Glucostat Discovery Has Implications for Diabetes Regenerative Therapies

Researchers in Sweden and the U.S. report new insights into how the human body sets its target blood glucose level – the glycemic set point – and say their findings could have implications for ongoing diabetes research and the development of regenerative therapies.

Every animal species has its own signature glycemic set point, and a normal glucose level for one species may be life threatening to another. What hasn’t been known until now, however, is which organ is responsible for defining that glycemic set point in each species. Karolinska Institutet researchers, led by Per-Olof Berggren, Ph.D., have now shown that transplanting the islets from different species into mice resulted in the recipient animals taking on the glycemic set point of the donor species.

“We found that the engrafted islets transferred the glycemic levels of the donor species,” comments Dr. Berggren, a researcher at the department of molecular medicine and surgery’s Rolf Luft Research Centre for Diabetes and Endocrinology. “This indicates that the pancreatic islets have the overall responsibility for maintaining normal blood glucose levels, making them the ‘glucostat’ in our bodies.”

Working with collaborators at the University of Miami, Miller School of Medicine, the team’s studies also highlighted differences in glucose regulatory mechanisms between species. Their results showed that, in contrast with rodents, in human pancreatic islets the cells that release glucagon also play a critical role in regulating insulin-producing beta cells, and so are also involved in the mechanisms that control glycemia.

“This means it is imperative to use human pancreatic islets when investigating how this complex microorgan regulates glucose homeostasis under normal conditions, and why this is not functioning in diabetes,” says Alejandro Caicedo, Ph.D., a researcher at the University of Miami, Miller School of Medicine. “Our findings have implications for transplantation and regenerative approaches to the treatment of diabetes, because restoring normal blood glucose levels may require more than replacing only the insulin-producing cells.” The researchers report their findings in Cell Metabolism, in a paper entitled “Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point.”

Blood glucose levels in humans are tightly regulated around a set point of 90 mg/dL, and either lower (hypoglycemic) or higher (hyperglycemic) levels are dangerous to health. Not every animal has the same glycemic set point, however. Normal blood glucose levels in the mouse, for example, would be considered diabetic in humans, the authors explain. Maintenance of blood glucose levels involves interactions between the liver, a metabolic regulatory organ, as well as the hypothalamus in the brain, and the pancreatic islets, which are endocrine organs. What scientists haven’t yet discovered is which organ in the body determines the glycemic set point. “Because of the intricate interactions between these organs and because each one of them has its own glucose set point, it remains unclear whether there is a leading organ or mechanism that maintains glycemia within the characteristic narrow range of the species,” the authors write. “There is no systematic study addressing where the target value for normoglycemia is set, that is, where the glucostat resides in the body.”

Previous studies had shown that transplanting islet grafts between species also transferred the glycemic levels that were typical of the islet donor species, “making the islet a plausible candidate for being the overall glucostat in the organism,” the authors state. But, while it has been proposed that beta cells in pancreatic islets represent the key regulatory element, the human islet comprises a number of different cell types, including beta, alpha, and delta cells, which could feasibly be involved.

“We wanted to test whether there is a leading organ or mechanism that maintains normal blood glucose levels within the characteristic narrow range in different animal species,” says first author Rayner Rodriguez-Diaz, Ph.D., a researcher at the University of Miami Miller School of Medicine, and Karolinska Institutet. “We therefore hypothesized that the glycemic set point results from the pancreatic islet working as an organ,’ the authors write, “where the hormonal output is governed by features and mechanisms intrinsic to the islet tissue.”

To test their hypothesis the team transplanted pancreatic islets from different species into diabetic and nondiabetic mice. Their results confirmed that the engrafted islets also transferred the glycemic levels of the donor species. “These results indicate that glucose sensing and insulin secretion from the islet was sufficient to establish target values for glycemia,” the researchers note. “The main conclusion from our studies is that the transplanted islets sense glucose levels and adjust insulin secretion until the organism reaches the species’ glycemic set point.”

But what the results didn’t indicate was whether glucostat function was the responsibility of just the islet beta cells, or whether glucagon-secreting alpha cells played a role as well. Interestingly, human islets contain a larger proportion of alpha cells than mouse islets contain, and these cells secrete glucagon and acetylcholine, which impact on glucose-induced insulin secretion in vitro. “We therefore hypothesized that alpha cell input, by increasing the efficacy of beta cell responses to glucose, affects glycemic levels.”

To investigate the role of alpha cells in maintaining the glycemic set point, the researchers treated human islet grafts with a human glucagon receptor antagonist that didn’t affect the mouse glucagon receptors. This treatment decreased insulin secretion from the human islet grafts and increased glycemia to prediabetic levels. “Our results further demonstrate that paracrine glucagon signaling in the islet is critical for the beta cell to secrete the appropriate insulin amounts that sustain the human glycemic set point,” they comment. “Based on our results, we conclude that the human glucostat depends on the functional cooperation between alpha and beta cells, not solely on the beta cell.”

The team points out that their findings have important implications for the development of approaches to diabetes therapy that aim to reconstitute beta cell populations, because without concomitant glucagon input, glycemic levels set by beta cells would likely be prediabetic. “In addition, new approaches to inhibit the contribution of glucagon to hyperglycemia need to be re-examined because inhibiting glucagon receptors systemically may also eliminate this crucial local input to the beta cell.”