Insulin at 100: An Inspirational but Complicated History
By James S. Hirsch
The discovery of insulin promised a new age for an ancient condition but introduced unexpected challenges. James S. Hirsch explores the riveting history of this miracle drug on its 100th anniversary.
It was hailed as a miracle cure, a boon to the human race, an elixir that turned death into life and whose discovery was freighted with Biblical allusions. This year marks the one-hundredth anniversary of insulin, and the drug, first coaxed from the pancreas of dogs by unheralded scientists in a crude Canadian laboratory, remains one of the most remarkable feats in medical history.
But the history of insulin is not one of unalloyed celebration. It has moments of triumph as well as grievance. Like diabetes itself, it’s complicated.
It’s easy to lose sight of what insulin’s discovery represented in 1921. As the historian John Barry notes, the previous 2,500 years had seen virtually no progress in the treatment of patients, and the world had just emerged from the Spanish flu, which killed more than 50 million people and was ultimately subdued not by medical science but by the immune system’s adapting to the virus.
In other words, doctors in 1921 were all but impotent against any serious disease, including diabetes.
Then came insulin.
Anyone today who uses insulin does not need to be told of its life-saving power, and I am hardly an impartial observer, as it has kept me alive for the past 44 years.
Insulin today, however, bears little resemblance to what it was when I was diagnosed, let alone to what it was in its early decades. Patients then relied on imposing glass syringes whose thick needles had to be sharpened on whet stones and boiled for reuse. Nowadays, the ultrafine needles are disposable; smart insulin pens communicate with the cloud; and sleek insulin pumps are connected to continuous glucose meters. The insulin itself has been transformed – from impure concoctions derived from the smashed, blood-soaked pancreases of pigs or cows to laboratory-created, gene-splitting analogs with an array of pharmacokinetic properties. Inhalable insulin, long promised and finally delivered, represents a vaporous new-age alternative.
Research on insulin has attracted some of the world’s most brilliant scientists, as Nobel prizes have been given for insulin-related research in four separate decades. The work conducted on human insulin in the 1970s and ’80s, involving recombinant DNA, helped give birth to the modern biotechnology industry, including such pillars as Genentech and Biogen.
But there is more to this history than scientific breakthroughs and professional laurels.
Insulin has been misrepresented and misunderstood, even by some of its most important standard bearers, to the detriment of patients. For many years, the miraculous power of insulin, promoted in marketing efforts and publicity stunts, misled the public about the real-life experiences of those actually living with diabetes. In more recent years, insulin has been shunned by type 2 patients who could be using it or has been underused by type 1 patients. We are in the midst of a global diabetes epidemic, but insulin use has actually been declining because better therapies for type 2 diabetes have usurped insulin’s preeminence. And as insulin prices have soared, the insulin companies themselves, in a stunning reversal, have been transformed in some eyes from saviors to villains.
Meanwhile, the future of insulin itself is not certain, as better therapies could someday make obsolete the miracle drug of 1921.
Insulin was not technically “discovered” in 1921. Its role in the body was already known, its connection to diabetes already established.
The disease was first identified in 1500 BC, and in 250 BC, the disorder was named “diabetes” from the Greek word syphon, as its victims suffered from excessive urination. (One researcher later described diabetes as “the pissing evil.”) Researchers’ understanding of the disease advanced in 1869, when a German medical student named Paul Langerhans discovered “islands of cells” in the pancreas; and over the next three decades, investigators identified these cells as regulating glucose metabolism and directly associating them with diabetes. By 1916, the word “insulin” had been coined to describe that pancreatic substance.
But after more than 3,000 years, there was still no effective treatment for the disease. Researchers, however, did recognize that carbohydrates accelerated a patient’s decline, so the best treatment, developed in the early 1900s, was to withhold food – also known as the starvation diet, which allowed patients to extend their lives in sinister emaciation. Most of these patients were children, so grieving parents had to watch their children waste away – sometimes clustered together in hospital wards – and die either from starvation or diabetic ketoacidosis.
That made the search for insulin even more desperate, as investigators around the world sought to discover a “pancreatic extract” to save these dying children against the ravages of an ancient disease.
