Detemir, Degludec (basal)
• Premixed: 70/30, 75/25, 50/50 combinations
• Concentrated: U-200, U-300, U-500 formulations
• Inhaled: Afrezza (technosphere insulin, inhaled powder)

Manufacturing

Recombinant Production

• E. coli: Inclusion bodies → refolding → purification
• Yeast (S. cerevisiae): Secretion pathway
• Mammalian cells: Full post-translational processing

Semi-synthetic

• From porcine insulin (identical to human except Ala(B30))
• Enzymatic transpeptidation: Porcine → Human (replace Ala with Thr)

Adverse Effects

Effect	Mechanism	Management
Hypoglycemia	Excess insulin relative to glucose	Glucose tablets, glucagon
Weight gain	Lipogenesis, reduced lipolysis	Caloric restriction, exercise
Lipodystrophy	Local tissue atrophy/hypertrophy	Site rotation
Hypokalemia	K⁺ uptake into cells	Monitor K⁺ levels
Allergic reactions	Anti-insulin antibodies	Insulin desensitization

Historical Significance

Insulin is one of the most important pharmaceutical discoveries in history:

• Before insulin (1921): Type 1 diabetes was a death sentence
• After insulin: Patients could live decades
• First biotech drug (1982): Recombinant human insulin (Humulin)
• Global market: >$25B annual revenue

References

1. Renter A, Smith LF. “Amino acid sequence of insulin.” Science 230:1365, 1985.
2. Sanger F. “The chemistry of insulin.” Science 129:1340-1344, 1959.
3. Hodgkin DC. “X-ray analysis and the structure of insulin.” Advances in Protein Chemistry 4:439-546, 1969.
4. DeFronzo RA, et al. “Insulin resistance, hyperglycemia, and coronary artery disease.” Diabetes Care 37:3170-3180, 2014.
5. American Diabetes Association. “Standards of Medical Care in Diabetes.” Diabetes Care 47:S1-S264, 2024.