LOS ANGELES – Sugar consumption has been implicated as a risk factor for the development of diabetes since at least the 1920s, but high salt intake may also increase the risk for obesity and prediabetes by stimulating fructose production in the liver.

“We think about high-salt diets as being associated with hypertension, but if you put people on a high-salt diet, you can induce insulin resistance within 5 or 10 days,” Richard J. Johnson, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There is a fair amount of published data suggesting that a high salt intake, defined as greater than 150 mmol per day, is associated with hypertension, insulin resistance, obesity, and metabolic syndrome. In fact, it’s been reported that obese people are slightly hyperosmolar and tend to have elevated vasopressin levels. Interestingly, sugar stimulates vasopressin production.”

In an unpublished mouse study, Dr. Johnson and his associates added 1% salt to drinking water and found that it stimulates fructose production in the liver. “It takes months, but when you put them on a high-salt diet, they become fat and develop features of metabolic syndrome,” he said. “The high-salt diet induced increased energy intake, and we could show that this was due to leptin resistance by doing leptin-injection experiments.”

Furthermore, the mice on high-salt diets became insulin resistant. “Their fasting glucose went up, their fasting insulin went up, and they developed marked fatty liver, obesity, abdominal fat, and hypertension,” Dr. Johnson added. The discovery supports the notion that osmolality is the mechanism by which salt drives blood pressure, not volume expansion. “And I think that’s going to turn out to be important in obesity and metabolic syndrome as well,” he said.

Dr. Johnson, a professor of medicine in the department of renal diseases and hypertension at the University of Colorado at Denver, Aurora, discussed the role of role of sugar and fructose in the development of diabetes as well. He noted that annual sugar consumption in the United States rose from about 4 pounds per person in 1700 to about 150 pounds per person today. About one-third of current sugar intake comes from soft drinks.

“The reason why we think that fructose is a good candidate for playing a role in the diabetes epidemic is because, when you give an animal water drinking combined with fructose, they will rapidly start increasing their energy intake,” he said. “They become lethargic and less active, and they gain weight.”

He and his colleagues have demonstrated that when rats are fed fructose over time, they become leptin resistant (Am J Physiol. 2008 Nov;295:R1370-5). “Not only that, it’s been shown in animals and humans that, if you feed people fructose over time, fructose will decrease resting energy expenditure,” he said. “Our work and that of others has shown that fructose stimulates weight gain by stimulating energy intake. It does so by inducing leptin resistance. It also works in the brain to stimulate dopamine and to drive food intake that way as well.”

Fructose also impairs fatty acid oxidation and reduces energy expenditure, he continued. In one human trial, in which men consumed 200g of fructose for 2 weeks, Dr. Johnson and his associates found that 25% of them developed features of metabolic syndrome (Int J Obes. 2010;34[3]:454-61). “Just think about how long it takes to get obese or metabolic syndrome,” he said. “We think in terms of years, but this was a 2-week study! This means there’s something special about fructose that seems to drive metabolic syndrome.”

A key player in the process appears to be an enzyme in the liver known as fructokinase, which metabolizes fructose so rapidly that it causes ATP depletion. “Normally, when glucose is metabolized, ATP levels stay normal in the cell because if you start to consume too much ATP in the initial phosphorylation, there’s a feedback mechanism,” Dr. Johnson said. “But not so for fructose; it’s a runaway train, and it activates a nucleotide degradation pathway, which we call the energy depletion pathway. This seems to be what is critical for fructose effects.”

Further evaluation of that pathway led him and his associates to discover that lowering uric acid reduced fatty liver formation in fructose-fed rats (PLOS One 2012 Oct. 24. doi:10.1371/journal.pone.0047948). “We started looking at how this worked, and we found that, when we put uric acid on liver cells, that they actually stimulated fat accumulation,” he said. “We showed that in an in vitro system, and we found that both fructose and uric acid stimulate oxidative stress in the mitochondria. It’s very specific. You can actually block the production of oxidative stress with allopurinol, a drug that lowers uric acid. We’ve been building a case that this pathway is involved in a lot of mechanisms that lead to obesity, insulin resistance, and hypertension.”

Dr. Johnson concluded by noting that not all calories are created equal. “Some additives, like salt, might be playing a role in metabolic syndrome, obesity, and diabetes,” he said. “We think that sugar and high fructose corn sugar are the major causes driving metabolic syndrome. High-glycemic carbs are working primarily through fructose to induce [insulin resistance]. We think that salt may accelerate this pathway as well.”

He disclosed that he holds patents and patent applications related to this work and that he has launched a start-up company trying to develop inhibitors of fructose metabolism.

Dr. Johnson reported having no conflicts of interest related to this article.

dbrunk@frontlinemedcom.com

Expert discusses the role of salt and fructose in diabetes