Insulin

• 1. Introduction

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  On the 30th of July 1921, in a hot Toronto laboratory, Frederick Banting and Charles Best injected an extract they called isletin into a dying diabetic dog. Within an hour, the animal's blood sugar dropped by 40 percent. The extract came from the islets of a dog whose pancreatic ducts had been tied off weeks earlier. Banting had scrawled the plan to himself before he ever owned a lab bench. Ligate the ducts, wait for the rest of the pancreas to wither, then isolate what survived. What survived was insulin, the first peptide hormone ever discovered. How did a substance measured in millionths of a gram come to govern whether the body builds itself up or breaks itself down? Why does its absence turn the blood sweet and the body starving at the same time? And how did a molecule older than animal life itself end up patented for a single dollar, brewed in bacteria, and even loaded into the venom of sea snails? The answers reach from a billion years of evolution to a 14-year-old boy's hospital bed.

• 2. The Body's Anabolic Switch

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  Insulin is the main anabolic hormone of the body, the signal that converts small molecules in the blood into large molecules inside cells. When it circulates, the liver, fat, and skeletal muscle absorb glucose and lock it away. In those tissues the glucose becomes glycogen through glycogenesis, or fats called triglycerides through lipogenesis. The liver does both at once. High concentrations of insulin also strongly inhibit the liver's own production of glucose, telling the body's furnace to stop adding fuel. Low insulin reverses every instruction. When blood insulin falls, the body shifts into widespread catabolism, breaking down its reserves, especially stored fat. This is the hormone's whole logic in miniature. Plenty means store, scarcity means spend. Insulin even tells arterial wall muscle to relax, increasing blood flow in the smallest arteries, and it pushes cells to absorb potassium from the surrounding fluid, lowering potassium in the blood plasma. Some recent medical literature has even proposed renaming it a reponic hormone, from the Latin repono, to store, arguing that its job is to conserve energy rather than build lean tissue like testosterone or growth hormone does.

• 3. A Conversation In The Blood

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  Beta cells of the pancreatic islets are exquisitely sensitive to blood sugar. When glucose rises they secrete insulin, and when glucose falls they fall silent. Their neighbors, the alpha cells, watch the beta cells and do the exact opposite. Alpha cells release glucagon when blood glucose is low and hold back when it is high. Glucagon raises blood glucose by driving glycogenolysis and gluconeogenesis in the liver. This push and pull between two hormones is the primary mechanism of glucose homeostasis. The release of insulin itself comes in two distinct phases. The first phase fires rapidly when glucose rises and lasts about 10 minutes. The second is a slow, sustained release of newly formed vesicles that peaks in 2 to 3 hours. These phases reflect different pools of insulin granules. The Readily Releasable Pool sits pressed against the plasma membrane and makes up only 0.3 to 0.7 percent of all granules. The Reserve Pool must be hauled into position first, and it empties at 6 granules per minute against the Readily Releasable Pool's 18. A weakened first-phase release may be the earliest detectable beta cell defect that predicts the onset of type 2 diabetes.

• 4. When The Signal Fails

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  Diabetes is the condition that follows when insulin activity weakens or disappears, leaving the blood flooded with sugar, a state called hyperglycaemia. In type 1 diabetes, an autoimmune reaction destroys the beta cells outright, so insulin can no longer be made or released. In type 2 diabetes the destruction is milder and is not autoimmune. Instead, amyloid accumulates in the pancreatic islets, likely disrupting their structure, while peripheral tissues grow resistant to insulin's message. Type 2 also features glucagon secretion that ignores blood glucose entirely, pouring out regardless, so sugar piles up in the blood. The damage can feed on itself. The transcription factors that switch on the insulin gene, including PDX1, NeuroD1, and MafA, can have their binding capacities destroyed by sustained high glucose, partly through oxidative stress, which then lowers insulin output further. Too much insulin causes the mirror-image emergency. Hypoglycemia, or low blood sugar, brings clumsiness, confusion, sweating, seizures, and even death, and its most common cause is the very medications used to treat diabetes. Metabolic syndrome, first called syndrome X by Gerald Reaven, links insulin resistance to high blood pressure, disturbed blood lipids, and a widening waist.

