Type 2 diabetes is known to be associated with obesity, but it’s not clear exactly why. Some explain it this way: obesity itself may not cause diabetes, but the behaviors that lead to weight gain -- taking in too many calories and burning too few -- probably do.

A few years ago, research from Duke’s Richard Surwit, PhD, Mark Feinglos, MD, and colleagues showed that in a particular strain of mouse which is genetically predisposed to diabetes and obesity, those who ate a high-fat diet went on to develop diabetes, while those fed a lower-fat diet did not -- even when eating the same number of calories.

Now basic research from Duke’s Sarah W. Stedman Nutrition & Metabolism Center is beginning to suggest why.

Basically, an overload of the byproducts created during fat metabolism can damage the machinery that regulates insulin sensitivity and production.

“We think that part of how insulin resistance comes about is that the muscle begins to inappropriately accumulate lipids and byproducts of lipid metabolism,” says Stedman Center director Christopher Newgard, PhD.

The scientists are also starting to see that overloading on fat can lead to reduced secretion of insulin.

“We can show in our cellular models that if you bombard insulin-secretion cells -- islet cells -- with elevated fat, for a couple of days for example, then you can see an impairment in insulin secretion.”

The researchers are currently working to pinpoint exactly which lipid-derived metabolites are the culprits, he says.

The researchers are also finding that an overload of all the nutrients, not just fats, is probably what’s wrong with the typical American meal of a fast-food sandwich, fries, and a soda. Their work suggests that byproducts of metabolizing too much protein, for instance, can have bad effects as well.

“That hamburger has protein in it too, and the 32-ounce soft drink has a ton of carbohydrate in it,” Newgard says.

Newgard is also in the very early stages of studying, in collaboration with Eric DeMaria, MD, chief of endosurgery, and Laura Svetkey, MD, director of clinical research at the Stedman Center, why patients who undergo bariatric surgery show improved insulin sensitivity very quickly -- within two to four weeks. (A 2004 meta-analysis published in JAMA found that over time diabetes was completely resolved in 76.8 percent of patients who underwent bariatric surgery.)

The pancreas was once thought to be the primary producer of hormones that regulate metabolism, but now scientists know that fat tissue itself as well as the gastrointestinal tract makes hormones that regulate energy balance and appetite.

“So if you’ve rerouted the stomach and the intestinal system through bariatric surgery, it stands to reason that you may have altered the production of hormones that are normally produced in the gut during food ingestion,” Newgard says.

If this is really what’s happening, he, DeMaria, and Svetkey want to find out exactly why. To do so, they will measure metabolites and other markers in patients both before and after bariatric surgery, and compare them to patients who lose weight by other means.

“We think this is going to be a very exciting model for understanding biochemical changes that drive improved insulin action,” Newgard says.