Shulman’s lab group has been studying the development of insulin resistance in muscle and the liver for nearly three decades. They want to know the precise sequence of events that occur when patients develop muscle insulin resistance, liver insulin resistance, NAFLD, and type 2 diabetes. So they have developed novel magnetic-resonance scanning techniques to noninvasively measure the concentrations of metabolites within liver and skeletal muscle in patients who are prone to develop type 2 diabetes and in those with well-established type 2 diabetes. Using this approach, they have found that healthy, young, lean, insulin-resistant offspring of parents with type 2 diabetes, who have a high likelihood of developing type 2 diabetes, have insulin resistance only in skeletal muscle and not in the liver.

“We have shown that selective insulin resistance in skeletal muscle—the earliest defect we can observe in these otherwise young, healthy, lean individuals—can predispose them to hyperlipidemia, NAFLD, and liver insulin resistance by diverting ingested carbohydrate away from muscle, where it is normally stored as glycogen, to the liver, where it is converted to fat,” says Shulman. “By screening patients for muscle insulin resistance, and understanding the progression to fatty liver and diabetes, researchers may be able to uncover new ways to stop these diseases in their early stages,” he says.

In a separate study, Shulman and his colleagues studied healthy, young, lean individuals in the New Haven, Connecticut, community from five different ethnic groups and found a striking increase in the prevalence of NAFLD associated with insulin resistance in the lean Asian-Indian male volunteers. “Just about everyone will develop NAFLD if they become obese, independent of ethnicity,” says Shulman. “But there appears to be something going on in the Asian-Indian men that predisposes them to develop NAFLD and hepatic insulin resistance at a much-lower body mass index.”

To further investigate this question, Shulman’s group teamed up with HHMI investigator Richard Lifton at Yale and found a different mutation than Hobbs’ team had uncovered. They pinpointed mutations in a gene called APOC3. While Hobbs’ PNPLA3 is involved in triglyceride breakdown within the liver, the APOC3 protein regulates the breakdown of triglycerides in the blood for storage in fat cells. Increased plasma concentrations of APOC3, which these gene variants have been shown to cause, will predispose these individuals to both NAFLD and increased triglyceride concentrations in the blood.

In transgenic mouse studies, Shulman’s team found that mice overexpressing human APOC3 developed both fatty liver and hepatic insulin resistance when fed a high-fat diet, supporting his theory that increased plasma concentrations of APOC3 predisposes an individual to the development of NAFLD, and that fatty liver can cause hepatic insulin resistance and contribute to the development of type 2 diabetes.

“I think the APOC3 variants that we describe predispose lean individuals to NAFLD and hepatic insulin resistance reflecting a gene-environment interaction. Just having high plasma concentrations of APOC3 will not do anything in itself, as reflected by the lack of fatty liver and hepatic insulin resistance in the APOC3 transgenic mice fed a regular chow diet,” says Shulman. “But if you add a little bit of fat to their diet, they get fatty liver and hepatic insulin resistance.” When the young, lean, Asian-Indian men with NAFLD lose a relatively small amount of weight, Shulman’s team has found, their fatty liver and hepatic insulin resistance can be reversed.

Hobbs’ and Shulman’s evidence of two different genes with profound effects on NAFLD hints at the complexity of this metabolic disease. More research will be needed to sort out how these genes, and likely others, affect the development of this devastating syndrome.

Bacteria’s Role

Doctors in the clinic need a way to identify patients who are at risk of developing worse forms of the disease—inflammation and scarring of the liver. After all, some people with fatty liver do just fine without treatment (although if Shulman is right, their fatty liver could be contributing to diabetes). In other patients, however, the liver becomes inflamed, clogged with immune molecules, and eventually begins to harden and stop working.

“We need to find out who is at risk for developing full-on liver disease and who isn’t,” says Loomba. “And then we need to focus our energy on stopping liver disease in those at risk.”

Patients with more risk factors—diabetes, smoking, poor diet, and alcohol consumption—are more likely to develop worse stages of liver disease. But even without those risk factors, some patients end up worse off than others.

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