NEW YORK—According to a study led by researchers at the Icahn School of Medicine at Mount Sinai and published in the Oct. 9 issue of the journal Cell Metabolism, a key mechanism behind diabetes may start in the brain.
Past studies had found that levels of a key set of protein building blocks, branched-chain amino acids (BCAAs), are higher in obese and diabetic patients, and that this rise occurs many years before someone develops diabetes. The current research suggests that early signs of the disease may be detectable through rising levels of these molecules, which had not previously been linked to insulin signaling.
“Our study results demonstrate for the first time that insulin signaling in the mammalian brain regulates BCAA levels by increasing BCAA breakdown in the liver,” said Dr. Christoph Buettner, associate professor of medicine at the Icahn School of Medicine and senior author of the new study, in the official news release about the team’s work. “This suggests that elevated plasma BCAAs are a reflection of impaired brain insulin signaling in obese and diabetic individuals.”
“What’s important is that rodents with impaired insulin signaling exclusively in the brain have elevated plasma BCAA levels and impaired BCAA breakdown in liver,” added Dr. Andrew C. Shin, an instructor of medicine at Icahn and the first author of this study. “Since disrupted brain insulin signaling may cause the early rise of BCAAs seen in persons who eventually develop diabetes, the insulin resistance that leads to diabetes may actually start in the brain. The results suggest that levels of BCAAs may prove to reflect brain insulin sensitivity.”
Shin also noted that the team’s newly discovered pathway is also found in organisms ranging from humans to rodents to worms, pointing out that mechanisms that are “conserved” across evolution are often of fundamental biological importance.
When asked to confirm whether these research findings would be potentially useful in terms of diagnostics, Buettner tells DDNews they should be, saying, “BCAAs seem to be a good marker for overall metabolic control and a predictor for future risk of diabetes.” He also confirms that the research findings might be useful in drug discovery and development, because “BCAAs seem to be under the control of the central nervous system (and CNS control of metabolism is impaired in diabetes and obesity), thus they should be good markers for restored or improved CNS control of metabolism.”
This line of research all started after proteomic and metabolomic studies of liver and plasma from rats that had been infused with insulin into the brain pointed toward a role of brain insulin signaling in BCAA catabolism, with Buettner noting, “Our study provides an example of how proteomics and metabolomics, techniques that survey proteins and metabolites, allow researchers to come up with a hypothesis. They are also great discovery tools.”
Using a variety of animal models—including mice, rats and roundworms—the researchers tested the concept and also confirmed in prediabetic monkeys and in obese and diabetic humans that elevated BCAAs are associated with decreased BCAA breakdown in liver.
Next steps, Buettner tells DDNews, are “To understand the mechanisms through which the CNS communicates with the liver, which part of the autonomic nervous system, which cell type in the liver is the primary target, are there humoral factors that communicate to the liver? We will be employing novel genetic mouse models that we have generated to get at these questions.”
This study was conducted through partnerships with Pacific Northwest National Laboratory, Pennsylvania State University College of Medicine, Duke University Medical Center, University of Ulm, University Medical Center Hamburg-Eppendorf and Oregon National Primate Research Center.
The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases to Shin and Buettner and from the American Diabetes Association to Buettner.
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the system has an extensive ambulatory network and a range of inpatient and outpatient services, from community‐based facilities to tertiary and quaternary care. The system includes approximately 6,600 primary and specialty care physicians, 12‐minority‐owned free‐standing ambulatory surgery centers, more than 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers.