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 signalling, according to an international study led by researchers at Mount Sinai Hospital.
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. Why and how BCAA breakdown may be impaired in diabetes and obesity remained unclear going into the current study.
The study results demonstrate for the first time that insulin signalling in the mammalian brain regulates BCAA levels by increasing BCAA breakdown in the liver. 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 signalling exclusively in the brain have elevated plasma BCAA levels and impaired BCAA breakdown in liver. Since disrupted brain insulin signalling 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. 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 signalling in BCAA catabolism. The study provides an example of how proteomics and metabolomics, techniques that survey proteins and metabolites allow researchers to come up with a hypothesis.
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.