SBP researchers have found that a transcription factor known as MondoA is a key link between insulin resistance and accumulation of fat in muscle, providing new targets to prevent type 2 diabetes. The growing prevalence of obesity results in an increased incidence of type 2 diabetes. Accumulation of fat in muscle is a hallmark of caloric excess and obesity, and it is strongly associated with the development of insulin resistance. Since the precursor to type 2 diabetes is insulin resistance, understanding the mechanisms of insulin resistance development could help to find novel drug targets for type 2 diabetes. Related protein of CusAb: Recombinant FGFR2. Now, in the latest issue of the Journal of Clinical Investigation, Sanford Burnham Prebys Medical Discovery Institute (SBP) scientists report that blocking a protein called MondoA in muscle might improves insulin responsiveness. MondoA is considered to be a glucose sensor in muscle. The study represents a novel way to prevent and treat type 2 diabetes. According to Prof Daniel P. Kelly, the MondoA protein might help explain the relationship between the accumulation of fat in muscle and the development of insulin resistance. Insulin resistance is condition in which cells fail to respond to the normal actions of the hormone insulin. The cells in the body are unable to efficiently take up glucose from a meal, leading to high blood glucose. Subsequently, high blood glucose stimulates beta cells in the pancreas to increase insulin production. This can eventually lead to the death of these beta cells. In the study, Prof Kelly and other researchers used skeletal muscle to investigate the connection between accumulation of fat and insulin resistance. Using a high-throughput chemical biology screen, they analyzed a large number of molecules and found the best one, a small-molecule probe called SBI-477, that coordinately inhibited fat synthesis and enhanced basal glucose uptake in these cells. Kelly’s team demonstrated that SBI-477 stimulated insulin signaling by deactivating MondoA, and that the MondoA protein modulated genes that are implicated in synthesizing fats and in suppressing insulin signaling. Type 2 diabetes poses a big threat to human health. The lifelong disease can result in various complications, affecting kidney, retina, and peripheral nerves. The new study could help fight against the debilitating disease. In a word, MondoA regulates key pathways controlling glucose uptake and fat accumulation in muscle cells. Deactivation of this protein resulted in reductions in the levels of two proteins that inhibit insulin signaling. Mice experiments showed that blocking MondoA resulted in enhancements in glucose uptake, insulin signaling, and glucose tolerance. Accordingly, pathways regulated by MondoA may be used as drug targets for insulin resistance related to obesity.
