Sirtuin enzyme could point to new therapies for diabetes and obesity

The abnormal uptake of glucose by the liver, resulting in dangerous blood-glucose spikes, may be able to be controlled by targeting certain enzymes.

Many people with Type 2 diabetes and obesity experience abnormal spikes in blood glucose, or hyperglycemia, following meals. It’s caused by abnormal glucose uptake in the liver, and it puts patients at high risk of suffering cardiovascular complications down the road.

A team of researchers in Japan has identified an enzyme that seems to mediate the process by which the liver processes glucose—and a resulting mechanism that could provide a new therapeutic target for Type 2 diabetes. The enzyme is Sirt2, a member of the sirtuin family, which has long been of interest to scientists studying metabolism and aging.

The researchers started by working with cells from mouse models of diabetes. By overexpressing Sirt2 in those cells, they were able to influence the activity of a key protein called glucokinase regulatory protein (GKRP). Sir2 binds to GKRP, reversing abnormal protein behavior that causes poor liver update of glucose, they discovered. They described the research in the journal Nature Communications.

They key to Sirt2’s ability to regulate hepatic glucose uptake is that it “deacetylates” GKRP, or it removes an acetyl group from the protein, affecting its function. Mouse experiments showed that introducing a type of GKRP that can’t be acetylated “perturbs” glucose uptake in the liver, researchers explained in a statement. That led them to conclude that targeting Sirt2 could offer a way to improve the liver’s uptake of glucose in people with Type 2 diabetes and obesity.

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Sirtuins were once a hot target in biotech. So hot, in fact, that GlaxoSmithKline laid out $720 million to acquire Sirtris, a startup working on therapies targeting Sirt1, in 2008. Sirtris was also studying resveratrol, a compound prevalent in red wine grapes that scientists believed could activate sirtuins. But later studies raised questions about the utility of sirtuins, and GSK ultimately shut down Sirtris.

Other enzymes could prove key to combating Type 2 diabetes and obesity. Last summer, scientists at the University of California in San Diego discovered that the enzymes IKKε and TBK1 are elevated in obese mice, and they found that an old asthma drug called amlexanox could inhibit those enzymes.

There are also several efforts underway to understand the proteins involved in turning unhealthy white fat into beneficial brown fat. Scientists at the University of Pennsylvania recently discovered that the protein FLCN works with mTOR to suppress the browning of fat, and that the process could be reversed by inhibiting FLCN.

The Japanese team that’s studying sirtuins was led by Kanazawa University with collaborators from the National Centre for Global Health and Medicine in Tokyo. They note in the statement that Sirt1 and Sirt2 have previously been shown to have overlapping functions, but that the role of Sirt2 in the process by which the liver absorbs glucose had not previously been explored.