17 September 2013

Cancer Drug Could Be Used To Target Diabetes Genes

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New research from a team of American scientists has identified both a biochemical pathway involved in the development of diabetes and a drug already approved by the FDA for the treatment of cancer that is capable of regulating that pathway.

Findings from the research were published as two separate online articles in Nature Medicine on Sunday.

After a meal, blood glucose levels increase and insulin causes cells in the liver to store the glucose as a substance called glycogen. When the body can’t produce insulin, as is the case in patients with type-1 diabetes, or when it can’t react appropriately to insulin, as in type-2 diabetes, blood glucose levels can become dangerously high.

To function properly, the liver must have easy access to blood, which carries both glucose and oxygen. Some liver cells with limited access to oxygen enter a state called hypoxia. Hypoxic liver cells produce certain proteins that allow them to live and function under these more severe conditions.

Through experiments with laboratory mice, the scientists found an unexpected link between how liver cells respond to insulin and hypoxia’s biochemical pathway.

“Proteins involved in this pathway could also be targeted for the development of new diabetes therapies,” said study author Amato Giaccia, a professor and director of radiation oncology at Stanford.

Study researchers found that one protein in the hypoxia pathway, HIF-2alpha, causes the expression of insulin receptor substrate 2 (IRS2) that boosts cells’ response to insulin. They also found that the drug aflibercept, a so-called VEGF inhibitor that treats cancer by starving cancerous tumors of oxygen, can increase the number of hypoxic cells in the liver of laboratory mice.

The result is an increase in HIF-2alpha levels and IRS2 expression which, in turn, results in the rodents becoming better able to handle increases in blood-glucose levels. The researchers observed that deletion of HIF-2alpha gene blocked the effect of the drug, while liver-specific initiation of HIF-2alpha expression also markedly improved the mice’s glucose tolerance.

“Much work remains to translate these mouse studies to human patients, but it will be interesting to explore VEGF inhibitors or drugs that can stabilize HIF-2alpha, such as prolyl hydroxylase inhibitors, for diabetes treatment, possibly in combination with pre-existing therapies to minimize toxicities,” study author Calvin Kuo, a professor of medicine at Stanford.

The researchers also found that blocking a protein called Phd3 specifically taps into the identified pathway, stabilizing the HIF-2alpha protein and extending its effect on IRS2 expression. Laboratory mice missing Phd3 were found to be more sensitive to insulin and showed improved glucose tolerance.

The research team noted that discovering the specific effect of Phd3 on HIF-2alpha is important. Since it doesn’t appear to affect other similar proteins in the liver, this finding could lead to possible a diabetes treatment that would avoid undesirable or dangerous side effects.

“Targeting the Phd3/HIF-2 pathway represents a new therapeutic approach for the treatment of diabetes with little toxicity,” said Giaccia. “These studies indicate that Phd specific inhibitors, especially Phd3, should be more widely developed for clinical development.”

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