Scientists find new links between obesity and insulin resistance

by Barbara Hewitt on September 1, 2014

New findings about the biological links between obesity, insulin resistance and type 2 diabetes may also shed light on the connection between obesity and cancer, according to scientists.

A team at the University of Texas at Dallas has found that a protein called HIF-1 alpha plays a key role in the development of insulin resistance and Type 2 diabetes in obese mice.

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The new findings may also shed light on the link between obesity and cancer, scientists say

The researchers genetically engineered the mice to lack the HIF-1 alpha protein within the animals’ fat cells, or adipocytes. The mice still made HIF-1 alpha in other types of cells and tissues in their bodies. Although the mice became obese when fed a high fat diet, they did not develop insulin resistance and diabetes to near the extent that other obese mice did.

‘There is clearly a greater chance among the obese human population to develop insulin resistance and diabetes. We still don’t know the exact mechanism, but now we know that HIF-1 alpha is very active in the pathogenesis of these diseases from obesity,’ said Dr. Jung-whan Kim, a co-lead author of the study.

He believes that the findings about HIF-1 hypoxia inducible factor-1 are significant for their possible application to fighting insulin resistance and diabetes as well as cancer. He explained that cells in the body normally consume oxygen to produce energy. But if oxygen levels decrease, for example, during strenuous exercise or at high altitudes, cells enter a condition called hypoxia, or low oxygen. With oxygen in short supply, cells switch their metabolism. Instead of energy, the cells produce reactive oxygen species, which are molecules that can damage or kill cells. To help mitigate the damage, hypoxic cells activate HIF-1 alpha, which 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.

In obesity, however, fat cells are in a chronic state of hypoxia. ‘If you look at adipose, or fat tissue, in the obese, there is massive and chronic inflammation. It’s a defence mechanism. The inflammatory cells are really good guys, but as obesity persists, inflammation becomes chronic,’ said Kim.

‘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,’ he added.

To study the effect HIF-1 alpha might have on the development of insulin resistance and diabetes, Kim and his colleagues used genetic engineering techniques to completely remove, or knock out HIF-1 alpha from adipose tissue in obese mice.

‘Once we knocked out HIF-1, everything got better. 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,’ Kim pointed out.

Kim said several pharmaceutical companies are developing HIF-1 alpha inhibitors, which might one day result in medications to treat type 2 diabetes and insulin resistance in obese people. But the primary reason behind the push for HIF-1 alpha inhibitors is cancer.


The opinions expressed in this article do not necessarily reflect the views of the DiabetesForum.com Community and should not be interpreted as medical advice. Please see your doctor before making any changes to your diabetes management plan.

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