The breakthrough happened in Toronto in 1921, led by a prickly researcher who was a mere five years out of medical school. Frederick Banting had tried his hand as a surgeon but couldn’t earn a living, so he turned to teaching. He had no research experience and knew little about diabetes; but he had read a paper on it, and he later said that he had a dream about discovering insulin. In a longshot bid, Banting began his work in May at the University of Toronto, and he was assisted by a young medical student named Charles Best. They removed the pancreases from dogs to make them diabetic and then developed pancreatic extracts to try to lower the blood sugars. It was bloody, messy, difficult work – seven dogs died the first two weeks – but by August, one of the extracts, delivered by intravenous injections, proved successful. A biochemist, James Collip, was summoned to try to purify it for human use – he later called it “bathroom chemistry” – and on January 11, 1922, a 14-year-old boy, Leonard Thompson, received the first injection of insulin.
It was described as a “murky, light brown liquid containing much sediment,” it was given to him over several weeks, and it worked: the sugar and ketones in the boy’s urine disappeared.
“Diabetes, Dread Disease, Yields to New Gland Cure,” the New York Times announced.
The Toronto researchers couldn’t mass produce insulin, but Eli Lilly could, at least in the United States. (Other companies did in Europe.) Eli Lilly is headquartered in Indianapolis and, at the time, was in convenient proximity to many stockyards. The company stored a million pounds of frozen pancreases from pigs and cows to keep up with demand – there were an estimated one million Americans who needed insulin – and the company’s scientists, managers, and laborers were every bit the heroes as the Toronto researchers.
This new miracle drug did not disappoint.
Frederick Allen, one of America’s leading diabetologists, said his patients, upon receiving insulin, “looked like an old Flemish painter’s depiction of a resurrection after famine. It was a resurrection, a crawling stirring, as of some vague springtime.”
Elliott Joslin, America’s preeminent diabetes clinician, described his patients who took insulin as the “erstwhile dead” and invoked Ezekiel’s vision of the valley of the dry bones, in which God says, “Come from the four winds, O breath, and breathe upon these slain, that they may live.”
The photographs told an even more dramatic story: In one famous picture, a naked 3-year-old boy who weighs 15 pounds clings to his mother, his face grimacing, his ribs exposed. After taking insulin for only three months, a head shot shows the boy with full cheeks, alert brown eyes, and dark locks of hair. He looks normal – and cured.
If there were any doubt about insulin’s curative powers, Elizabeth Evans Hughes removed them. Her father, Charles Evans Hughes, had been the governor of New York, a justice on the U.S. Supreme Court, a candidate for president, and in 1922, was the U.S. Secretary of State. Elizabeth had been diagnosed with diabetes in 1919, so when she took her first dose of insulin in 1922, she became the poster child for this new drug.
“Hughes’ Daughter ‘Cured’ of Diabetes” declared one unidentified newspaper. After more than three millennia, it appeared that medical science had defeated diabetes.
The discovery of insulin in 1921 was heralded as the cure for diabetes. The reality was different.
Insulin, to be sure, could temporarily lower blood sugars to near-normal ranges, but it could also cause hypoglycemia – blood sugars that are too low – that could lead to shakiness and confusion or, in extreme cases, seizures, loss of consciousness, or death. Insulin was a daily, self-administered drug, but if used incorrectly, it could kill a patient just as well as it could save a patient. No self-administered therapy, before or since, has quite those same attributes.
What’s more, insulin’s therapeutic powers were overestimated. Yes, insulin lowered blood sugars, but maintaining near-normal levels was still very difficult – and elevated blood glucose over time was still dangerous. As a result, by the middle of the 1930s, patients who were taking insulin began developing serious complications caused by elevated glucose levels, including damage to the eyes, kidneys, nerves, and heart. Insulin hadn’t cured anything but had turned diabetes from a deadly condition into a chronic condition, and a perilous one at that. At the dawn of the insulin age and for many decades thereafter, even those who understood the importance of maintaining near-normal blood sugars did not have the tools to do so. Blood sugar levels were measured by proxy through urine tests, in which samples had to be boiled for three minutes. Simpler methods were developed by the 1940s, but home glucose monitoring was not available until the late 1970s.
Until then, patients – unaware of their blood sugar levels – gave themselves insulin doses flying blind.
But few people outside the diabetes world knew about the daily rigors and risks of the disease – not only because it affected a relatively small percentage of people but also because the insulin narrative was too powerful.
