Diabetes occurs when insulin-secreting ß cells in the pancreas don’t function properly or are depleted and so not enough insulin is produced to stop blood glucose levels from rising. Researchers at Stanford University have now developed a potential approach to selectively trigger the regeneration of pancreatic ß cells so that insulin production can be increased, but without indiscriminately affecting cells elsewhere in the body. The strategy exploits the fact that ß cells accumulate zinc, and uses a zinc-chelating agent to deliver a ß-cell-regenerating drug directly to the insulin-producing islet cells.

Although the technology is still in the very early stages of development, the Stanford University team, reporting in Cell Chemical Biology, said that results from their in vitro studies represent “a critical first step toward validating a readily transferable ß-cell-targeted drug-delivery strategy.” Research lead Justin Annes, M.D., Ph.D., and colleagues reported their findings in a paper titled, “Zinc-chelating small molecules preferentially accumulate and function within pancreatic ß-cells.”

Blood glucose levels are normally kept within strict limits by two hormones, glucagon and insulin, which are produced by pancreatic islet α cells and ß cells, respectively, the authors explained.  In diabetes, not enough insulin is produced and blood glucose levels rise. While symptoms can be managed by administering regular insulin, ideally it would be possible to use drugs to trigger ß-cell regeneration and so reinstate adequate insulin production.

There has been significant progress in identifying small-molecule drugs that might stimulate ß cells, but “the application of these compounds is limited by their indiscriminate replication-promoting activity,” the researchers noted. “Given the central role of ß cells in maintaining glucose homeostasis, developing methods for ß-cell-targeted drug delivery and imaging of ß-cell mass in vivo has emerged as a research priority.”

Source: Cell Chemical Biology DOI:https://doi.org/10.1016/j.chembiol.2018.10.019

A number of approaches have been taken to identify ß-cell-specific surface markers that could act as targets for selective drug delivery, but expression levels of candidates such as the glucagon-like peptide 1 receptor (GLP-1R) GLP44 and the somatostatin receptor SSTR2 are possibly too low and expression insufficiently restricted to allow their use for ß-cell-targeted drug delivery. Researchers also haven’t yet devised a way to harness the glucose transporter member  (GLUT2) as a “Trojan horse” to smuggle in drug candidates.


One quirk of ß cells is their propensity to accumulate zinc. This feature has been used as a way to stain and image ß cells in pancreatic tissue samples, but it hasn’t yet been exploited for drug delivery applications. “The unusual ability of islet ß cells to bio-concentrate zinc has been used for decades to identify islets with zinc-dependent dyes,” the team wrote. However, “despite the extensive work done to develop highly specific zinc-sensitive probes, the potential use of zinc chelators for ß-cell-targeted compound delivery has not been explored.” Scientists also haven’t known whether zinc-binding compounds would even accumulate in the zinc-rich ß cells. Nevertheless, Dr. Annes reasoned that it may be possible to harness the zinc-accumulating feature of ß cells for selective drug targeting. “The only problem was, I didn’t know how to generate compounds that could test this hypothesis,” he commented.

Dr. Annes worked with graduate student Timothy Horton and Mark Smith, who is director of the Medicinal Chemistry Knowledge Center at Stanford ChEM-H, to develop a strategy based on chelation, the process by which compounds form tight bonds with metals. The researchers first confirmed that their chosen chelating agent would accumulate in the ß cells, and then demonstrated that a hybrid comprising the zinc-chelation agent coupled to the ß cell-regenerating drug GNF-4877would also accumulate in ß cells growing in the laboratory.

Their tests confirmed that the hybrid molecule accumulated more in ß cells than in other cell types, and when administered to different types of rat cells in vitro, resulted in the regeneration of ß cells by 250% more than that of other cell types. The same effects, albeit to a lesser degree, were also observed when the chelating agent-regeneration drug compound was administered to different human cells in vitro. The ß cells replicated about 130% more than other human cell types.

The researchers acknowledge that their approach hasn’t yet been tested in vivo, and will need further development to improve selectivity—the magnitude of zinc-dependent and preferential ß-cell drug accumulation and activity was relatively small in the reported studies. Other potential limitations of the approach will also need investigating, the team added. It’s not known whether zinc-chelation-dependent drug targeting will affect normal cellular functions such as insulin storage in ß cells, for example. There are also other cell populations in tissues including the prostate, pituitary gland, as well as some types of neurons, that accumulate high levels of zinc. “… further experimentation is necessary to extend our proof-of-concept in vitro studies toward a safe, broadly applicable in vivo strategy for ß-cell-selective drug delivery,” the authors concluded. Nevertheless, stating that “… application of this principle yielded a proof-of-concept method for ß-cell-targeted delivery and bioactivity.” The authors are hopeful that the reported results could be the first step in developing new ß cell regenerative drugs. “We’re at the earliest stages,” Dr. Annes commented. “This is the first demonstration of a selectively delivered replication molecule in ß cells.”

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