THE long-standing mystery of why fat people have a high risk of developing diabetes is on its way to a solution thanks to a protein that apparently causes the body to waste away.
Obese people often suffer from a form of diabetes in which the body becomes resistant to the effects of insulin. When this happens, their blood sugar levels can rise to dangerous levels. Until recently, scientists had few clues about this process beyond a hunch that changes within fat cells were to blame.
Two years ago, G枚khan Hotamisligil and his colleagues at Harvard Medical School in Boston found that when people become obese, their fat cells make large quantities of a protein called tumour necrosis factor alpha. When fat people lose weight, however, the TNF-伪 production decreases and they stop being insulin resistant.
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Now Hotamisligil thinks he knows how TNF-伪 knocks out the body鈥檚 response to insulin. His team has shown that TNF-伪 instructs cells to add phosphate groups to a molecule called insulin receptor substrate-1 (IRS-1). This molecule is the start of a molecular signalling pathway inside the fat cells that comes into play when insulin binds to receptors on the cell surface. When phosphorylated, however, IRS-1 cannot pass the signal on (Science, vol 271, p 665).
Overproduction of TNF-伪 has been linked to wasting diseases, including the severe weight loss seen in AIDS patients, which leads Hotamisligil to suspect that it suppresses appetite. 鈥淚t鈥檚 possible that TNF-伪 is a response to obesity,鈥� he says. 鈥淭he insulin resistance could be a side effect.鈥�
Unfortunately, it is not possible to treat diabetes by designing drugs that attack TNF-伪 because the protein is also a vital part of the body鈥檚 immune defences. It is produced by white blood cells called macrophages, and sets off a chain of reactions that cause the immune system鈥檚 killer T-cells to divide. But now that IRS-1 has been implicated in the story, says Hotamisligil, it may be possible to target drugs against this molecule instead.