Diabetes, after all, had been cured or at least resolved. That’s what all the pictures showed. That’s what the headlines blared. And that’s what the ads promoted.
Eli Lilly’s ads, for example, initially touted insulin as “An Epoch in the History of Medicine” and later featured a beautiful bride on her wedding day, kissing her beaming father, with the tagline, “Our favorite picture of insulin.”
Even that picture paled in comparison to the astonishing newspaper and magazine stories about insulin, and not just those about Elizabeth Evans Hughes. Insulin was a redemptive tale about science and survival.
Eva and Victor Saxl were Czech immigrants who fled to Shanghai during World War II. There, Eva was diagnosed with diabetes, and when her insulin supplies ran short, Victor, a textile engineer, found a book that described how to make insulin and, using the animal organs from a nearby slaughterhouse, brewed up enough insulin for his wife to survive. After the war, they immigrated to the United States, and when their story was discovered, they soon found themselves on numerous radio and television shows, including Edward R. Murrow’s, and a movie was also produced – about a husband’s devotion to his wife, expressed through the salvation of insulin.
Other life-saving medical breakthroughs occurred – antibiotics in the 1940s, the polio vaccine in the 1950s – and these would treat more people than insulin. But the unique circumstances of insulin’s discovery, with the young, untested scientists finding the potion that would bring children back from the brink of death, was too dramatic to ignore. In 1988, that story was the subject of a television movie on Masterpiece Theater called “Glory Enough for All,” based on Michael Bliss’s definitive book, “The Discovery of Insulin.”
I watched the movie on PBS when it was released, and it featured the brawling Toronto researchers – Banting and Collip literally came to blows over control of the experiments. But ultimately, the movie was about the triumph of medical science in saving dying children, and among the researchers, there was “glory enough for all.”
And then the movie ended.
There was nothing about living with diabetes – about the wildly fluctuating blood sugars, about the relentless demands, about the injections and the doctor visits and the complications, about the dietary restrictions, about the stigma and the isolation and the limitations of insulin.
“Glory Enough for All” was introduced by Alistair Cooke. An American-born Brit with a silver tongue, Cooke was enthralled not only by insulin’s inspirational story but also by the phrase “islets of Langerhans,” used to describe the island of pancreatic cells discovered by Paul Langerhans. “Islets of Langerhans” just rolled off Alistair Cooke’s tongue. To him, insulin was not just a miracle. It was poetry.
The lyrical beauty of insulin was lost on patients. Many of them, in fact, were frustrated that their own stories weren’t being heard. The parents of young patients were frustrated as well.
In 1970, a professional singer in Philadelphia, Lee Ducat, had a 10-year-old boy with type 1 diabetes, and she was miffed by the breezy disregard of his doctor, who told her that “insulin was the cure.” Ducat knew that wasn’t true, so with several other parents, she formed the first chapter of the Juvenile Diabetes Foundation (which is now the JDRF). Other parents soon opened chapters in New York, Washington, New Jersey, and Miami, and their mission was to educate the public about the stark challenges of diabetes in hopes of raising money and finding a cure.
They had no use for the American Diabetes Association, which was founded in 1940 and for many years was little more than a social club and referral service for physicians. As far as the parents were concerned, the ADA was complicit in perpetuating the jaunty insulin narrative that had hurt the cause for decades. Unless the truth about diabetes was known, how could lawmakers, regulators, philanthropists, and journalists – not to mention clinicians – do what had to be done to improve the lives of people with diabetes?
That question was driven home when the JDF chapter in Miami bought a full-page newspaper ad in 1972 to publicize its cause. The ad featured a little boy in a crib holding a glass syringe, and it described the many complications that could arise from diabetes, including blindness and amputations. The headline read, “The Quiet Killer.”
On the day the ad appeared, Marge Kleiman, whose son has type 1, was working in the JDF office, and the phone rang.
“I’m Charles Best,” the caller said, “and I discovered insulin.”
Now retired, Best had become an icon who, after Fred Banting died in 1941, carried the mantle for the Nobel-winning team that had discovered insulin. Best had been praised by the pope, the queen of England, and other heads of state, and he had given the keynote address at the ADA’s first meeting and later served as its president. He happened to be in Miami on the day the JDF ad appeared, and he was outraged.
“What kind of propaganda are you using?” he screamed. “You’re frightening people! This is not the way it is!”
Kleiman knew better. “Dr. Best, what you did was wonderful,” she said. “It allowed people to live longer. But we’re not trying to frighten people. If you tell the truth, maybe they can avoid these complications. Please don’t tell us to keep quiet.”
The JDRF, now a massive international organization focused primarily on type 1, has continued to tell the truth about diabetes – and fund research – ever since, but changing the insulin narrative was not going to be easy.
Patients could at least take solace that the insulins kept getting better. The first extended-action insulins were introduced in 1936 and continued with widely used NPH insulin (1946) and the Lente insulins (1951). But the real improvement came in the 1970s, spurred by concerns about actual insulin supply. Meat consumption was declining, and slaughterhouses were cutting production, while the number of people with diabetes had been rising steadily (in 1976, there were about 5 million Americans with the disease). At some point, insulin demand could outstrip the animal-based supply.
As described in the book Invisible Frontiers: The Race to Synthesize a Human Gene, by Stephen S. Hall and James D. Watson, the specter of an insulin shortage triggered a race to develop genetically engineered insulin using recombinant DNA technology. Investigators succeeded by inserting the insulin gene into bacteria, which produced insulin that was chemically identical to its naturally produced counterpart.
The first human insulins, Humulin (made by Eli Lilly) and Novolin (made by Novo Nordisk), were introduced in the 1980s. Whether they were superior to animal-based insulins is a matter of debate, but they alleviated fears about an impending global insulin shortage.
Moreover, researchers soon discovered that changing the order of two amino acids in the human insulin molecule created a faster-acting formulation, and that led to the introduction of Humalog (1996) and Novolog (1999). Known as “insulin analogs” because they are more analogous to the body’s natural release of insulin, they were considered clear advancements. Another huge leap came with long-lasting basal insulin analogs, specifically Lantus (by Sanofi in 2000) and Levemir (by Novo Nordisk in 2005). These insulins keep blood sugar levels consistent during periods of fasting and, typically taken once a day, replicate the insulin release of a healthy pancreas. They were immensely popular and also used by many type 2 patients – Lantus was a $5 billion a year drug by 2011.
The improved insulins changed how patients cared for themselves, as the new formulations led to “basal-bolus” therapy – a 24-hour insulin complemented by a mealtime insulin – and that became the standard of care for type 1 diabetes. (Insulin pumps use the same basal-bolus framework.)
A new era of diabetes care, thanks to these insulin breakthroughs, appeared to beckon.
As further refinements in insulin occurred, the insulin narrative should have become even more powerful – that insulin not only saves people, but in reaching new pharmacological heights, it is allowing patients to live healthier, better, and more productive lives. These should be insulin’s glory days – as well as days of unprecedented commercial opportunity. According to the International Diabetes Federation, in 2019, the global population of people with diabetes had increased a staggering 63 percent in just nine years – to 463 million patients.
Insulin sales should be booming, with a new generation of Elizabeth Evans Hughes and Eva Saxls to tell the story. In fact, insulin sales are declining, and insulin has no spokespeople. Reasons vary for these developments, but one fact is undeniable: insulin has lost its halo.
Insulin is still essential for any person with type 1 diabetes, though even with type 1 patients, insulin is sometimes under-prescribed as doctors fear getting sued over a severe hypoglycemic incident. The belief is that patients are responsible for high blood sugars, doctors for low blood sugars.
Where insulin has lost its appeal is with type 2 patients, which has driven the diabetes epidemic in the U.S and abroad. According to the CDC, from 2000 to 2018, America’s diabetes population surged 185 percent, from 12 million to 34.2 million, and an estimated 90 percent to 95 percent of that cohort has type 2. (The global percentage is similar.) These patients have long had options other than insulin – metformin, introduced in 1995, remains the ADA’s recommended first-line agent. But as a progressive disease, type 2 diabetes, in most cases, will eventually require a more intensive glucose-lowering therapy. Nothing achieves that objective better than insulin, but insulin is delayed or spurned entirely by many type 2 patients.
