New Discoveries in Diabetes Call into Question Some Approaches to Treatment and Research

What is a normal blood glucose level? Pancreatic islets are programmed to know the answer, but that answer differs from species to species. What’s more, the original programming remains, even when the islets are transplanted from one species to another.

3D illustration of glucose-induced insulin secretion in pancreatic beta cells.

If, for example, pancreatic islets are transplanted from humans to mice, they continue to dictate the blood glucose levels that are normal for humans. That means the islet acts as a “glucostat.” Similar to a thermostat that works to maintain the same temperature in a home, a glucostat keeps glucose levels within a normal range for any given species.

This surprising finding, uncovered by researchers at the University of Miami Miller School of Medicine, helps explain which cellular functions can go awry in people living with diabetes. It also has important implications for treatment and research.

The Miller School investigators, collaborating with colleagues in Sweden, made this discovery by transplanting pancreatic islets from different species into diabetic and non-diabetic mice. They then measured glycemia and glucose tolerance in the recipient mice.

Their findings were published in an article, “Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point,” in the journal Cell Metabolism.

A second important discovery is that the beta cells in the pancreas — the only cells in the human body that make and secrete insulin — do not act alone. Other endocrine cells in the pancreatic islet are part of an intricate production that help the human body sustain its “glycemic set point” — or normal blood glucose level.

“The islet imposes its glycemic set point on the organism, making it the bona fide glucostat in the body,” said lead study author Rayner Rodriguez-Diaz, Ph.D., research assistant professor of medicine.

He and his colleagues demonstrated that interventions that only target beta cells are therefore likely missing the full picture.

“These findings impact transplantation and regenerative approaches to treat diabetes,” Rodriguez-Diaz said. “Furthermore, therapeutic strategies using glucagon receptor antagonists to reduce high blood glucose in diabetics need to be reassessed, as they may negatively impact the function of the cells that produce insulin, the hormone diabetic patients need the most.”

Although their translational research involved both human tissue and mice, the researchers emphasized one uniquely human point. Unlike with rodent islets, glucagon input from the alpha cell to the insulin-secreting beta cell is necessary to fine-tune the distinctive human set point.

“This means that it is imperative to use human islets of Langerhans when investigating how this complex micro-organ regulates glucose homeostasis under normal conditions, and why it is not functioning in diabetics,” Rodriguez-Diaz said.

Going forward, the research team plans to continue studying the complex physiology of the human islet in vivo in mice. Collaborating with investigators at Columbia University in New York, for example, they plan to induce and follow the maturation of stem cell-derived human pseudo-islets in vivo.

“Our goal is to develop mature stem cell-derived islets into micro-organs that are fully capable of taking over the glucose homeostasis and reverse diabetes in experimental models as a proof-of-concept,” said Rodriguez-Diaz.

Miller School co-authors of the study were Alejandro Caicedo, Ph.D., Ruth Molano, D.V.M., Jonathan Weitz, Ph.D., Midhat H. Abdulreda, Ph.D., Dora M. Berman, Ph.D., Norma Sue Kenyon, Ph.D., Camillo Ricordi, M.D., Antonello Pileggi, M.D., Ph.D. Research collaborators from the Karolinska Institute in Stockholm were Barbara Leibiger, Ingo B. Leibiger, Ph.D., and Per-Olof Berggren, Ph.D.

The research was also highlighted in Pancreatic Cell News and Science Daily.

The Diabetes Research Institute Foundation, the National Institutes of Health, an American Diabetes Association Innovative grant, the Swedish Diabetes Association Fund and the Swedish Research Council provided financial support for the current study. Other support came from Novo Nordisk Foundation, the Family Erling-Persson Foundation, Strategic Research Program in Diabetes at Karolinska Institute, the ERC-2013-AdG 338936-BetaImage, the Family Knut and Alice Wallenberg Foundation, Skandia Insurance Company Ltd, Diabetes and Wellness Foundation, the Bert von Kantzow Foundation, and the Stichting af Jochnick Foundation.

Tags: glucostat, glycemic set point, pancreatic islets, Rayner Rodriguez-Diaz