New insights into potential therapeutics for type 2 diabetes

Diabetes is a chronic disease that exacts a heavy toll, with 11.3 percent of Americans diagnosed with the disease as of 2022, according to the Centers for Disease Control and Prevention. The three primary forms of diabetes are type 1, type 2 and gestational diabetes. There are ways to treat the disease—and more medications continue to emerge—but researchers from Texas A&M University and Johns Hopkins University now believe there could be other potential treatment methods for type 2 diabetes that focus on restoring the expression of a specific protein called PITPNA.

Their insights come from a new study conducted by a multidisciplinary team led by Johns Hopkins All Children’s Hospital and including researchers from the Texas A&M School of Medicine and the Texas A&M College of Agriculture and Life Sciences that was recently published in the journal Nature Communications.

Insulin, which is a hormone that helps the body use or store the glucose (sugar) gained from eating, is made within a specific type of cell inside the pancreas called beta cells. However, in type 2 diabetes there is impaired insulin signaling and reduced beta cell mass. These defects contribute to beta cell failure, furthering the severity of the disease. Methods to promote insulin release and protect these pancreatic beta cells from degeneration and failure are crucial to develop new treatments.

Previous studies in knockout animal models demonstrated that functional ablation of a specific protein called phosphatidylinositol transfer protein alpha (PITPNA) results in degeneration of insulin producing beta cells in the pancreas. These cells are essential for proper insulin secretion in response to elevations in blood glucose, and PITPNA plays a key role in insulin granule biogenesis and maturation. Both processes are essential for proper insulin function.

The current study, led by Yu-Te Yeh and Chandan Sona from the laboratory of Matthew Poy at Johns Hopkins, found that depleting PITPNA exclusively from the beta cells of animal models leads to high blood sugar due to reduced insulin secretion along with reduced beta-cell mass. The study also found that PITPNA is depleted in the beta cells of human patients with type 2 diabetes, suggesting that loss of PITPNA activity could be related to the dysfunction seen in beta cells. Direct evidence to that effect was obtained from experiments that showed silencing of PITPNA in human beta cells led to impaired insulin granule biogenesis, maturation and glucose-triggered insulin secretion. Finally, the research team found that restoring PITPNA expression in the human cells substantially reversed the beta cell defects.

Overall, the results of this study identify PITPNA deficiency as a major contributing factor to the reduced insulin output and beta cell failure seen in type 2 diabetes patients. This raises the idea that simply restoring PITPNA expression, by gene delivery or other means, in the failing beta cells of type 2 diabetes patients will help reactivate glucose-stimulated insulin responses in those cells and alleviate the disease.

Vytas Bankaitis, University Distinguished Professor and E.L. Wehner-Welch Foundation Chair in Chemistry in the School of Medicine’s Department of Cell Biology and Genetics, is one of the researchers on the project. He is particularly excited about how these findings could play a role in the development of new treatments for type 2 diabetes. Bankaitis stated this project is an example of how “what was initially perceived as a non-translational line of basic science research focusing on the biochemistry and cell biology of an understudied protein in mice became extremely translational in a high-impact disease context.”

This study was funded through grants from the Johns Hopkins All Children’s Foundation, the National Institutes of Health, the Robert A. Welch Foundation, the Helmholtz Gemeinschaft, the European Foundation for the Study of Diabetes, the Swedish Science Council, the NovoNordisk Foundation, and the Deutsche Forschungsgemeinschaft.