• 5. Fifty One Amino Acids

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  The human insulin protein is built from exactly 51 amino acids and weighs 5808 daltons, a structure that surprised early scientists who assumed hormones would be tiny chemical molecules. It is a heterodimer of an A-chain of 21 amino acids and a B-chain of 30, lashed together by disulfide bonds at the cysteine positions A7-B7 and A20-B19, with a third bond inside the A-chain between positions A6 and A11. The molecular formula reads C257H383N65O77S6. Insulin's sequence is fiercely conserved across species. Bovine insulin differs from the human form in only three amino acid residues and porcine in just one, which is why porcine insulin treated type 1 diabetics before recombinant human insulin could be mass-produced. The body stores insulin not as a single molecule but as a hexamer, six molecules clustered into three dimeric units around zinc atoms held on an axis of symmetry by three histidine residues at position B10. The hexamer is stable and inert, a way of keeping a reactive protein safe yet ready. The monomer is the active, fast-acting form, and because diffusion runs faster for smaller particles, converting hexamers to monomers is one of the central problems of designing injectable insulin. A faster drug means an injection no longer has to precede a meal by hours.

• 6. Older Than Animals

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  Insulin may have originated more than a billion years ago, reaching back to the simplest single-celled eukaryotes. Insulin-like proteins exist not only in animals but in fungi and protists, and even in some invertebrates the sequence stays close enough to the human version to produce similar physiological effects. Most vertebrates make insulin in the beta cells of the pancreatic islets, while some teleost fish use a structure called the Brockmann body. The molecule has also been turned into a weapon. The venomous cone snails Conus geographus and Conus tulipa, which hunt small fish, lace their venom with modified insulin. That insulin toxin is built closer to the structure of fish insulin than to the snails' own, and it disables prey by crashing their blood glucose. Insulin even appears inside the brain, where it enhances learning and verbal memory, and where reduced levels are linked to Alzheimer's disease. Intranasal insulin sharpens the body's thermoregulatory and glucoregulatory response to food, hinting that insulin in the central nervous system helps coordinate a wide range of regulatory processes.

• 7. Coined Before It Was Caught

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  The word insulin was coined in 1916 by Edward Albert Sharpey-Schafer, for a hypothetical molecule he believed the islets of Langerhans produced to control glucose, drawing on the Latin insula for island. He did not know that Jean de Meyer had introduced the nearly identical word insuline in 1909 for the same idea. The trail of discovery ran for half a century before the name found its substance. In 1869 Paul Langerhans, a medical student in Berlin, spotted scattered clumps of unfamiliar cells in the pancreas that would later bear his name. In 1889 Oskar Minkowski and Joseph von Mering removed a healthy dog's pancreas and found sugar in its urine, the first proof linking the pancreas to diabetes. In 1901 Eugene Lindsay Opie narrowed the source to the islets themselves. Others came tantalizingly close. Nicolae Paulescu produced a pancreatic extract that normalized a diabetic dog's blood sugar, publishing his Bucharest research in 1921, only to have World War I and later the Nobel committee pass him by. The physiologist Ian Murray spent years trying to correct what he called the historical wrong done to Paulescu.

• 8. One Dollar And A Nobel Prize

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  Charles Best won his place in history on a coin toss. When John Macleod offered Banting two undergraduate assistants for the summer, Banting needed only one, so Best and Clark Noble flipped a coin and Best won the first shift, which became the whole summer. By December 1921 the team had extracted insulin from adult cow pancreas, and Macleod brought in the biochemist James Collip to purify it. On the 11th of January 1922-14-year-old Leonard Thompson, dying at Toronto General Hospital, received the first injection, but the extract was so impure he suffered a severe allergic reaction. Collip worked day and night for 12 days, and a second dose on the 23rd of January cleared the sugar from Thompson's urine with no obvious side effects. The first American patient was Elizabeth Hughes, daughter of the U.S. Secretary of State. Rather than profit, the discoverers assigned the patent to the University of Toronto's Board of Governors on the 15th of January 1923 for one dollar, so that no one could secure a monopoly. The 1923 Nobel Prize in Physiology or Medicine went to Banting and Macleod. An incensed Banting shared his half with Best, and Macleod shared his with Collip. Two more Nobel Prizes followed insulin's story. Frederick Sanger took the 1958 Chemistry prize for sequencing it, the first protein ever fully sequenced, and Rosalyn Sussman Yalow won in 1977 for the radioimmunoassay that measures it. In 1978 Arthur Riggs and Keiichi Itakura made the first recombinant human insulin in E. coli, and in 1982 it went on sale as Humulin, beginning the era when most of the world's insulin would be grown, not extracted.