Potential Diabetes Treatment Approach Focuses on Preserving Pancreatic Beta Cells

Potential Diabetes Treatment Approach Focuses on Preserving Pancreatic Beta Cells
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A hallmark of both type 1 diabetes (T1D) and type 2 diabetes (T2D) is a loss of pancreatic beta cells the help to produce insulin. Yet, to date, there have been no therapeutics to treat the disease aimed at preserving beta cell mass. But new findings from researchers in the U.S. and Italy, reported today in Nature Communications, have identified a harmful cellular pathway that causes these cells to die. Further, when the investigators blocked the pathway in mice and in human islets, where beta cells reside, they preserved beta cells, increased insulin production, and prevented or delayed the onset of diabetes.

The team found protective effects of blocking the pathway—called TMEM219—either genetically or with an antibody in three different diabetes mouse models with studies in human cells consistent with what was observed in the mouse models. The team hopes this research can help inform the development of new therapies that block TMEM219 for the treatment of type 1 diabetes.

The TMEM219 pathway consists of a “death receptor” on insulin-producing beta cells coupled with insulin-like growth factor binding protein 3 (IGFBP3), which interacts with this receptor. When IGFBP3 binds to TMEM219, the researchers found, beta cells die through the process of apoptosis.

“We believe this might be a natural mechanism to keep the beta cell population under control,” said Paolo Fiorina, of Boston Children’s Hospital who led the research effort. “We think that in disease, IGFBP3 production may be increased, so there is a loss of beta cells.”

To support this idea the researchers also tested different groups of people with diabetes and found higher levels of IGFBP3 circulating in their blood as compared with nondiabetics. Increased IGFBP3 was also observed in people at risk for developing diabetes and in diabetic and prediabetic mice.

The approach taken for the research is counter to direction most research has taken in diabetes, which has been to understand what factors can promote the growth and replication of beta cells and hence increase insulin production. To date, little has been uncovered that shows the mechanisms of beta cell loss.

“The present study demonstrates that the death receptor TMEM219 is expressed in islet beta cells and that, when bound to its ligand IGFBP3, TMEM219 induces Caspase-8-dependent apoptosis of beta cells, which leads to beta-cell loss. Moreover, the addition of IGFBP3 in vitro alters the insulin secretory machinery in beta cells, resulting in beta-cell dysfunction,” the researchers wrote. “The observation that IGFBP3 levels are increased in patients with T1D or T2D and in those at risk for developing diabetes, as well as in pre-diabetic and diabetic mice, suggests a dysregulation of the IGFBP3/TMEM219 pathway in the context of diabetes.”

Adding to this, Fiorina noted “The common thought for type 1 diabetes is that it is autoimmune. But immunotherapy doesn’t completely cure diabetes. We think that dysregulation of beta cell homeostasis also plays a role and that IGFBP3 acts as a ‘betatoxin.’”

Fiorina is the founder of the Italian biotech company Enthera which is seeking to develop therapeutics based on these discoveries. The intent is to begin in-human testing of an antibody that blocks the IGFBP3/TMEM219 pathway as early as September.