Coming Attractions: Insulin’s Intriguing Future

Smart insulin. Once-a-week insulin. Thermostable insulin. Researchers around the world are working on a variety of insulin innovations, some of which could be available sooner than you think.

In a world where everything is becoming smart — phones, speakers, cars, watches, and even doorbells — will it soon be insulin’s turn?

The answer is yes, according to Michael Weiss, MD, PhD, chair of the Department of Biochemistry and Molecular Biology at the Indiana University School of Medicine in Indianapolis. Smart, glucose-responsive insulin that is more active in the presence of glucose and less active in the absence, is one of the innovations on the horizon.

As we look ahead during celebrations of the centennial of the discovery of insulin, it’s hard to know what the next 100 years will bring. But in addition to a smarter molecule, the potential breakthroughs in the next few years include tissue-specific, once-a-week, and nonrefrigerated formulations.  

Insulin analogs have made important strides in recent years, but it is remarkable how little insulin delivery has changed. “Essentially the same substance is being given by the same rather primitive route as it was 100 years ago,” according to Philip Home, MA, DPhil, DM, professor emeritus at the Translational and Clinical Research Institute at Newcastle University in the U.K. Glycemic control remains “suboptimal, although it is a lot better than it used to be. The tools we have available with the insulin analogs, pumps, and glucose sensors have made a difference.”

Smart Insulin

Despite these advances, current science is not able to mimic the human body’s complex subtleties in the interaction of insulin and glucose metabolism. Smart insulin would be a step in this direction. At least two proof-of-concept papers on glucose-responsive insulin were published recently.

Weiss and colleagues published a report in PNAS earlier this year on inserting an artificial ligand-dependent switch into the insulin molecule to this end.

“Essentially the same substance is being given by the same rather primitive route as it was 100 years ago.” Glycemic control remains “suboptimal, although it is a lot better than it used to be. The tools we have available with the insulin analogs, pumps, and glucose sensors have made a difference.”

Philip Home, MA, DPhil, DM, professor emeritus at the Translational and Clinical Research Institute at Newcastle University in the U.K

“Insulin changes shape when it binds to the receptor,” Weiss tells Endocrine News. “We were part of an international team that figured out a way to make the change in shape inhibitive in the absence of glucose. Our formulation requires glucose to change shape. So, it is the world’s smallest glucose-responsive insulin system because it doesn’t require a copolymer or something.” The process is reversible, so the insulin would be activated in the presence of glucose and inactivated in its absence in cycles even in the blood stream.

The paper reported successful use of a fructose-specific model in human liver-derived cells, and Weiss says that the team has begun testing a glucose-responsive version in rats.

A team of researchers from UCLA, MIT, and the University of North Carolina at Chapel Hill reported on another glucose-responsive system last year in Nature Biomedical Engineering. The researchers created a transdermal patch filled with microneedles loaded with insulin and a glucose-responsive polymer matrix.

The microneedles penetrate the skin and can sense blood glucose levels, delivering insulin in response to higher glucose and holding back in the absence of glucose. The patches are the size of a quarter and succeeded in controlling glucose levels in mini-pigs with type 1 diabetes for about 20 hours. The researchers have applied to the U.S. Food and Drug Administration for approval to conduct human clinical trials on a planned once-a-day patch.

Weiss thinks a smart insulin could make it to the market in five years or so, although Home thinks of it more as a “dark horse.”  

Tissue- or Organ-Specific Insulin

Weiss says that “tissue-specific or organ-specific insulins have been a holy grail for 30 to 40 years” because insulin action is different in different parts of the body. 

“Weight gain is a side consequence of insulin therapy, and that creates a vicious cycle where people are mildly obese, and they get diabetes and they go on insulin, then they are likely to experience weight gain” that exacerbates the problem, Weiss says. “But insulin action in the brain actually promotes satiety and weight loss. The insulin receptor in the brain has a different glycoform than the insulin receptor in the periphery. So, in principle, there is a way of targeting the brain insulin circuitry.”

In addition, subcutaneous insulin administration tends to lead to too much insulin in the periphery and not enough in the liver, compared with endogenous secretion from the beta cells, so researchers are also working on “hepato-selective” insulin. “There is lots of basic science going into that, and it will eventually get solved,” but it is farther away than some of the other likely innovations, Weiss says, especially in comparison to longer-lasting formulations and thermostable formats.

Once-a-Week Insulin

“Once-weekly insulins will most likely be the next addition to the insulin armamentarium,” writes Tim Heise in an article in Diabetes Research and Clinical Practice. “To date, clinical data of two once-weekly insulins in development have been published.”

One of these is insulin icodec, an analogue that Novo Nordisk has in Phase 3 clinical trials. The molecule has amino acid substitutions and a fatty diacid attached via a hydrophilic linker, modifications that “lead to strong albumin binding, reduced enzymatic degradation, and attenuated insulin receptor binding and clearance,” Heise writes.

Eli Lilly has a product in Phase 1 and 2 clinical trials called basal insulin Fc, which Home describes as “an Fc-coupled insulin in development for people with type 2 diabetes. This insulin has an apparent half-life of more than 10 days.”

Home agrees that weekly insulin analogues are the most likely to see the market next of these advances, and “could be used in combination with GLP-1 receptor analogues in type 2 diabetes.”

“Weight gain is a side consequence of insulin therapy, and that creates a vicious cycle where people are mildly obese, and they get diabetes and they go on insulin, then they are likely to experience weight gain … But insulin action in the brain actually promotes satiety and weight loss. The insulin receptor in the brain has a different glycoform than the insulin receptor in the periphery. So, in principle, there is a way of targeting the brain insulin circuitry.”

Michael Weiss, MD, PhD, chair, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Ind.

Thermostable Insulin

Weiss thinks that the advance that might come the most quickly relates to “ultrastable insulins to circumvent the need for a cold chain. Now we need to keep insulin from getting exposed even transiently to temperatures above 30 or 35 degrees centigrade. Insulin that does not require the cost and complexity of the present system of distribution that is a barrier to treating the pandemic of diabetes in the developing world and would enable international global delivery of insulin.”

Whichever advance comes to market first, the experts agree that with all the resources and research advancing it, patients will soon experience improvements in insulin therapy. “Glucose-responsive insulins would minimize the risk of hypoglycemia and make people feel comfortable with being more aggressive in their glycemic targets,” Weiss says.

Seaborg is a freelance writer based in Charlottesville, Va. In the October issue, he wrote about how underserved populations were being reached via booklets written in their native languages to help them easily understand developing diabetes technology.

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