Making exercise easier might do more than just slim corpulent bodies. Faulty fat-burning pathways portend diabetes, says HHMI investigator Gerald I. Shulman at Yale University, so activating those circuits could stave off the metabolic disease. He has studied sedentary people in their 20s whose parents have diabetes. The young people aren't yet diabetic, but they're already showing insulin resistance despite having a relatively normal body mass index, and Shulman wants to understand why. His team used nuclear magnetic resonance spectroscopy to noninvasively probe the molecular basis of insulin resistance—the first sign of diabetes. They found that the muscle cells of young people with insulin resistance accumulate lipids, which in turn dampen insulin's signal, preventing cells from taking up glucose.

People with insulin resistance have 30 percent fewer mitochondria than normal, and 30 percent less capacity to metabolize lipids. They hang on to energy, says Shulman, which is useful when food is scarce but deadly in modern societies where food is abundant. Accruing lipids might prime young people for diabetes later on.

Shulman aims to prevent this fate, and exercise can help. Vigorous activity activates fatty acid oxidation in mitochondria, restores the insulin response, and boosts numbers of mitochondria. But as much as doctors prescribe physical activity, only a small percentage of patients comply, says Shulman. "If we know mechanistically what's causing diabetes, we can come up with novel agents that mimic exercise and reduce diabetes and even obesity." He's focused on altering specific biochemical pathways to prevent them from making nefarious lipids such as diacylglycerol, which Shulman posits is the main trigger of insulin resistance in liver and muscle cells.

Drugs that activate PPARdelta might help, too. Evans's group reported in the February 28, 2006, issue of the Proceedings of the National Academy of Sciences that fat-fed animals treated with the PPARdelta drug controlled their blood sugar better than untreated animals. Evans is now working with Salk colleague and HHMI investigator Joseph P. Noel to capture three-dimensional pictures of PPARdelta and its partner proteins to devise new and improved PPARdelta drugs. The drug they've been using is a useful lab tool, but Evans sees room for improvement. He and Noel are aiming for second-generation compounds that might, for instance, be more easily absorbed and safer or that might target specific tissues: for instance, liver for metabolic diseases in the liver, muscle for endurance, and fat for weight loss.

Such new and improved drugs won't likely permit would-be couch potatoes to avoid exercise altogether, but they might someday make people's workouts easier or more effective.

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