By Randolph Fillmore
According to the U.S. Centers for Disease Control and Prevention (CDC), more than 37 million Americans have diabetes and 90 to 95 percent of those afflicted have Type 2 diabetes (T2D). Type 2 diabetes occurs when the body produces inadequate amounts of insulin, which is produced by the beta-cells of the pancreas.
There are likely multiple contributing factors to development of Type 2 diabetes and their identities remain largely unknown. Susceptible individuals develop pre-diabetic symptoms, which include insulin resistance, a condition where the pancreas produces more insulin in response to both high caloric food intake and increased body weight, and this is frequently associated with obesity. Over time as this hyperinsulinemic, pre-diabetic state continues, the beta-cells cannot keep up with the increased demand for insulin and they begin to “fail.” As beta-cells lose their ability to manage blood glucose (sugar), sugar levels continue to remain elevated in the bloodstream, and this leads to diabetic complications.
Recent ground-breaking research carried out by an international team of scientists led by scientists at Johns Hopkins All Children’s Hospital in St. Petersburg, Florida, has shed new light on the causes of Type 2 diabetes, which offers a potential strategy for developing new therapeutic approaches that could restore dysfunctional pancreatic beta-cells or, perhaps, even prevent Type 2 diabetes from developing.
Matthew Poy, Ph.D., who is an associate professor of Medicine and Biological Chemistry in the Johns Hopkins University School of Medicine and leader of the Johns Hopkins All Children’s team within the Institute for Fundamental Biomedical Research along with contributing international scientists, carried out the research that was recently published in the journal Nature Communications. The paper, is entitled “Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction,” explains how the functionality of beta-cells can be increased and restored. The paper is now available online.
Type 2 Diabetes, Beta-cells, Insulin and ‘Little Packages’
“Type 2 diabetes most often develops in people during adulthood but, it is increasingly observed in children and teens,” Poy says. “Why Type 2 diabetes is increasing in younger people is unclear, but obesity, in addition to poor diet and a lack of exercise, are all widely recognized as contributing to poor health outcomes.”
“Nearly 1 in 3 children within that Tampa Bay area meet criteria of obesity and rates of severe obesity in children have also increased following the COVID-19 pandemic,” notes Raquel Hernandez, M.D., associate professor of Pediatrics in the Johns Hopkins University School of Medicine and medical director of the Healthy Weight Initiative at Johns Hopkins All Children’s. “Because so many more children have weight-related health issues, preventing the associated T2 diabetes has become increasingly urgent as a pediatric and public health priority. The work by Dr. Poy and his team provides hope that we may be able to finally understand ways to prevent and treat Type 2 diabetes in children.”
Briefly, the new study shows that the beta-cells of Type 2 diabetes patients are deficient in a cell trafficking protein called “phosphatidylinositol transfer protein alpha” (or PITPNA), which can promote the formation of “little packages,” or intracellular granules containing insulin. These structures facilitate processing and maturation of insulin “cargo.” Poy and colleagues show that by restoring PITPNA in the Type 2 deficient beta-cells, production of insulin granule is restored and this reverses many of the deficiencies associated with beta-cell failure and Type 2 diabetes.
According to Poy, it is important to understand how specific genes regulate pancreatic beta-cell function, including those that mediate insulin granule production and maturation like PITPNA to provide therapeutic options for people.
“Cells are like little factories where there is constant movement of molecules including proteins and lipids that are delivered to different compartments of every cell in an orderly fashion. It is like the movement of raw materials on an assembly line in a factory,” Poy explains. “And, like on an assembly line, the cargo needs to be efficiently managed or problems occur like delays and deficits in producing the final product. Within beta-cells, pressuring the cell to constantly produce insulin without any reprieve is a stress and when the system is overloaded, the assembly line collapses leading to the dysfunction associated with beta-cell failure.”
Poy explains that PITPNA functions as an assembly line manager that directs the shuttling of specific cargo molecules called “phospholipids” in beta-cells, and this plays a central role in producing insulin granules. He explains that if PITPNA is depleted, insulin is not properly packaged or accurately delivered.
Subsequent Studies Now Underway
Poy adds that their follow-up work is focused on whether PITPNA can enhance the functionality of stem-cell-derived pancreatic beta-cells. Since stem cell-based therapies are still in their relatively early stages of clinical development, it appears a great deal of the potential of this approach remains untapped. Poy believes that increasing levels of PITPNA in stem cell-derived beta-cells is an approach that could enhance the ability to produce and release mature insulin prior to transplantation in diabetic subjects.
“Our dream is that increasing PITPNA could improve the efficacy and potency of beta-like stem cells,” Poy says. “This is where our research is heading, but we have to discover whether the capacity of these undifferentiated stem cells that can be converted into many different cell types can be optimized — and to what level — to be converted into healthy insulin producing beta-cells.”
Could that be a cure for Type 2 diabetes?
“That would be the ‘holy grail,’” Poy concludes.
This study was funded through grants from the Johns Hopkins All Children’s Foundation, the National Institute 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.