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.

Barbara K. Hecht, Ph.D.
Frederick Hecht, M.D.

How Obesity Leads to Type 2 DiaBetes, Cancer “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,” 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,” Kim said. “In the obese, HIF-1 is aberrantly and chronically elevated and is the master regulator of ominous chronic inflammation.”

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,” 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.”

Diabetes & Obesity
According to the Center for Disease Control, we are eating ourselves into a diabetes epidemic. The International Diabetes Foundation (IDF) says that, “Diabetes and obesity are the biggest public health challenge of the 21st century.” The supporting statistics they cite are staggering:

As of 1999, diabetes affected 16 million (six percent) of Americans - an increase of 40 percent in just ten years.

- During the same period, the obesity rate climbed from 12 percent to almost 20 percent.
- Last year the diabetes and obesity rates increased 6 percent and 57 percent.
- Every three seconds, someone is diagnosed with diabetes.
- Of the children born in 2000, one in three will eventually develop diabetes.

Although both diabetes and obesity risk factors are often associated with race, age, and family history, it’s becoming more and more clear that the conveniences of modern life also contribute to the development of both diseases. For example, sedentary lifestyles (reduced physical activity) and the popularity of high fat, high energy diets (think “Super Size Me”) and convenient foods are known to lead to obesity - but do they also cause diabetes?

Is There a Link Between Obesity and Diabetes?

Of the people diagnosed with type II diabetes, about 80 to 90 percent are also diagnosed as obese. This fact provides an interesting clue to the link between diabetes and obesity. Understanding what causes the disease will hopefully allow us to prevent diabetes in the future.

Being overweight places extra stress on your body in a variety of ways, including your body’s ability to maintain proper blood glucose levels. In fact, being overweight can cause your body to become resistant to insulin. If you already have diabetes, this means you will need to take even more insulin to get sugar into your cells. And if you don’t have diabetes, the prolonged effects of the insulin resistance can eventually cause you to develop the disease.

Kim said several pharmaceutical companies are developing HIF-1 alpha inhibitors to block the protein from functioning, which might one day result in medications to treat type 2 diabetes and insulin resistance in obese people. But the primary reason the pharmaceutical industry is already investigating HIF-1 alpha inhibitors is cancer.

“Tumor cells grow really fast, but the blood vessels that feed them oxygen cannot grow fast enough, so tumor cells become hypoxic,” Kim explained. “The tumor cells have to develop some sort of mechanism to survive under hypoxic stress, and that’s HIF-1 alpha.

“If you can inhibit HIF-1 alpha in a tumor cell, you can kill the cell, and that’s why pharmaceutical companies are interested in HIF-1 inhibitors.”

Kim said one motivation for the Cell study was to gain a better understanding of the links between obesity and cancer.

“There is a clear correlation between the two, but it’s not clear why obese people have a greater chance of developing certain cancers,” he said. “If you look at breast cancer, the glands that produce milk are completely surrounded by fat cells.

“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.”




Provided by ArmMed Media