According to the National Cancer Institute, obesity is associated with an increased risk of breast, colorectal, thyroid, and several other types of cancer. Now research conducted by scientists at the University of Texas, Dallas has tried to figure out the link between insulin resistance in obese diabetics and cancer. The study is published in the journal Cell on June 5, according to a press release.
Using mouse models, Dr. Jung-whan (Jay) Kim from UT Dallas and scientists from University of California, San Diego found that a protein called HIF-1 alpha (hypoxia inducible factor-1), found in cells when oxygen concentrations are low, plays a key role in the development of insulin resistance and type 2 diabetes in obese mice.The scientists genetically engineered mice to lack HIF-1 alpha protein in their fat cells, or adipocytes. The mice were then fed a high fat diet to make them obese. But these obese mice did not develop insulin resistance or diabetes while normal mice with the HIF-1 alpha protein, did.
According to Kim, HIF-1 alpha influences not only insulin resistance and diabetes in humans but also cancer.
Previous studies have shown that overexpression of HIF-1 alpha induces and also increases cancer mortality. The reason behind this is that when the body is deprived of adequate oxygen supply, cells enter a state known as hypoxia or low oxygen. Under such conditions cells alter their metabolism and start producing reactive oxygen species, which are molecules that can damage or kill cells, similar to what happens in cancerous tumors. To overcome this, hypoxic cells activate HIF-1 alpha, which in turn shuts down the production of reactive oxygen species and signals inflammatory cells to migrate to the hypoxic areas.
"Organisms need to be able to temporarily adapt to the stress of hypoxic conditions until the situation changes, so when inflammatory cells see this kind of signal, they come to the hypoxic area to do their normal job, which is to basically eat damaged cells," Kim said.
But in obesity, fat cells are constantly in hypoxia.
"If you look at adipose, or fat tissue, in the obese, there is massive and chronic inflammation," he said. "It's a defense mechanism. The inflammatory cells are really good guys, but as obesity persists, inflammation becomes chronic. HIF-1 alpha is important for hypoxia adaptation, but it's constantly activated in the obese, and that's where it turns bad. In the obese, HIF-1 is aberrantly and chronically elevated and is the master regulator of ominous chronic inflammation."
So when the scientists removed HIF-1 alpha from the fat cells of obese mice, they found that the mice were less resistant to insulin.
"Once we knocked out HIF-1, everything got better," he said. "The fat cells survived and the mice remained obese, but we saw less inflammation in the fat tissue. These mice responded better to insulin than their normal counterparts, which means insulin sensitivity was improved and glucose tolerance was improved."
Several pharmaceutical companies are already researching and developing drugs to block HIF-1 alpha, which can potentially cure insulin resistance and diabetes and also inhibit cancer cells. Kim said he next plans to study the correlation between obesity and breast cancer.
“If you look at breast cancer, the glands that produce milk are completely surrounded by fat cells”, he says. "Tumor tissue is hypoxic. Obese tissue is hypoxic. HIF-1 alpha is important in both conditions. I'm very motivated to study the interaction between breast cancer cells and fat cells."