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Insulin Turns 100

The discovery of insulin in 1921 sparked a revolution beyond improving diabetes care.
By Jennifer L.W. Fink

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One hundred years ago, four men and a few dogs changed the course of history. Frederick Banting was an unknown orthopedic surgeon who developed an interest in the pancreas and diabetes while preparing a medical school lecture. John Macleod, the ninth president of the American Physiological Society (APS) and a professor of physiology at the University of Toronto, was “unimpressed with Banting’s range of knowledge about diabetes and the pancreas,” according to the Science History Institute, but he allowed Banting to use his lab and assistant, Charles Best.  

“Macleod gave them 10 dogs, supplies and took off for the summer,” says Jay Dean, PhD, chair of the APS History of Physiology Interest Group and a professor in the Morsani College of Medicine, Molecular Pharmacology and Physiology at the University of South Florida.  

In a few months, Banting and Best isolated insulin from dogs and demonstrated that insulin injections could reverse high blood glucose levels. Biochemist James Collip helped them purify the resulting insulin extract so it could be used to treat diabetes in humans. 

The team presented their findings to the wider diabetes research community for the first time on December 30, 1921, at the APS meeting in New Haven, Connecticut. Banting and Macleod were later awarded the 1923 Nobel Prize in Physiology or Medicine for the discovery of insulin. 

“The discovery of insulin wasn’t just great for type 1 diabetes; it was proof of concept for the idea that, if you understood the science of disease, you could develop medicines to treat the disease.”

Daniel Drucker, MD, PhD

The men’s work “sparked a revolution in the scientific basis of medicine,” says Daniel Drucker, MD, PhD, professor of medicine at the University of Toronto and a senior scientist at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto. “If we go back 100 years, we couldn’t really address, with medicine, the underlying reason for a disease,” Drucker says. “The discovery of insulin wasn’t just great for type 1 diabetes; it was proof of concept for the idea that, if you understood the science of disease, you could develop medicines to treat the disease.” 

A century later, scientists are still building on the work of these men and those who came before and after them, including Nicolae Paulescu, a Romanian physiologist who may well have discovered insulin before the Canadian team of four. (Paulescu, in fact, wrote a letter to the Nobel Committee, emphasizing his achievements, after Banting and Macleod were awarded the Nobel.) 

Type 1 diabetes is no longer a death sentence, and clinicians and casual observers now understand that insulin resistance plays a role in type 2 diabetes, obesity and cardiovascular disease. Ongoing research continues to reveal improved diabetes treatments, as well as previously unimagined links between insulin and overall health. 

As Max Petersen, MD, PhD, and Gerald Shulman, MD, PhD, FAPS, wrote in the abstract of a 2018 Physiological Reviews article, “The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued.”  

Biomarker for Metabolic Health 

Early researchers identified the muscles, liver and fat tissue as insulin-responsive and recognized their role in metabolism. In fact, muscles are the main site for deposition of the glucose we ingest, and this deposition is a key response to insulin. Accordingly, muscles are major determinants of blood glucose levels, says Amira Klip, PhD, FAPS, senior scientist at Canada’s SickKids Research Institute and professor at the University of Toronto. However, over the past decade or so, there’s been increasing recognition that insulin receptors exist on most cells of the body, “even in cells where we didn’t know of any insulin action,” says C. Ronald Kahn, MD, head of the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School in Boston.  

Insulin receptors have been identified on white blood cells and in the brain. The kidneys and blood vessels are now known to be insulin-responsive, and ongoing research is investigating whether insulin resistance may directly contribute to hypertension.  

“Insulin has a small but very important vasodilatory action, and there’s a lot of research on whether the vessels become insulin resistant when there is insulin resistance elsewhere in the body and if there’s a resulting lack of vasodilation that is part of hypertension,” Klip says. “There’s controversy on how important that step is in the onset of insulin resistance, but it certainly contributes to the overall picture of type 2 diabetes.”

Clinicians have documented a connection between diabetes, neurodegeneration and neuropsychiatric disorders, including depression and anxiety, Kahn says. “We still really don’t know yet how important insulin action or insulin resistance is in some of these diseases.” 

Kahn and others are researching how insulin regulates gene expression changes in the brain, in hopes of understanding the physiologic link (if one exists) between insulin resistance and neurologic disease. To date, his studies with mice have revealed that “insulin in the peripheral blood regulates the expression of more genes in the brain than in the liver and muscle—the two most classic insulin-sensitive tissues—combined.” 

