Sugar-Coated Proteins Trigger Insulin Resistance

The report in the April 16, 2002, issue of the Proceedings of the National Academy of Sciences describes how proteins involved in the insulin pathway fail to work properly after becoming coated with too many sugar molecules.

Type 2 diabetes, the most common form in adults, occurs when muscle, fat and other tissues stop responding to insulin's signals to remove excess sugar from the blood. "Cells do not respond to insulin itself. Instead, a whole cascade of events, set in motion by insulin, eventually causes cells to take in sugar,” explains Dr. Gerald Hart of Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu). "We now have an explanation of how sugar can affect these signals, and even a hypothesis for how high blood sugar could cause tissue damage in diabetes--by improperly modifying proteins.”

The research team developed new methods for analyzing simple sugars with special emphasis on O-linked beta-N-acetylglucosamine (O-GlcNAc), which is frequently used by the cell nucleus and protoplasm to label proteins and modify their behavior. In the current study, the scientists employed a blocker called PUGNAc to force the glycosylation of cellular proteins without adding extra sugar, as had been done by others to create insulin resistance.

Not only did the blocker increase the amount of O-GlcNAc bound to proteins, but also the increase caused the cells to stop responding to insulin. Two proteins from the insulin-signaling pathway, beta-catenin and insulin receptor substrate-1 (IRS-1), were found to be more glycosylated than normal. The researchers suspect that the ability of these proteins to function is adversely affected by the extra sugars they carry. Thus, increasing O-GlcNAc on proteins is, by itself, a cause of insulin resistance, rather than an effect or a coincidence.



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