A key mechanism behind diabetes may start in the brain, with early signs of the disease detectable through rising levels of molecules not previously linked to insulin signaling, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai published today in the journal Cell Metabolism.
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 patient, and that this rise occurs many years before someone develops diabetes. Why and how BCAA breakdown may be impaired in diabetes and obesity remained unclear going into the current study.
"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, MD, PhD, Associate Professor of Medicine at the Icahn School of Medicine and senior author of the new study.
"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," said Dr. Andrew C. Shin, PhD, an Instructor of Medicine at the Icahn School of Medicine at Mount Sinai 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," Dr. Shin added. Dr. Shin also pointed out that the team's newly discovered pathway is also found in organisms ranging from humans to rodents to worms. Mechanisms "conserved" across evolution are often of fundamental biological importance.
The initial discovery that started this line of investigation was made 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. "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," said Dr. Buettner.
The team then went on to test the concept in a variety of animal models such as mice, rats, and round worms. They were also able to confirm in prediabetic monkeys as well as obese and diabetic humans that elevated BCAAs are associated with decreased BCAA breakdown in liver.
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 (NIDDK) to Drs. Shin and Dr. Buettner and the American Diabetes Association to Dr. Buettner.
About the Mount Sinai Health System
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 Health 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, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.
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