Some concerns are longstanding; namely, that insulin can lead to weight gain because patients now retain their nutrients. Some type 2 patients wrongly associate insulin with personal failure surrounding diet or exercise, so they want to avoid the perceived stigma of insulin. Some people just don’t like injections. Meanwhile, other patients associate insulin with the medication that an ailing patient takes shortly before they die: insulin as a precursor to death. Some clinicians who care for Hispanic patients refer to insulin pens as las plumas to avoid using a word that carries so much baggage.
What’s striking is how dramatically the cultural narrative has changed, from insulin the miracle drug to insulin the medical curse. And where are the commercials, the movies, the documentaries, and the splashy publicity campaigns about the wonders of insulin? They don’t exist.
The greatest impact on insulin use in type 2 diabetes has been the emergence of a dozen new classes of diabetic drugs. These include incretin-based therapies known as GLP-1 agonists and DPP-4 inhibitors (introduced in the 2000s) as well as SGLT-2 inhibitors (introduced in 2014). diaTribe has covered these therapies extensively, and their brands are all over TV: Trulicity, Jardiance, Invokana, and more. They all seem to have funky names, and like insulin, they can all lower blood sugars but – depending on which one is used - some have other potential advantages, such as weight loss. (Some have possible disadvantages as well, including nausea.)
The expectations for these drugs were always high, but what no one predicted was that GLP-1 agonists and SGLT-2 inhibitors have been shown to reduce the risk of both heart and kidney disease – findings that are a boon to type 2 patients, who are at higher risk of these diseases. These findings, however, were completely accidental to the original mission of these therapies.
Insulin, the miracle drug, has been eclipsed by drugs that are even more miraculous!
Consider Eli Lilly, whose Humalog is the market-leading insulin in the United States. In 2020, Humalog sales fell 7 percent, to $2.6 billion, while Trulicity, its GLP-1 agonist, saw its sales increase by 23 percent, to $5 billion.
That’s consistent with the global insulin market. Worldwide insulin sales in 2020 declined by 4 percent, to $19.4 billion, marking the first time since 2012 that global insulin sales fell below $20 billion.
It’s quite stunning. Amid a global diabetes epidemic, and with the purity, stability, and quality of insulin better than ever, insulin sales are falling. (Pricing pressures from insurers and government payers have also taken a revenue toll.) In 2019, Sanofi announced that it was going to discontinue its research into diabetes, even though its Lantus insulin had been a blockbuster for years. More lucrative opportunities now lay elsewhere.
Falling sales may not be the insulin companies’ biggest problem. Public scorn is. Though the insulins kept getting better, the prices kept rising, forcing many patients to ration their supplies, seek cheaper alternatives in Canada or Mexico, or settle for inferior insulins. Some patients have died for lack of insulin. According to a 2019 study from the nonprofit Health Care Cost Institute, the cost of insulin nearly doubled for type 1 patients in the United States between 2012 and 2016 – they paid, on average, $5,705 a year for insulin in 2016, compared to $2,864 in 2012.
Many patients are outraged and have used social media to rally support – one trending hashtag was #makeinsulinaffordable. Patient advocates have traveled to Eli Lilly’s headquarters to protest. In March of this year, nine Congressional Democrats demanded that the Federal Trade Commission investigate insulin price collusion among Eli Lilly, Novo Nordisk, and Sanofi, asserting they “are using their stranglehold on the market to drive up costs.” The letter notes that as many as one in four Americans who need insulin cannot afford it, and at least 13 Americans have died in recent years because of insulin rationing.
The criticism has been unsparing. In April 2019, in a hearing for the U.S. House of Representatives on insulin affordability, Democrats and Republicans alike pilloried the insulin executives. At one point, Rep. Jan Schakowsky (D-Illinois) said to them, “I don’t know how you people sleep at night.”
Insulin is hardly the only drug whose price has soared, but as the Washington Post noted last year, insulin is “a natural poster child of pharmaceutical greed.”
In response, the insulin companies have adopted payment assistance programs to help financially strapped consumers. They also blame the middlemen in the system – the PBMs, or the Pharmaceutical Benefit Managers – for high insulin prices, who in turn blame the insulin companies, and everyone blames the insurers, who point the finger at the companies and the PBMs.
