American Researchers Tie Insulin Resistance to Mitochondrial Dysfunction

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Researchers from Stanford University School of Medicine and the University of Wisconsin have found a new gene, involved in a cell’s energy production, which could explain more about insulin resistance.

The body’s inability to use insulin normally has been established as a primary leading cause of type 2 diabetes. But, how insulin resistance develops has remained a mystery.

Many research studies have provided different insights into what may cause insulin resistance, some more tangible than others. Recently, scientists from Duke University have, for example, suggested that insulin resistance could be brought on by excess sugar in the liver.

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While this whole body of research is important for our understanding of how metabolic disorders come about, readers should note that these findings won’t have an immediate impact on the way diseases like type 2 diabetes are managed.Our best tool to enhance diabetes management remains controlling environmental causes, like an unbalanced diet, sedentary habits, and other negative lifestyle factors that can contribute to making someone more vulnerable to the disease.In this study, lead author Indumathi Chennamsetty from Stanford, and his colleagues began untangling new connections between mitochondria, which produce the energy currency of the cells, a mouse gene causing metabolic dysfunction that has an equivalent in humans, and insulin resistance.

Previous work by the group’s senior author, Joshua Knowles, linked a variant of a human gene called NAT2 with molecular mechanisms behind insulin resistance.

At the time, Knowles tested whether suppressing a similar gene to NAT2 in mice, called Nat1, caused metabolic dysfunction. The results indicated that it resulted in decreased insulin sensitivity and led to elevated blood sugar, insulin and triglycerides levels.

The current findings, published in the journal Cell Reports, show that suppressing the suspect gene Nat1 in mice caused additional notable deleterious effects.

It appears that mice whose Nat1 gene had been eliminated experience a loss of mitochondrial function, gain more weight, display larger fat cells and have higher levels of biomarkers used to detect inflammation.

An inflammatory state has been put forward as one of the underlying causes leading to various diabetes-related complications, like cardiovascular disease and fatty liver disease.

The decrease in mitochondrial function detected in the mouse models manifested as the inability to use fat for energy, as well as a lower level of endurance on the exercise wheel.

Nat1 knockout mice that were put on a treadmill had a hard time keeping up with the pace of normal mice, which can explain why they were unable to burn fat for fuel.

The body tends not to dig into fat stores for energy until it has used up all available glucose in the muscles through prolonged vigorous exercise.

The researchers drew a parallel between this observation in mice, and insulin resistance in humans, which is characterized by the incapacity of cells to partition fuel for energy.

This can lead to decreased uptake of sugar by muscle and fat cells, and increased risk of type 2 diabetes.

Overall, these findings suggest that Nat1 may support good mitochondrial function, thereby somewhat cutting the risk of developing insulin resistance.


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