The RISE Study, which tested interventions designed to preserve or improve beta-cell function in prediabetes and early type 2 diabetes, continues to offer important insight into differences between adults and youth in the onset and progression of type 2 diabetes.

A panel of RISE investigators discussed the latest findings during the Scientific Sessions symposium New Insights from the Restoring Insulin Secretion (RISE) Study—Differences Between Adults and Youth with Prediabetes and Type 2 Diabetes. The presentation can be viewed by registered meeting attendees at ADA2020.org through September 10, 2020. If you haven’t registered for the Virtual 80th Scientific Sessions, register today to access all of the valuable meeting content.

Sharon Edelstein, ScM, Lead Research Scientist at the Milken Institute School of Public Health at George Washington University, kicked off the symposium with a look back at the major findings from RISE.

“In individuals with impaired glucose tolerance or recently diagnosed type 2 diabetes, RISE showed youth were more insulin resistant and secreted more insulin than adults,” Edelstein said. “In adults, some interventions improved beta-cell function during active treatment, but no persistent benefits were observed after medication withdrawal. In youth, insulin resistance and beta-cell dysfunction were unresponsive to interventions. After withdrawal of the interventions, beta-cell dysfunction progressed and was worse than at baseline.”

Given these differences in adult and youth populations, investigators are looking more closely at the RISE data to see if the differences can be explained.

Thomas Buchanan, MD, Principal Investigator of the Adult Surgery Arm of the RISE Study, shared observations from the study about alpha-cell function.

“Could increased glucagon levels in youth explain their greater insulin resistance and heightened beta-cell responsiveness compared to adults?” asked Dr. Buchanan, Professor of Medicine at the University of Southern California. “In RISE, we see youth with impaired glucose tolerance or recently diagnosed type 2 diabetes tend to have lower glucagon levels than adults. We also see fasting glucagon concentrations increase with fasting glucose levels in adults, but not in youth.”

Dr. Buchanan examined RISE data to see if the study’s interventions had any impact on alpha-cell function as assessed by glucagon levels and responses.

“While the interventions in RISE failed to induce durable improvements in beta-cell function, liraglutide and gastric banding were associated with reductions in glucagon that were explained statistically by reductions in body mass index,” he said. “Lower circulating glucagon levels in youth compared to adults with impaired glucose tolerance or early type 2 diabetes indicate that alpha-cell dysfunction does not explain insulin resistance or beta-cell hyper-responsiveness in youth. Rather, beta-cell hyper-responsiveness may contribute to suppression of glucagon levels in youth.”

Kristina Utzschneider, MD, Associate Professor of Medicine at the University of Washington, reviewed unpublished RISE data that may shed light on why youth are more insulin resistant than adults.

“Modeling of C-peptide shows higher insulin secretion in youth with impaired glucose tolerance and type 2 diabetes compared to adults,” Dr. Utzschneider said. “The data show insulin secretion is higher in youth at any given glucose value. In addition, data show beta cells are more responsive in youth with impaired glucose tolerance compared to adults with impaired glucose tolerance. This increased sensitivity was not seen in youth with type 2 diabetes compared to adults with type 2 diabetes.”

Kristen Nadeau, MD, MS, Professor of Pediatrics at the University of Colorado, explored RISE results in the context of existing literature and discussed remaining knowledge gaps that need further study. Her conclusions reinforced those of her fellow speakers.

“Youth with impaired glucose tolerance and type 2 diabetes are more insulin resistant, have higher insulin secretion and lower insulin clearance, have more rapid beta-cell deterioration, and poorer response to interventions compared to adults,” she said.

More data is needed on the natural history of normal metabolic changes in puberty, she said, as well as further research to identify likely progressors earlier and to examine contributing factors such as lifestyle, sleep, activity, and diet.

“We also need studies on the impact of new therapies on beta-cell function,” Dr. Nadeau said. “In youth, what is the beta-cell response to GLP-1 (glucagon-like peptide-1) analogues and the longer term impact of GLP-1 analogues? What about the impact of SGLT2 (sodium-glucose cotransporter 2) inhibitors?”