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Regeneration: Recent Key Advances, Fall 2008
Molecular Basis of Beta Cell Growth in Pregnancy Revealed
JDRF researchers at Stanford University found that menin, a protein known to suppress tumors, also plays a role in restraining insulin-producing beta cells from multiplying. The study raises the possibility that a therapy aimed at reducing menin levels could regenerate beta cells in people with type 1 diabetes.
The researchers were interested in menin's role in gestational diabetes, a temporary form of diabetes that develops in 2-5% of women during pregnancy. They created mice that overproduce the hormone and found that when these mice became pregnant, the islets grew insufficiently, and the animals developed diabetes. A separate part of their study showed that the hormone prolactin, which is abundant during pregnancy, reduced menin levels and increased beta cell mass in nonpregnant mice.
JDRF is funding a follow-up project to this research to validate the role of menin in humans and to identify peptides that inhibit menin's actions. This work holds the potential to lead to new methods to treat type 1 diabetes.
Pancreatic Progenitor Cells Found in Mice
Researchers at the JDRF Center for Beta Cell Therapy in Diabetes in Brussels, Belgium, identified a bona fide pancreatic progenitor cell that has the capacity to generate new insulin-producing beta cells in mice. This study demonstrates the existence of this elusive cell, and it underscores the potential of beta cell regeneration as a cure for type 1 diabetes.
Researchers were able to activate the beta cell progenitors by tying off a duct that drains digestive enzymes from the pancreas - an event that led to a doubling of beta cell mass in the injured part of the pancreas within two weeks and to the production of more insulin. Proliferation of the new beta cells was dependent on the activity of Neurogenin 3, a master gene also expressed in embryonic progenitor cells. Importantly, the new beta cells proved to be glucose-responsive.
The researchers noted that if the finding made in mice holds for humans, the newfound progenitor cells may represent "an obvious target for therapeutic regeneration of beta cells in diabetes." JDRF is planning to fund follow-up studies to extend these results.
Researchers Identify Potential Biomarker for Beta Cell Mass and Function
A JDRF-funded researcher has identified a potential biomarker for assessing beta cell mass and function and a novel target for the stimulation of beta cell proliferation. The work has piqued the interest of several biotechnology and pharmaceutical companies that have initiated internal research and development programs to further explore this finding.
The potential biomarker is a protein called Tmem27 that regulates cell growth in islets but not in other cell types. In the study, researchers looked at the protein's ability to stimulate beta cell replication in vivo and in vitro. Furthermore, they sought to determine whether plasma levels of this protein correlate with pancreatic beta cell mass and hence can be used as a biomarker in patients with type 1 and type 2 diabetes, as well as in patients who have received a combined pancreas and islet transplant. They established that Tmem27 controls islet growth in vivo in mice - further validating it as the basis for a potential therapy to stimulate the growth of beta cells.
In type 1 diabetes, there are very few biomarkers - molecular, biological or physical characteristics that scientists can measure to gain critical information about what's going on inside a person. JDRF believes that identifying additional biomarkers would be a powerful means to improve the diagnosis and treatment of the disease and to speed up research. If Tmem27 proves to be an effective biomarker, it could be used to quantify beta cell mass in the body in order to monitor the progress and success of regeneration and/or islet transplantation therapies.
JDRF and Industry Partner Advance Promising Treatments
JDRF is partnering with the biotechnology company Transition Therapeutics to conduct clinical trials of a second-generation regenerative product (GLP1-I.N.T., or gastrin combined with a glucagon-like peptide analogue) that may prove to have even better effects than E1-I.N.T., a combination therapy containing gastrin and epidermal growth factor that is being developed for the regeneration of insulin-producing beta cells. Among type 1 patients receiving the drug for four weeks, more than half decreased their average daily insulin usage by more than 20%, and reduced their HbA1c levels (a long-term measure of blood sugar control). The therapeutic combination used in the trial is based on preclinical studies funded by JDRF in the late 1980s.
In March 2008, Transition Therapeutics announced a licensing and collaboration agreement with Eli Lilly and Company to develop and commercialize its gastrin-based therapies for beta cell regeneration. The agreement demonstrates the success of JDRF's strategy to fill gaps in the drug pipeline by helping small companies move discovery research through early clinical testing until bigger companies step in to fund the large trials needed for FDA approval of drugs and treatments for diabetes.
