One Step Closer to Designer Insulin

An entirely new method of modifying insulin may pave the way for designing insulin-based pharmaceuticals, according to a new study.

The approach could open the door to more personalized medications with fewer side effects for patients with type 1 diabetes.

Human insulin assembles into homogenous grid-like structures called hexameres. The great challenge in producing insulin medications is to create equally homogenous nanostructures. The more uniformly insulin can be assembled, the more likely it is that it can be released in predictable amounts, and at steady rates, stated the researchers, led by Dr. Knud J. Jensen, a professor in the Department of Chemistry at the University of Copenhagen in Denmark.

The study results were published online in the journal Angewandte Chemie.

The researchers have devised a method that induces manufactured insulin to self-assemble in homogenous chemical grid constructs. The manufactured insulin self-assembles into nanostructures that are well suited to form depots in fat. The researchers tested the new form of insulin on rats, and found that it induced the lowering of blood glucose levels.

Bipyridine, a chelating ligand that forms complexes with most transition metal ions, sits at the end of all insulin molecules. The bipyridine serves as the hook that insulin uses to hitch onto other molecules. By hooking an iron ion to the bipyridine, the researchers learned how to control insulin assembly with great precision.

“Using iron to make proteins self-assemble is a new type of chemical process. That is to say, that we have conducted fundamental research. But we have chosen to conduct our fundamental research on a molecule that is relevant for an important industrial partner. That our fundamental research can lead to the development of new medications make our work feel all the more relevant,” Jensen stated.

The insulin grid structures were also studied in solution using the nanotech methods Atomic Force Microscopy to photograph the surfaces of molecules and small angle X-ray scattering to photograph the internal structures. They found that the addition of iron allowed the insulin to assemble itself into an unusually homogenous manner.

The researchers are optimistic about opportunities using the new method. “We have demonstrated that we can influence the manner in which insulin assembles, and we have demonstrated that the insulin can then be released,” Jensen said. “A great deal of work remains before the principles of our nano-insulin can be translated into a medication. But for me, it is absolutely clear that this could be a good method for designing medications that release over extended periods of time, from depots beneath the skin.”

He added that “because we are able to control the insulin’s self-assembling properties so precisely, I believe that the method can also be used to design insulin with a variety of properties.”

The precise control of protein self-assembly “provides nanoscale structures with potential applications in nanomedicine,” they concluded.

Reference: Munch HK, et al. Construction of insulin 18-mer nanoassemblies driven by coordination to iron(II) and zinc(II) ions at distinct sites. Angew Chem Int Ed Engl. 2016 Feb;55(7):2378-2381.