How Obesity Leads to Type 2 Diabetes, Cancer

Findings about the biological links between obesity, type 2 diabetes and insulin resistance may also shed light on the connection between cancer and obesity, a researcher says.

In a study published online June 5 in the journal Cell, UT Dallas' Dr. Jung-whan (Jay) Kim and colleagues at the University of California, San Diego 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.

The researchers genetically engineered mice to lack the HIF-1 alpha protein within the animals' fat cells, or adipocytes. The animals 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 genetically normal, 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 Kim, a co-lead author of the study who conducted the research while a postdoctoral researcher at UC San Diego and the Salk Institute for Biological Studies. He joined the UT Dallas faculty as an assistant professor of molecular and cell biology in 2013.

Kim said the findings about HIF-1, which stands for hypoxia inducible factor-1, are significant not only for their possible application to fighting insulin resistance and diabetes, but also cancer. Here's why:

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 in turn shuts down the production of reactive oxygen species and signals inflammatory cells to migrate to the hypoxic areas.

Why Does Obesity Causes Diabetes? Being overweight increases the chances of developing the common type of diabetes, type 2 diabetes. In this disease, the body makes enough insulin but the cells in the body have become resistant to the salutary action of insulin. Why does this happen?

New Research: A report this week in Science proposes that being overweight stresses the insides of individual cells. Specifically, overeating stresses the membranous network inside of cells called endoplasmic reticulum (ER). When the ER has more nutrients to process than it can handle, it sends out an alarm signal telling the cell to dampen down the insulin receptors on the cell surface. This translates to insulin resistance and to persistently high concentrations of the sugar glucose in the blood - one of the sure signs of diabetes.