TWO drugs used to treat liver disorders could be turned against obesity-related diabetes.
People with type 2 diabetes are unable to regulate the amount of glucose in their blood because they have developed resistance to insulin, the hormone that usually stimulates glucose uptake by cells. The disease generally affects overweight adults, and if not controlled by diet and exercise, increases the risk of heart disease, strokes, nerve damage and blindness.
Now a study in severely obese mice with insulin resistance suggests that two drugs already in clinical use for liver disease and disorders of the urea cycle could also treat diabetes by returning glucose levels to normal.
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Obesity is thought to play a central role in the development of type 2 diabetes by placing stress on each cell鈥檚 endoplasmic reticulum (ER), its protein production factory. Like every factory, there is a limit to the ER鈥檚 processing power and obesity places extra demands on it by forcing it to traffic excess fat molecules.
To cope with the extra work, the ER recruits chemical 鈥渃haperones鈥� to help assemble and transport proteins. In extreme cases, though, the ER also shuts down insulin signalling pathways, so cells no longer respond to the hormone. This is because insulin increases protein production by forcing cells to absorb circulating amino acids and transport them to sites of protein synthesis. 鈥淲hen the ER no longer wants to face any more proteins, it has developed a way to shut down the main pathways that produce them,鈥� says G枚khan Hotamisligil of Harvard University School of Public Health.
The pancreatic beta cells that produce insulin try to compensate for the fact that cells aren鈥檛 responding to it by churning out more insulin, until many collapse under the strain. As a result, insufficient insulin is produced and dangerously high levels of blood glucose build up.
To prevent this chain of events, Hotamisligil and his colleagues gave obese mice extra chemical chaperones to relieve the strain on the ER, in the form of the drugs PBA and TUDCA. The blood glucose levels of mice treated with either drug returned to normal within four to seven days and remained so until the treatment was stopped after three weeks (Science, vol 313, p 1137).
鈥淭hese appear to be remarkable findings,鈥� says Ian Godsland, a specialist in metabolic medicine at Imperial College London. Since the drugs have already been approved for other conditions in humans, Godsland says clinical trials could start sooner than would usually be expected for a novel drug.
鈥淭he drugs have already been approved for other conditions, so clinical trials might start sooner than usually expected鈥�
Such drugs would not help the estimated 20 per cent of people with inherited type 2 diabetes whose low insulin production results from a genetic mutation rather than abnormal ER function. However, since there are also signs of disturbance to the ER in type 1 diabetes and atherosclerosis, the drugs could help back up existing treatments for these conditions.