Drug pricing in America is so convoluted it’s impossible for any patient to accurately apportion blame, but the history of insulin explains in part why the companies have come under such attack. When Banting made his discovery, he sold the patent to the University of Toronto for $1. He said that insulin was a gift to humankind and should be made available to anyone who needs it. Insulin was always profitable for Eli Lilly and the few other companies who made it, and critics have complained that the companies found ways to protect their patents by making incremental improvements in the drug.
But for years, those complaints were easily dismissed. The companies were revered for their ability to mass produce – and improve – a lifesaving drug that symbolized the pinnacle of scientific discovery while doing so at prices that were affordable.
When prices became unaffordable – and regardless of blame – the companies were seen as betraying the very spirit in which insulin was discovered and produced, and their fall from grace has few equivalents in corporate history.
Is the criticism fair?
Hard to say, but even the companies would acknowledge that they’ve squandered much good will. Personally, I’m the last person to bash the insulin companies – they’ve kept me and members of family alive for quite some time. Collectively, my brother, my son, and I have been taking insulin for 117 years, so I feel more regret than anger: regret that at least one insulin executive didn’t stand up and say loudly and clearly:
“Insulin is a public good. No one who needs it will be without it. And we will make it easy for you.”
Whatever that would cost in dollars would be made up for in good will – and such a public commitment would honor the many anonymous men, women, and children, before 1921 and after, who gave their lives to this disease.
The next chapter for insulin? It will almost certainly include continued improvements. Both Eli Lilly and Novo Nordisk are trying to develop a once-a-week basal insulin to replace the current once-a-day options – that would be a major advance is reducing the hassle factor in care. Research also continues on a glucose-sensitive insulin, in which the insulin would only take effect when your blood sugar rises. That would be a breakthrough, but investigators have spent decades trying to make it work.
Since its discovery, the ultimate goal of insulin has been to make it disappear, as that would mean diabetes has been cured. It turns out that insulin therapy may indeed disappear someday, even if no cure is found.
Stem-cell therapy has long held promise in diabetes – specifically, making insulin-producing beta cells from stem cells, which the body would either tolerate on its own (perhaps by encapsulating the cells) or through immunosuppressant drugs. Progress has been halting but is now evident. Douglas Melton began his research in this area in 1991, and in 2014, he reported that his lab was able to turn human stem cells into functional pancreatic beta cells. The company that Melton created for the effort was acquired by Vertex Pharmaceuticals, and earlier this year, Vertex announced that it had received approval to begin a clinical trial on a “stem-cell derived, fully differentiated pancreatic islet cell therapy” to treat type 1 diabetes. Another company, ViaCyte, also announced this year that it will begin phase 2 of a clinical trial using encapsulated cells in hopes that they will mature into insulin-secreting beta cells.
It may take 10 to 15 years, but leaders in the field are cautiously optimistic that a cell-based therapy will someday provide a better option than insulin.
Diabetes would survive, but the therapy once touted as its cure would be dead.
Because I have a soft spot for happy endings – and because so much of own life has been intertwined with insulin – I have my own vision for insulin’s last hurrah.
A group of researchers in Europe are conducting a clinical trial to prevent type 1 diabetes. Called the Global Platform for the Prevention of Autoimmune Diabetes, the initiative began in 2015, and researchers are testing newborns who are at risk of developing type 1 to see if prevention is possible.
And what treatment are they using?
Like the discovery of insulin itself, this effort is a longshot, but if it works, insulin will have eradicated diabetes – a fitting coda for a medical miracle.
I want to acknowledge the following people who helped me with this article: Dr. Mark Atkinson, Dr. David Harlan, Dr. Irl Hirsch, Dr. David Nathan, Dr. Jay Skyler, and Dr. Bernard Zinman. Some material in this article came from my book, “Cheating Destiny: Living with Diabetes.”
James S. Hirsch, a former reporter for The New York Times and The Wall Street Journal, is a best-selling author who has written 10 nonfiction books. They include biographies of Willie Mays and Rubin "Hurricane" Carter; an investigation into the Tulsa race riot of 1921; and an examination of our diabetes epidemic. Hirsch has an undergraduate degree from the University of Missouri School of Journalism and a graduate degree from the LBJ School of Public Policy at the University of Texas. He lives in the Boston area with his wife, Sheryl, and they have two children, Amanda and Garrett. Jim has worked as a senior editor and columnist for diaTribe since 2006.