In January 1922, Leonard Thompson, a 14-year-old boy in a diabetic coma in Toronto, received the first injection of purified pancreatic extract. Within 24 hours, his blood glucose fell from 520 mg/dL to near-normal levels. He survived thirteen more years — long enough to see insulin transform diabetes from a terminal disease to a manageable chronic condition.
Structure: a small protein with precise architecture
Human insulin is a 51-amino acid peptide in two chains: Chain A (21 amino acids) and Chain B (30 amino acids), connected by two disulfide bridges (A7-B7 and A20-B19). A third intracatenary disulfide bridge (A6-A11) stabilizes the A chain. These three disulfide bonds are essential for activity — reduction of any one inactivates the hormone.
The insulin receptor: a receptor tyrosine kinase
The insulin receptor (IR) is a tetrameric receptor tyrosine kinase — two extracellular α subunits (bind insulin) linked by disulfide bonds to two transmembrane β subunits with intracellular tyrosine kinase domains. Insulin binding triggers trans-phosphorylation of tyrosine residues, activating two main cascades: PI3K-Akt (GLUT4 translocation to plasma membrane → glucose uptake in muscle and adipose; glycogen synthesis; inhibition of gluconeogenesis) and MAPK-ERK (cell growth, differentiation, protein synthesis).
Type 1 vs Type 2: two mechanisms, one hormone
Type 1 (autoimmune): The immune system destroys β cells, eliminating insulin production. Without insulin, glucose cannot enter tissues → hyperglycemia while cells "starve in a sea of glucose." Fat mobilization produces ketone bodies → diabetic ketoacidosis (potentially fatal). Requires lifelong exogenous insulin.
Type 2 (insulin resistance): Target cells (muscle, liver, adipose) respond inadequately to insulin. The pancreas compensates by producing more insulin — for years β-cell hyperplasia maintains near-normal glycemia. When β cells exhaust from chronic overproduction, frank hyperglycemia appears. Visceral obesity, chronic inflammation, ER stress, and lipotoxicity contribute.