Study of Mice Provides Insight on How Fructose Consumption Spurs Diabetes

October 21, 2016
Andrew Smith

Investigators studied mice that had been engineered so that the insulin signaling pathways in their livers were always fully activated. According to the dominant understanding of glucose production, this should have made it impossible for those mice to produce glucose in their livers.

New research on genetically modified mice explores the mechanism by which excessive sugar consumption—and especially excessive fructose consumption–may drive the worldwide increase in type II diabetes.

Investigators studied mice that had been engineered so that the insulin signaling pathways in their livers were always fully activated. According to the dominant understanding of glucose production, the insulin signaling should have made it impossible for those mice to produce glucose in their livers. As it turned out, according to a new paper in The Journal of Clinical Investigation, the consumption of fructose triggered glucose production despite the all the insulin signaling designed to halt it.

The fructose the mice ate caused the activation of a molecular factor known as carbohydrate-responsive element-binding protein, or ChREBP. Investigators believe that this protein — which is found in the metabolic organs of humans as well as mice — caused the mice to stop responding properly to insulin signals. They hypothesize, moreover, that ChREBP may be the cause of the insulin resistance that precedes diabetes in humans.

“For the past several decades, investigators have suggested that there must be a problem in the way the liver senses insulin, and that is why insulin-resistant people make too much glucose,” said study co-author Mark Herman, MD. “We found that no matter how much insulin the pancreas made, it couldn’t override the processes started by this protein, ChREBP, to stimulate glucose production. This would ultimately cause blood sugar and insulin levels to increase, which over time can lead to insulin resistance elsewhere in the body.”

This finding adds weight to the idea that many people consume medically excessive amounts of sugar and that this excessive sugar consumption is a major cause of type 2 diabetes. Indeed, the study is one of the first to propose a specific process by which sugar consumption (or fructose consumption, at least) would eventually lead to diabetes.

A number of previous studies have found that high levels of fructose consumption cause a number of metabolic problems in animals and are associated with a number of metabolic problems in humans.

Some of those have speculated that fructose leads to weight accumulation, which leads to non-alcoholic fatty liver disease which leads to insulin resistance and diabetes (as well as an increased risk of heart attack.) The new study indicates that the accumulation of fat, either in the body or the liver, is not necessary for insulin resistance.

The authors of the new study called for more research to confirm their findings and learn more about the process they describe. Herman, moreover, thinks the study’s finding may justify some research into possible techniques for disrupting ChREBP activation and its effects.

“If we can develop drugs to target this process, this may be a way to prevent the process early in the development of the disease,” said Herman, who noted that consumption of fruit alone was unlikely to trigger any of the effects that the new study identified.

“You could eat three apples and not get the same amount of fructose you might get from a 20-ounce sugar-sweetened beverage,” he said. “The major sources of excessive fructose are in foods like sodas and many processed foods, which are foods most doctors would say to limit in your diet.”

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