Research Links Sugar Consumption, Fat Production, and Diabetes

Jenny Mei April 3, 2011 1

Diabetes and obesity are two of the most critical health issues in the United States today, with millions of dollars poured into research every year to further uncover the sources of this epidemic in order to cure the disease. Researchers at the Yale School of Medicine working with Dr. Varman Samuel, Assistant Professor of Endocrinology, have recently uncovered a feed-forward mechanism whereby excess sugar consumption may lead to increased fat production in the liver and the ensuing development of diabetes.

An Urgent Issue
As a medical resident in training, Samuel was struck by the number of patients who had Type II Diabetes, which can lead to a range of serious complications, including heart attacks, limb and vision loss, and renal failure. Since Type II Diabetes closely follows obesity in many patients, Samuel began his research efforts trying to understand how obesity leads to diabetes. “The main issue of concern is the increase in total sugar consumption, not just that of high fructose corn syrup,” says Samuel. “This has paralleled the rise in obesity over the past decades.” Excess fructose consumption is particularly unhealthy; while glucose is easily stored as glycogen in the body, fructose is more likely to be turned into fat by the liver. Given that fatty liver is a common complication of obesity, it is not surprising that fatty liver is the most common chronic liver disease in the United States, affecting 10-20% of Americans.

This side-by-side comparison shows a normal versus fatty liver. Fatty liver is the most common chronic liver disease in the United States. Image courtesy of Mayo Foundation for Medical Education and Research.

Type II Diabetes, another common disease linked to obesity that affects over 25 million Americans, results from resistance to insulin, a hormone that triggers sugar uptake and storage from the bloodstream into bodily tissues. Insulin binds to receptors on target membranes to activate a series of proteins in the cell to perform its task. The accumulation of fat within key tissues activates other proteins that interfere with the insulin pathway. Thus, “if there is too much fat in the liver,” explains Samuel, “the ability of insulin to activate those signals is impaired, making those cells resistant to insulin.” With such a background, Samuel began research on how fructose can lead to fatty liver and subsequent resistance of the body to insulin.

The Loop
Too much fructose consumption can lead to excess levels of hepatic lipogenesis, or excess fat production in the liver, which then activates proteins that block insulin signaling. Samuel notes that our cells have feed-forward loops in which a little bit of fat accumulation further enhances the expression of key enzymes involved in lipogenesis, resulting in even more fat accumulation. Though these enzymes rapidly increase lipid production from fructose, the feed-forward loop is completely dependent on availability of substrate – i.e. if fructose is available, more fat will accumulate, but if fructose consumption is reduced or stopped, fat accumulation also halts.

Fat accumulation disrupts insulin signaling through a cascade of interactions. One lipid structure, diacylglycerol (DAG), accumulates as lipid droplets within the cell, acting as mini organelles with membranes that regulate the size of the droplet as well lipid movement in and out of the droplet. Increasing amounts of DAG within the droplets activate the Protein Kinase C (PKC) family of enzymes. PKC leads to production of nPKC molecules, which then interfere with insulin signaling. One way Samuel analyzed this correlation was through PKC epsilon, an isoform of PKC that links fat accumulation and insulin resistance. Samuel used antisense oligonucleotides (ASOs) to analyze proteins that help coordinate cellular responses to certain nutrients, like fructose, as well as proteins that were implicated in lipogenesis. Thus, decreasing expression of target proteins like PKC epsilon would elucidate its role in the cellular response that leads to lipogenesis.

This diagram shows the cellular mechanisms behind insulin resistance in patients with Type II Diabetes. When glucose transporters such as GLUT4 have defects in cellular signaling, there is insufficient uptake of glucose from the bloodstream. Image courtesy of ChattahBox.com.

The ASO Method: Smart Drug Design
ASOs work by tricking the cell to destroy specific mRNAs by mimicking a hybrid DNA-mRNA duplex characteristic of viruses. When an ASO complementary to the mRNA of the protein of interest enters the cell, it binds to the mRNA, creating a hybrid molecule that the cell recognizes as foreign. The cell then activates mechanisms within the cell to deplete all the foreign mRNA, inducing a rapid decrease in the expression of that particular protein of interest. In Samuel’s case, his analysis of PKC-epsilon showed that when this protein is absent, even without fatty liver, the experimental animal does not become as insulin-resistant. Another protein Samuel investigated through the ASO method was PGC1-beta. Without this protein, in vivo experiments with rats show the animals not converting fructose into fat and thus not becoming as insulin resistant. Such experiments allow isolation of specific proteins for analysis in this correlation among sugar consumption, fat production, and diabetes risk.

When asked how he arrived at his hypothesis and reasoning, Samuel explains that he considered research done on the correlation between the rising rate of sugar consumption and parallel rises in obesity rates over the past several decades in the United States. The initial hypothesis was that the primary culprit behind sugar-induced health issues was high fructose corn syrup, a cheaper substitute that has replaced cane sugar in many processed foods and carbonated beverages; however, Samuel, along with many other scientists today, disagree with this conclusion. He proposes that Americans are simply consuming too much sugar in general, and most of that sugar happens to come from widely used high fructose corn syrup.

Going Forward
Samuel has recently begun human studies to see whether these mechanisms translate into the same results for humans. Liver biopsies of obese patients show that some morbidly obese individuals surprisingly lack resistance to insulin, showing a weak correlation between obesity and insulin resistance. Instead, there was a strong connection with DAG – the more DAG in a patient’s liver, the more insulin resistant the patient. Thus, DAG serves as a much better predictor of insulin resistance in humans than obesity alone. Such results also suggest that leaner individuals can still end up with more fatty liver and subsequent insulin resistance; heavier people just tend to have more fat cells that can store fat, thus rendering them more sensitive to insulin in general.

As for overall implications of this research and potential for future treatments, Samuel says the current project is focused on analyzing these links in human patients and looking into molecules that are good targets for drug design. Ideally, such drugs could specifically inhibit molecules involved in the feed-forward mechanism, such as PKC epsilon or PGC1-beta, which could possibly reduce fatty livers and the onset of diabetes.

At the end of the day, however, Samuel wishes that his research could highlight the importance of good diet and health. As a practicing endocrinologist in Internal Medicine at the Yale-New Haven Hospital with many diabetic patients, Samuel hopes that this research will inform the public about nutrition and educate our legislature and nutritionists about the process behind the diabetes epidemic. Ultimately, the root problem is excess sugar consumption, and the only way to halt this diabetes epidemic is to “grab the bull by its horns” by overhauling people’s dietary habits. “Research isn’t the hardest part,” claims Samuel. “It’s much harder to change people’s behavior. Research helps us head in that direction.”

One Comment »

  1. Heather November 30, 2011 at 9:45 AM - Reply

    Thank you for this article. I am referencing it for a sophmore level class presentation on the risks of excess sugar to replace healthy fat and protien consumption due to erroneous ideas that all calories are the same.

    See you at the farmer’s market!

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