Insulin at 100: An Inspirational but Complicated History

This content originally appeared on diaTribe. Republished with permission.

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.

PART 1: The Discovery

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.

Research

Image source: iStock Photo

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.Tweet this“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.

After more than three millennia, it appeared that medical science had defeated diabetes.Tweet this“Hughes’ Daughter ‘Cured’ of Diabetes” declared one unidentified newspaper. After more than three millennia, it appeared that medical science had defeated diabetes.

Stay tuned for parts two and three of this riveting story over the next two weeks!

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.”

About James

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.

Source: diabetesdaily.com

Advancements in Treatment: The Use of Adjunctive Therapies in Type 1 Diabetes

This content originally appeared on diaTribe. Republished with permission.

By Paresh Dandona and Megan Johnson

Read on to learn about the research around GLP-1, SGLT-2, and combination therapy use in type 1 diabetes. Dr. Paresh Dandona is a Distinguished Professor and Chief of Endocrinology at the University of Buffalo, and Megan Johnson is a fellow on his team

For people living with type 1 diabetes, new treatments are finally on the horizon. The University at Buffalo (UB) Endocrinology Research Center is helping to revolutionize the treatment of this condition. Among the most promising new therapies are two non-insulin medications currently used in type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists.

SGLT-2 inhibitors, such as Farxiga, act the kidney to help the body excrete more glucose in the urine. Meanwhile, GLP-1 receptor agonists like Victoza work in several different ways: increasing the body’s natural insulin production, decreasing the release of the glucose-raising hormone glucagon, slowing the emptying of the stomach, and curbing excess appetite. Some people with type 1 diabetes take these medications as an addition to insulin treatment as an “off-label” drug. To learn more about off-label, check out the article: Can “Off Label” Drugs and Technology Help You? Ask Your Doctor.

Why consider these medications?

In people without diabetes, the body is constantly releasing more or less insulin to match the body’s energy needs.  People with type 1 diabetes do not make enough insulin on their own and have to try to mimic this process by taking insulin replacement – but it isn’t easy.

People with type 1 diabetes often have fluctuations in their blood sugars, putting them at risk for both low blood sugars (hypoglycemia) and high blood sugars (hyperglycemia). Many individuals are unable to manage their blood sugars in a healthy glucose range with insulin alone. In fact, less than 30% of people with type 1 diabetes currently have an A1C at the target of less than 7%.

Can GLP-1 agonists be safely used in type 1 diabetes?

Over the past decade, the endocrinologists at the University at Buffalo and other research groups have been conducting studies to see whether GLP-1-receptor agonists can safely be used in type 1 diabetes.

  • The first of these was published in 2011 and showed a decrease in A1C within just four weeks of GLP-1 agonist treatment. Importantly, people given GLP-1 agonists plus insulin also had much less variation in their blood sugars, as measured by continuous glucose monitors (CGM).
  • Another study involved 72 people with type 1 diabetes who took GLP-1 agonist or placebo (a “nothing” pil) in addition to insulin for 12 weeks. The GLP-1 group had decreases in A1C, insulin requirements, blood sugar fluctuations, and body weight. People in this group did report more nausea – a common side effect of GLP-1 agonists.
  • Since then, multiple studies, some involving over 1000 people and lasting up to 52 weeks, have shown that GLP-1 treatment in people with type 1 diabetes can reduce A1C and body weight, along with insulin dosages.

Many of these studies, but not all, have suggested that GLP-1 agonists can do this without increasing the risk for hypoglycemia or diabetic ketoacidosis (DKA). There is also some evidence that GLP-1 agonists can improve quality of life in type 1 diabetes.

Who should consider GLP-1’s?

The effects of GLP-1 agonists seem to be especially strong in individuals who are still able to make some insulin on their own, although it also works in people who do not.

In one notable study, researchers gave a GLP-1 agonist to 11 people with type 1 diabetes who were still able to produce some insulin. To get an estimate of insulin production, they measured levels of a molecule called C-peptide, which is produced at the same time as insulin. In these 11 individuals, C-peptide concentrations increased after GLP-1 treatment. By the 12-week mark, they had decreased their insulin dosage by over 60%. Incredibly, five people were not requiring any insulin at all. Even though the study was very small, the results were exciting, because it was the first study to suggest that some people with type 1 diabetes had sufficient insulin reserve and thus, could – at least temporarily – be treated without insulin.

Can SGLT-2 inhibitors be used in type 1 diabetes?

SGLT-2 inhibitors like Farxiga have also shown tremendous potential. In two large studies called DEPICT-1 and DEPICT-2, adults with type 1 diabetes were randomly assigned to take either placebo or SGLT-2 inhibitor in combination with insulin. Over 700 people from 17 different countries participated in DEPICT-1, and over 800 people with type 1 diabetes participated in DEPICT-2. At the end of 24 weeks, people taking dapaglifozin had a percent A1C that was lower, on average, by 0.4 compared to people who had received placebo, and it was still lower, by over 0.3, at 52 weeks. The number of hypoglycemic events was similar in both groups.

As with GLP-1 agonists, people taking SGLT-2 inhibitors had weight loss and decreased insulin requirements. People taking SGLT-2 inhibitor, however, did have an increased risk of diabetic ketoacidosis (DKA). If individuals consider this therapy, they should be cautious about not missing meals or insulin, and not drinking large amounts of alcohol, as these behaviors can lead to increased ketone production.

Several other research groups, in trials recruiting up to 1000 individuals, have seen similar results when using this class of medications.  Researchers have been conducting additional studies to try to determine how best to minimize the risks associated with them. Farxiga (called Forxiga in Europe) has now been approved as the first oral agent as an adjunct treatment for type 1 diabetes in Europe and Japan.

Promising Combination Therapy

Now, endocrinologists are also looking at whether GLP-1 agonist and SGLT-2 inhibitor combination therapy could increase the benefits of each of these treatments. A study conducted on a small number of people showed that GLP-1 agonists can help prevent ketone production, so it is theoretically possible that this medication could reduce the risk of DKA that was seen with SGLT-2 inhibitors.

In an early study involving 30 people with type 1 diabetes who were already on GLP-agonist and insulin were randomly assigned to take SGLT-2 inhibitor or placebo, as well. People who received both drugs saw an 0.7% reduction in A1C values after 12 weeks, without any additional hypoglycemia. People on the SGLT-2 inhibitor did make more ketones, though, and two individuals in the combination group experienced DKA. Larger studies are now being conducted to expand on these results and learn more about how to give these drugs safely. The hope is that non-insulin therapies will soon be approved for type 1 diabetes. By unlocking the potential of these therapies, we can do more than manage blood glucose levels – we can improve people’s lives.

Source: diabetesdaily.com

LADA – Debunking a Common Type 2 Diabetes Misdiagnosis

This content originally appeared on diaTribe. Republished with permission.By Kara Miecznikowski and Divya Gopisetty What is LADA? How is it diagnosed and treated? Read on to learn more and hear from people living with LADA Just like type 1 diabetes, LADA is a form of autoimmune diabetes. This means that the body’s own immune system […]
Source: diabetesdaily.com

Diabetes Cheatsheet for Family and Friends

This content originally appeared on Blood Sugar Trampoline. Republished with permission. Do you struggle to explain your type 1 diabetes to your friends and family? Or maybe you are just tired of explaining it again and again, and again? Here is a quick rundown of some of the basics that you can share with your […]
Source: diabetesdaily.com

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