The Insulin Evolution

endocrine reviews 10 2020 cover

On the cusp of the 100-year anniversary of the discovery of insulin, Endocrine Reviews takes a look at how this therapy has evolved throughout the last century as well as how it has informed treatment options with a comprehensive guide that will prove to be an invaluable resource for another hundred years.

 

Endocrinologists worldwide are gearing up for a very important centennial — the 100th anniversary of the discovery of therapeutic insulin by physiologist J. J. R. Macleod, surgeon Frederick C. Banting and his student Charles Best, and biochemist J.B. Collip.

Since this Nobel prize–winning discovery in 1921, insulin has helped millions of people lead healthier lives and is worthy of the highest commendation as the central treatment of diabetes, a scourge affecting more than 400 million people globally. But there’s still more to celebrate. A team led by Irl B. Hirsch, MD, professor of medicine at the University of Washington Medicine Diabetes Institute in Seattle, recently published “The Evolution of Insulin and How It Informs Therapy and Treatment Choices” in the October issue of Endocrine Reviews. As the title suggests, this paper provides a pharmacopoeia for exogenous insulin.

Since the first isolation of insulin from animal pancreata a century ago, a lot has happened, starting with commercial production of insulin soon after its discovery and taking off from there.

“I’m sure there will be more insulins coming out over time, and I’m sure there will be more research, especially looking at comparisons of these different insulins and so forth, but I think this paper is going to stand the test of time.” – Irl B. Hirsch, MD, professor of medicine, University of Washington Medicine Diabetes Institute, Seattle, Wash.

Development of types of insulin has “exploded” explains Hirsch. Indeed, the expansion of insulin formulations as well as their various routes of administration offers patients with diabetes an array of treatment options. However, in order for a select therapy to work as it should, the prescribing clinician must truly understand it.

“The field has exploded to the point that it is very confusing for clinicians to keep track of the subtle differences, as these new insulins continue to come out,” Hirsch says. “In the late 1980s when I was in my endocrine fellowship training, we were just getting used to human insulin and phasing out animal insulin in that era. Now we’re contending with all of these new insulin analogs, especially in the last 20 years.”

One-Stop Insulin Shop

Innovation in the field of insulin development has led to numerous formulations that resemble the endogenous insulin response — a highly advantageous outcome — by altering the insulin molecule, which influences its mechanism of action. Ay, there’s the rub. Achieving the desired mechanism of action in the desired time frame requires keeping track of which formulation does what. Adding an extra layer of complexity, the reality in the U.S. is that clinicians do not usually have the say-so when it comes to which formulation to prescribe, a choice typically made by an insurance company or otherwise based on what the patient can afford.

“With so many insulins now available,” Hirsch says, “we felt that we needed to give a comprehensive review of their pharmacokinetics and pharmacodynamics and how they differ. They’re not all the same.” Thanks to Hirsch and team, if a clinician has to prescribe an insulin he or she does not have much experience with, this guide will explain the ins and outs of all things insulin from injectable versus inhalable formulations, to rapid-acting versus long-acting, concentrated versus mixed, to follow-on biologics.

“There are huge problems when somebody is doing fine on one regimen, such as a basal insulin and a prandial insulin, and then they get switched either because of the insurance company, or they’re admitted to the hospital and the insulin they were on is not on that formulary,” Hirsch says. “What does the clinician have to know about what the patient was on to switch them to whatever is on the formulary in the hospital?”

Now, instead of having to consult multiple sources to figure out how to administer the new formulation and have it work as effectively as the patient’s original, the clinician has the information all in one place — with extremely useful graphical and tabular comparisons, even. “What’s really nice about this paper is that you don’t have to read the whole thing, you can just go read about that insulin,” Hirsch says.

Hirsch and team, which includes Rattan Juneja, one of Hirsch’s research fellows in the 90s who now works for Eli Lilly, recognized the clear and urgent need for this “Insulin How-To.” “I trained him on insulin, now he works for a pharmaceutical company, and it was really the two of us who decided to do this,” Hirsch says. “Nothing has been done like it in a long time. And now when we have all of these new insulins, it’s really kind of overwhelming, especially to the non-endocrinologists who maybe trained 10 or 20 years ago, or back in the 80s like me. This was a topic where there were no options. We didn’t have this kind of guidance; in those days, there was controversy over whether we should even be doing fingerstick glucose testing.”

Insulin Onslaught

 The field has advanced rapidly, so rapidly in fact, that about 95% of what Hirsch and team’s paper covers is new. “I’m hoping this gets referenced frequently in the literature because I don’t think there’s anything like this out there right now,” he says. “I’m very proud of it and I’m very proud of my co-authors. We really put a lot of time into this.”

“The field has exploded to the point that it is very confusing for clinicians to keep track of the subtle differences, as these new insulins continue to come out. In the late 1980s when I was in my endocrine fellowship training, we were just getting used to human insulin and phasing out animal insulin in that era. Now we’re contending with all of these new insulin analogs, especially in the last 20 years.”– Irl B. Hirsch, MD, professor of medicine, University of Washington Medicine Diabetes Institute, Seattle, Wash.

Of course, the biggest benefit of all is improved patient care and fewer clinician mistakes. By and large, it’s the primary care provider prescribing insulin to a patient. Hirsch is considering an abridged version of the paper with less biochemical detail that would be targeted to that audience. “Having said that, for a fellow trying to learn all of this — ‘drinking from a fire hose’ is the analogy — this is the perfect article for somebody getting into this for the first time right now,” Hirsch says. “I’m sure there will be more insulins coming out over time, and I’m sure there will be more research, especially looking at comparisons of these different insulins and so forth, but I think this paper is going to stand the test of time.”

It’s no accident that Hirsch and team’s paper published just before the 100th anniversary of the discovery of insulin. Unfortunately, the pandemic has curtailed some of the planned celebrations. Nevertheless, the paper reveals the true scope of what the advent of insulin has done for humankind. “This paper will give you all the details of what has happened in the last century,” Hirsch says. “But I think the most important thing it will do is put in perspective how far we’ve come in the last 20 years out of the last 100.”

Horvath is a freelance writer based in Baltimore, Md. In the October issue, she wrote about the underlying effects of obesity on COVID-19 patients.

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