Before 1922: diabetes was a death sentence
Before insulin, a diagnosis of type 1 diabetes, especially in children, meant death within months. The only treatment was the Allen starvation diet: eating so few calories that the body would not have enough glucose to develop ketoacidosis. Patients survived a few months longer, literally wasting away on 500–800 kcal a day, until exhaustion or infection finished what diabetes had started.
In January 1922, Leonard Thompson, a 14-year-old boy gravely ill with diabetes in Toronto, received the first injection of pancreatic extract. That first, still impure extract had little effect. On 23 January he received the preparation purified by the biochemist James Collip, and within 24 hours his blood glucose fell from 520 mg/dL to about 120 mg/dL. He lived thirteen more years, long enough to see insulin turn diabetes from a terminal illness into a manageable chronic condition.
Structure: a small protein with precise architecture
Human insulin is a peptide of 51 amino acids arranged in two chains:
- A chain: 21 amino acids, with two α-helices
- B chain: 30 amino acids, with a central α-helix and a β-strand segment near the C-terminus
The two chains are joined by two interchain disulfide bridges (A7–B7 and A20–B19). The A chain also has an intrachain disulfide bridge (A6–A11). These three disulfide bridges are essential for the hormone's three-dimensional structure and biological activity; breaking any of them inactivates it.
In physiological solution, insulin exists in equilibrium between monomer (the biologically active form), dimer and hexamer (the storage form in pancreatic β cells, stabilised by two Zn²⁺ ions, each held by three histidine-B10 residues). Intermediate-acting preparations such as NPH are crystalline suspensions of insulin with protamine and zinc that dissolve slowly under the skin; rapid-acting insulins (lispro, aspart) carry changes that hinder dimer and hexamer formation.
Biosynthesis: from gene to active hormone
Insulin is made in the β cells of the islets of Langerhans in the pancreas as preproinsulin, 110 amino acids long. Maturation has three stages:
1. Preproinsulin → proinsulin. The N-terminal signal peptide (24 amino acids) steers preproinsulin into the rough endoplasmic reticulum, where it is cut off. Proinsulin (86 amino acids) then forms its three disulfide bridges with the help of chaperone proteins.
2. Proinsulin → insulin + C-peptide. In secretory granules, prohormone convertases (PC1/3 and PC2) cut out the C-peptide (31 amino acids) that links the A and B chains. Mature insulin (A and B chains joined by disulfides) and C-peptide are secreted in equal molar amounts.
3. Why C-peptide matters. Long dismissed as a functionless by-product, C-peptide has shown biological effects of its own in experimental studies, such as stimulating endothelial nitric oxide production, although its clinical relevance is still debated. Measuring it in blood is the best marker of the body's own insulin production (as opposed to injected insulin in type 1 diabetes).
The insulin receptor: a tyrosine kinase
The insulin receptor (IR) is a tetrameric receptor tyrosine kinase: two extracellular α subunits (which bind insulin) linked by disulfide bridges to two transmembrane β subunits with an intracellular tyrosine kinase domain.
When insulin binds the α subunits, it triggers a shape change that brings the kinase domains of the two β subunits together, allowing reciprocal trans-phosphorylation of tyrosine residues in their activation loops. The activated kinase then phosphorylates intracellular substrates (IRS-1, IRS-2, Shc) that switch on two main cascades:
The PI3K-Akt pathway: moves GLUT4 glucose transporters from internal vesicles to the cell membrane, so muscle and fat take up glucose. It also activates glycogen synthase (storing glucose as glycogen) and suppresses glucose production by the liver.
The MAPK-ERK pathway: promotes cell growth, differentiation and protein synthesis.
Type 1 vs type 2 diabetes: two mechanisms, one hormone
Type 1 diabetes (autoimmune): the immune system attacks and destroys the pancreatic β cells, wiping out insulin production. Without insulin, glucose cannot enter the tissues; it builds up in the blood (hyperglycaemia) while cells "starve" in a sea of glucose. The body turns to ketogenesis as an alternative: fatty acids are converted into ketone bodies, whose build-up causes potentially fatal diabetic ketoacidosis. Lifelong insulin treatment is required.
Type 2 diabetes (insulin resistance): target cells (muscle, liver, fat) respond poorly to insulin because the receptor and its signalling pathways are partly switched off. The pancreas compensates by making more insulin, and for years the expanded β-cell mass keeps blood glucose fairly controlled. When the β cells wear out from chronic overproduction, the insulin they release is no longer enough and overt hyperglycaemia appears. Abdominal obesity, chronic inflammation, endoplasmic reticulum stress and lipotoxicity all contribute.
From pig insulin to recombinant human insulin
Until 1982, all medicinal insulin was extracted from pig or cow pancreas. Pig insulin differs from human insulin in a single amino acid (B30: alanine in pigs versus threonine in humans); cow insulin differs in three. Both could provoke an immune response, and many patients developed anti-insulin antibodies that reduced its effect.
In 1982 the FDA approved the first recombinant human insulin (Humulin), made by Escherichia coli genetically engineered with the human insulin gene. For the first time a human protein was produced industrially by biotechnology, a milestone that opened the era of modern biologic drugs.
Today's designer insulins (insulin analogues) change specific points in the sequence to alter how they behave in the body. Insulin lispro swaps amino acids B28 and B29 (Pro-Lys → Lys-Pro) to hinder dimer formation, so it starts working within about 15 minutes. Insulin glargine adds two arginines to the end of the B chain (B31 and B32) and replaces Asn-A21 with Gly, so it precipitates under the skin and dissolves slowly, acting for about 24 hours.
The protein that changed medicine
Insulin is one of the few proteins you can view in Studio. Look at its two chains (A and B) and the three disulfide bridges that hold its structure together: without them, the molecule unfolds and loses its activity.
🔬 Insulin in Studio
The next article closes the neuroscience and hormones block with the molecule that regulates sleep and the biological clock: melatonin, how darkness switches it on, what it really does, and whether supplements deserve their popularity.