Insulin is a hormone secreted by the pancreas that helps fat and muscle cells take glucose from the blood. When a person's cells stop responding to insulin, the person has insulin resistance and glucose builds up in the blood, signaling the pancreas to produce ever more insulin.

"We've identified a mechanism for insulin resistance that involves a gene that ties insulin resistance to mitochondrial function," said senior author of the work was published in Cell Reports.

Previous work by the team linked a variant of a human gene called NAT2 with insulin resistance in humans. In mice, suppressing a similar gene, called Nat1, caused metabolic dysfunction, including decreased insulin sensitivity and higher levels of blood sugar, insulin and triglycerides.

The new study shows that suppressing the expression of the Nat1 gene in mice interferes with the function of mitochondria—cell structures that make ATP, the energy currency of cells. Without ATP, cells cannot live and function.

In addition, mice whose Nat1 gene had been eliminated gained more weight and had larger fat cells and higher levels of biomarkers indicating inflammation than did regular mice, even though all the mice got the same amount of food and water.

The mice without Nat1 also had a decreased ability to use fat for energy, said the senior author, and they were also pretty slow on the exercise wheel. "When we put mice on a treadmill and make them exercise really, really hard, the mice that lack this Nat1 gene don't have the ability to keep up with normal mice," senior author said. "And that supports the hypothesis that poorly functioning mitochondria are part of the problem."

Exactly why the Nat1-free mice have trouble running is something researchers and his colleagues are still working out. "Is that physically an effect on muscle, skeletal muscle? Is that an effect on the heart? We don't know exactly yet," senior author said. Upcoming work will focus on identifying a factor that links all these metabolic effects.

http://med.stanford.edu/news/all-news/2016/10/gene-could-help-explain-insulin-resistance.html