Even someone slim may be hiding signs of type 2 diabetes.

He looked the picture of health. In his early 30s, when many of his peers on the faculty at the Yale School of Medicine had put on some pounds, he had kept his weight down. But looks can be deceiving.

“I was shocked,” he recalled after learning he had fatty liver disease and insulin resistance. Left untreated, he was on a path to type 2 diabetes and other metabolic disorders with long-term and potentially lethal health effects.

The Yale scientist, who asked that his name not be used, was part of a study run by HHMI investigator Gerald I. Shulman, who wasn’t surprised at all. He’s been studying young, outwardly healthy men for nearly two decades to sleuth out the causes of diabetes in apparently fit adults.

Shulman and HHMI investigator Richard P. Lifton, also at Yale, identified a genetic variant common among a group of Asian Indian men now living in New Haven, including Shulman’s stunned Yale colleague. They were in their 20s and early 30s, had no signs of health problems, and kept themselves lean. On the inside, however, they had fatty liver disease and insulin resistance. That discovery, published in the March 25 New England Journal of Medicine, may pave the way to new treatments for type 2 diabetes for everyone.

For the past six years, Shulman has conducted a series of studies to examine how fat moves inside the body. He has shown that far more Asian Indian men have unexpectedly large pools of liver fat, a condition known as nonalcoholic fatty liver disease, and that they are markedly insulin resistant.

Standard theories have blamed increased body fat, particularly around the midsection, for causing inflammation and eventually type 2 diabetes. That theory makes rising U.S. rates of obesity the big culprit behind the huge increase seen in the disease. However, Shulman believes the root cause for insulin resistance lies in “an unbalanced shifting of fat into liver and muscle cells.” This focused accumulation of fat, he theorizes, could put even a person who is young and lean on the path to type 2 diabetes. Over the years, his team mapped out a likely metabolic pathway that pushes fat to build up in liver and muscle cells. It was time to look for a genetic factor behind the process.

Illustration: VSA Partners

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