Insulin. Since its discovery more than 100 years ago, science has taken what nature has conserved across generations of vertebrate evolution and has tweaked it to make it more stable, more accessible, and more effective.¹ Like nature, the World Health Organization (WHO) sees insulin as an essential medicine.² What does the future hold for insulin? As part of the 2022 American Diabetes Association (ADA) session on The Future of Insulin, Michael A. Weiss, MD, PhD, chair of biochemistry and molecular biology, Indiana University School of Medicine said:
“Our view is that insulin is a human right. Towards the goal of insulin for all, our goal over the next decade would be to make all this technology sufficiently robust for international distribution.”
The future technologies presented in the session may determine the international fate of insulin. Near future technologies included discussions on:
weekly insulin analogues with long flat release profiles and similar or lower hypoglycemic risks as daily insulin, making treatment more accessible³˒⁴
oral insulin analogues that overcome gastrointestinal barriers, improving therapeutic efficacy and lowering overall insulin needs⁵
Dr. Weiss presented on a far future technology that puts the insulin molecule and its receptor front and center of the research. The idea is to create a glucose responsive insulin that triggers the insulin receptor only when needed.
Insulin and the Fourth Bridge
Briefly, in its native state, insulin is a combination of two peptide chains, A and B, which are connected via a short C-domain that acts like a hinge between the two. The insulin molecule also contains three native disulfide bridges stabilizing the tertiary structure.⁶ The first one is set between chain A amino acid 7 (A7) and chain B amino acid 7 (B7), or the A7-B7 bridge. The other two disulfide bridges are located at A20-B19, and A6-A11.⁷
There are several sites where a fourth disulfide bond could happen. These sites have been explored in the development of different insulin analogues. For example, a disulfide bridge at A10-B4 increases thermodynamic stability and increases potency, thereby potentially serving as a good insulin candidate in geographical areas and communities with unreliable storage.8 Other sites where a fourth bridge have been explored are:⁷˒⁹
A0 (N-terminus)-B17
A0-B22
A0-B26
A8-B10
A14-B10
A22-B22
B10-B22
Smart Insulin
A smart insulin is one that provides hormonal activation proportional to blood glucose levels, thus minimizing glucose excursions without relying on external monitoring systems. To Dr. Weiss, this means “exploiting the conformational switch that underlies the mechanism by which the hormone binds to and triggers the insulin receptor.”
The basic mechanism Dr. Weiss and colleagues are exploring is the insertion of a fourth disulfide bridge with a glucose responsive tether, making a reversible glucose switch.¹⁰ In a hypoglycemic state the glucose switch is closed, and the molecule is sterically incapable of binding to its receptor. In a hyperglycemic state, the switch opens, giving the receptor binding domain access to the insulin receptor.¹¹ Model calculations found that one site, A0-B26, could be used and still retain the structural features needed for a functional insulin molecule.
Studies exploring the in vitro and in vivo feasibility are yet unpublished, but Dr. Weiss hinted at positive results. Furthermore, in silico human modeling is being used to determine if the extent of glucose responsiveness found in principle is sufficient to be clinically relevant.
Insulin’s Future Depends on Technology
One hundred years ago, the discovery, isolation, and clinical use of insulin was mired in debate.¹²˒¹³ Today it can still precipitate strong opinions regarding its availability and access for geographically and economically challenged people.¹⁴ The hope for a future where all people with diabetes can reasonably get insulin (or an analogue) will be found in new insulin technologies.