How Obesity-Induced Diabetes Begins

By Jane Farrell

Scientists from the University of California, San Diego School of Medicine have discovered the sequence of early cellular responses that can ultimately lead to obesity-induced insulin resistance and diabetes.
The cells respond, the investigators said, to a high-fat diet.

“We’ve described the etiology [cause] of obesity-related diabetes. We’ve pinpointed the steps, the way the whole thing happens,” said Jerrold M. Olefsky, MD, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego. “The research is in mice, but the evidence suggests that the processes are comparable in humans and these findings are important to not just understanding how diabetes begins, but how better to treat and prevent it.”

Diabetes, one of the most serious health problems in the U.S., affects more than 25 million Americans. Another 79 million Americans are estimated to be pre-diabetic. The illness is characterized by high blood sugar levels that occur because of inadequate regulation by insulin, or insufficient response by cells to insulin. It is a major risk factor for heart disease and stroke.

Previous research by Olefsky and others has shown that obesity is characterized by low-grade inflammation in fat tissue and that this state can become chronic and result in diabetes. This latest research describes the earliest stages of that process.

In the study, the researchers fed mice a high-fat diet and ultimately zeroed in on the protein ANT2 and a “transcription factor” in fat cells called HIF1-alpha. The activation of ANT2 led to an inadequate oxygen supply in cells, and that in turn activated the damaging activity of HIF1-alpha. Mice who were genetically engineered to lack HIF-1 alpha in their fat tissues were protected from the inflammation, insulin resistance and elevated glucose levels induced by high-fat diet.

The discovery of the sequence, the scientists said, suggested that ANT2 and HIF-1alpha could be therapeutic targets.

The findings were published in the journal Cell.