History of Islet Regeneration Research

The avenue of islet regeneration research began in 1983 at the University of Michigan, when Dr. Vinik and his research partner, Dr. Lawrence Rosenberg, were conducting experiments to induce pancreatitis. Their experiments led to an unexpected, or "sarandipitous," discovery.

Pancreases, wrapped in saran to induce the pancreatitis, were not damaged, but instead produced islet regeneration. Drs. Vinik and Rosenberg continued their investigations and demonstrated that saran wrapping reversed streptozotocin-induced diabetes in hamsters.

The research team identified the active principle as "ilotropin," but spent several more years looking for the protein within the pancreas responsible for regenerating islets. Eastern Virginia Medical School and the Diabetes Institutes Foundation recruited Dr. Vinik and his research team to the Diabetes Institutes in 1990. Joint collaboration continued between Dr. Vinik and Dr. Rosenberg who had relocated to McGill University in Canada.

In the early 1990s, new technology became available that allowed researchers to find the genetic message within ilotropin. They continued their search for the gene and in 1997 announced in the Journal of Clinical Investigation the discovery on INGAP (Islet Neogenesis Associated Protein).

The research team showed that INGAP is capable of stimulating islet neogenesis and producing lower blood glucose levels in hamsters made diabetic with steptozotocin. Through molecular biologic methods, scientists then created a recombinant form of INGAP which they used in further investigations to treat and reverse diabetes in animals.

In those experiments, researchers discovered several important findings: (1) recombinant INGAP stimulated pancreatic duct proliferation, (2) it was indeed the major component of ilotropin, and (3) INGAP antibodies could neutralize the regenerative effect.

From their work with hamsters, the scientific team found that for every log dose increase of INGAP, there was a progressive reduction in blood glucose concentration. Each administered dose dropped the blood glucose 35 mg per deciliter that translated into a 1% drop in hemoglobin A1c. Repetition of the process produced a reversal of diabetes in the animals 30% - 40% of the time.

Researchers then continued their investigations to find the active protein fragment within INGAP that successfully duplicated the action of the mature INGAP gene. Out of 155 amino acids that comprise the mature gene, scientists found 15 amino acids that produced regenerative effect. They synthesized the INGAP Peptide in vitro and began further testing on the Peptide.

In experiments to see if the Peptide would reach its target and stimulate islets, Drs. Gary Pittenger and David Taylor-Fishwick, directors of the Protein Chemistry and Cell and Molecular Biology laboratories, tagged the synthesized Peptide with a fluorescent marker and administered in intraperitoneally. The tags showed that the Peptide immediately traveled to the pancreas where it stimulated new islets within the ductal cells.

With the Peptide’s success established in hamsters, researchers moved on to investigate the Peptide’s effectiveness in other species. They chose to work with the C57BL/bt black mouse because when made diabetic, it gets pancreatic inflammation and the cells exactly resemble those of people with Type 1 diabetes. In a small study of eight animals, in which half received injections of salt water and half received INGAP Peptide injections, all animals administered with INGAP Peptide experienced a reversal of their diabetes.

Scientists looked closer at how INGAP Peptide reversed the diabetes. All the animals that received salt water continued to have high blood glucose levels. As INGAP Peptide was administered, the animals experienced lower blood glucose levels. When INGAP was stopped, levels remained lower. These experiments established that insulin was not producing the effect because it only works while it’s in the body. They showed that INGAP Peptide has an effect that goes beyond insulin – it creates new islets that the body recognizes as its own.

Islet Regeneration Research Reaches a Fork in the Road

In 2000, islet regeneration research came to a fork in the road – one avenue would develop INGAP Peptide as a pharmaceutical agent in clinical trials, the other avenue would continue to investigate the mechanism of islet regeneration and eventually move beyond INGAP to investigate the other factors that are vital to the regenerative process.

In the realm of pharmaceutical development, GMP Companies, Inc. worked with the Strelitz Diabetes Research Institute to design clinical trials that would test dose, safety, efficacy, and route of administration. Trials continued in other animal species to ascertain if the Peptide was likely to be safe in humans. In the fall of 2001, the Food and Drug Administration approved Phase 1-2a trials in humans. In December, the trials began at four locations nationwide.

In the Strelitz Diabetes Research laboratories basic science research continued to investigate INGAP’s mechanism for islet regeneration. By understanding what INGAP controls and what controls INGAP, scientists believe that they will be able to expand the possibilities for regenerative therapy.

Both avenues of research saw success.

In 2001, pharmaceutical giant Procter & Gamble partnered with GMP Companies, Inc. for INGAP Peptide development in clinical human trials. In 2003, Phase 2 clinical trials expanded to 20 sites nationwide. The trials tested for dosage, route of administration and efficacy in people with Type 1 and Type 2 diabetes. The trials were complete in the spring of 2004.

In the basic science laboratories, researchers discovered INGAP’s mechanism, and in 2002, were able to create islet regeneration without using the gene itself. Since that time, new discoveries have posed intriguing new challenges.