“If everyone in your family has type 2 diabetes by the age of 50, it may be a good idea for you to start monitoring insulin and glucose with CGM at age 40.”

Dominic D’Agostino, PhD

Given insulin’s action throughout the body, Dominic D’Agostino, PhD, associate professor in the Morsani College of Medicine, Molecular Pharmacology and Physiology at the University of South Florida, believes that “insulin is probably the most important metabolic biomarker.”  

“We think that hyperinsulinemia is the canary in the coal mine,” he says. “In type 2 diabetes, high levels of insulin happen way before blood glucose gets out of control, yet insulin measurements are not part of routine bloodwork. We’re doing research now to hopefully demonstrate that it’s something that needs to be tracked longitudinally over time concomitantly with continuous glucose monitoring (CGM)—and then, you may be able to prevent type 2 diabetes before it occurs.” 

New Treatments for Type 1 Diabetes 

Since insulin was discovered, regular insulin injections have been the standard treatment for type 1 diabetes. Clinical advances, such as the invention of long-acting insulin and implantable insulin pumps, have decreased the number of pokes patients must experience and have led to improvements in blood glucose control. Yet, regular injection of insulin remains, a century later, the primary treatment for type 1 diabetes.  

“I think there are still tremendous opportunities to advance the state of diabetes therapies,” Drucker says. “Fred Banting himself, in the 1920s, said that insulin is not a cure for type 1 diabetes. It will keep people alive, but it will not make the disease go away.”  

Some researchers are actively studying the immunology of type 1 diabetes, “trying to tame the immune system,” Drucker says. Scientists know there’s a link between insulin and inflammation, but don’t understand how the immune system responds to insulin or how insulin resistance exacerbates inflammation.  

“The whole immune system responds to insulin in a way,” Klip says. “This is a very hot area that begs for new discoveries because it could lead to using anti-inflammatories in a very selective way to contribute to the treatment of diabetes.”  

Researchers who work with stem cells are attempting to create beta cells that can produce insulin in response to blood glucose levels, while evading detection by the body’s immune system. In the meantime, engineers continue work on automatic glucose-sensing insulin delivery devices that act as an artificial pancreas.  

“At this point in history, I’d say mechanical approaches to diabetes treatment have gone a bit faster than the biological approaches; I didn’t think that would happen,” Kahn says. “I would have predicted that biology would beat engineering.”  

Scientists are also working to create “smart insulin,” which will only work in the body when blood glucose levels are elevated. “There’s been very exciting progress in that area,” Drucker says. “The science looks very promising, and clinical testing is already underway. I’m pretty confident we’ll see the development of smart insulin, and that type of innovation will make life much easier for people with diabetes.” 

D’Agostino, meanwhile, is exploring the history and application of specialized diets to help manage type 1 diabetes. “Before insulin, a very calorie- and carbohydrate-restricted ketogenic diet was the only treatment for diabetes. Frederick Madison Allen published a book—that influenced Banting—called ‘Total Dietary Regulation in the Treatment of Diabetes,’ and he had success in extending the lives of people with type 1 diabetes for another year or two with this diet,” D’Agostino says.  

Though diet has long been a cornerstone of diabetic management, “if I were to get on a stage 10, or even five, years ago and say people with type 1 diabetes should implement a low-carbohydrate ketogenic diet, I would be thrown off the stage,” D’Agostino says. Yet, emerging research shows that people with type 1 diabetes who eat a very low-carb ketogenic diet require less insulin and achieve better glycemic control and less glycemic variability.  

Expect more discussion of ketogenic diet as an intervention for diabetes. “Right now, it’s a very hot topic at the American Diabetes Association for both type 1 and type 2,” D’Agostino says.  

Advances in Treating Type 2 Diabetes and Insulin Resistance 

Efforts to understand the pathophysiology of insulin resistance have already resulted in new treatments for type 2 diabetes—and may soon lead to new treatments for obesity, short bowel syndrome and fatty liver disease. 

Frederick Sanger’s efforts to understand the structure of insulin garnered the 1958 Nobel Prize in Chemistry and unlocked the possibilities of genetic manipulation. Later, peptide sequencing of the glucagon gene led to the realization that glucagon-like peptide 1 (GLP-1) controls blood glucose and insulin production—a discovery that led to the creation of GLP-1 agonists, which are now a standard of care for type 2 diabetes. Researchers have also found that GLP-1 controls hunger, and in June 2021, semaglutide was approved by the U.S. Food and Drug Administration for chronic weight management.  

“The beauty of GLP-1 therapy is that, beyond helping people control diabetes and body weight, it also reduces heart attacks, strokes and rate of death,” Drucker says. “It’s actually quite an advancement.” 

Dipeptidyl peptidase 4 (DPP-4) inhibitors, which are medications that prevent breakdown of GLP-1 in the body, are currently used by hundreds of millions of people to control type 2 diabetes, and GLP-2 inhibitors are being developed as a therapy for short bowel syndrome, Drucker says.

“One of the many amazing things about insulin is how it’s sort of led to the creation of scientific fields before people even knew those fields existed.”

C. Ronald Kahn, MD

“Any one of these discoveries alone would have been like winning the lottery,” he says. “Having four to five discoveries become clinically meaningful and useful as a disease therapy is like constantly buying lottery tickets and winning every time.”  

Of course, identifying and reversing insulin resistance before it causes significant health problems is the ultimate goal. That’s one reason why health insurance companies are expressing interest in techniques to measure insulin in the blood, as emerging research suggests that insulin levels spike well before glucose levels. 

“If everyone in your family has type 2 diabetes by the age of 50, it may be a good idea for you to start monitoring insulin and glucose with CGM at age 40,” D’Agostino says, “so you can take actionable steps through dietary intervention, exercise and drugs to prevent that from leading to overt diabetes.” 

The Next 100 Years 

Despite the advances made over the past century, additional mysteries remain to be unraveled. 

“One of the mysteries still ongoing is once insulin is in the blood, how does it cross into the various tissues in which it has to act?” Klip says. “How do cells organize all the signals that insulin sends so they can respond in an appropriate and proportional way?” 

Klip expects that future research will include scrutiny of the location of key molecules, their interactions, the role of mechanical motors and physical changes of the membrane “skeleton” within various cells—including muscle, fat, liver and brain cells—which will almost certainly lead to additional investigation and innovation. 

“One of the many amazing things about insulin is how it’s sort of led to the creation of scientific fields before people even knew those fields existed,” Kahn says. “Insulin has really been at the forefront, whether you’re interested in basic science, clinical science or applications to new technologies.” 


This article was originally published in the November 2021 issue of The Physiologist Magazine.

 
Rising Costs Keep Insulin out of Reach for Many

In the 100 years since insulin was discovered, access to the lifesaving diabetes drug has increased as the price of the drug has skyrocketed. In the past 15 years, prices nearly tripled, according to the Endocrine Society, a leading research and policy advocacy group. The result is that many people who need insulin most—those who are low-income, underinsured or uninsured—are priced out of accessing it. 

Other groups of people being squeezed by high insulin costs, according to the Endocrine Society, are those with high-deductible health plans, beneficiaries using Medicare Part B to purchase insulin delivered using a pump, Medicare beneficiaries in the Part D donut hole (prescription coverage gap), and people 26 and older who are no longer eligible for coverage through their parents’ insurance.

Today, 7.4 million people in the U.S. treat their diabetes with insulin. When people can’t afford it, they are sometimes forced to ration insulin—leading to hospitalizations or other dangerous complications from comorbidities associated with diabetes—to pay for other costly medications, transportation, housing or utilities. 

The American Diabetes Association estimated in 2017 that people with diagnosed diabetes incur average yearly medical expenditures of approximately $16,750, with roughly $9,600 directly attributed to diabetes. Many of those dollars are likely used for insulin. 

The Endocrine Society says reasons for high insulin costs are complex and include:

  • Complexity of the supply chain, making it difficult to identify specific causes of rising costs.
  • Difficulty navigating decentralized programs to decrease out-of-pocket costs.
  • Lack of transparency among insulin manufacturers and insurance providers.

There are ways to lower the cost of insulin, however. These include:

  • Improving access to patient assistance programs.
  • Limiting future list price increases to the rate of inflation.
  • Allowing government negotiation of drug prices.

Making insulin affordable is a tall order with millions of lives depending on a resolution.