Wednesday, July 25, 2012

Excerpt from a systematic review I wrote on Fructose and Insulin Resistance

The Effects of Fructose on Insulin Resistance in Humans: A Systematic Review

Sugar consumption has been steadily increasing in the U.S. and across the world, and has been implicated as a potential causal agent in the development of obesity and other metabolic diseases. Dietary sugars usually come in the form of cane sugar or high-fructose corn syrup, both of which are made of roughly equal parts of the monosaccharides fructose and glucose. Fructose, as opposed to glucose, has been linked in a number of studies to biomarkers for metabolic disease, such as insulin resistance and dyslipidemia. Since the presence of insulin resistance predisposes individuals to an increased risk of most chronic diseases, this review attempts to elucidate the relationship between fructose and impaired insulin sensitivity among studies published in peer-reviewed journals in the last decade. Ten studies were included in this review, the majority of which display a statistical relationship between fructose consumption and biomarkers of increased insulin resistance. An adequate number of studies with sufficient statistical power do not yet exist to determine whether fructose is the nutrient primarily responsible for the formation of insulin resistance but these preliminary study results indicate the need for additional research in this field.

            Chronic diseases, including obesity, diabetes, and heart disease, are quickly spreading across the world. The World Health Organization estimates that these diseases will cause twice as many deaths in the next decade as malnutrition, infectious disease, and childbirth combined, killing 388 million people (1). Type 2 diabetes mellitus rates alone are expected to double within the next generation, from 190 million to a projected 335 million by 2025(2).  Many health professionals are beginning to understand these chronic metabolic diseases are linked, and possibly have common causes. This is based on the presence of a few shared characteristics, one of which is insulin resistance.
These chronic diseases are grouped together into a condition called “metabolic syndrome”, or “insulin resistance syndrome”, as it is sometimes referred. There are a variety of disease criteria an individual must display in order to be diagnosed with metabolic syndrome. Usually these must include the presence of diabetes or some marker of insulin resistance (like impaired glucose tolerance or impaired fasting glucose levels) along with high blood pressure, dyslipidemia, or visceral adiposity. Once diagnosed with metabolic syndrome, an individual is at a greatly increased risk for any number of these metabolic diseases, which include diabetes, hypertension, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), stroke, obesity, and even cancer(3). Nutrition scientists often link the development of these Western diseases to a range of potential dietary causes, one of which is the increasing consumption of fructose - primarily from sugar and high-fructose corn syrup. This systematic review evaluates recent studies published in scientific journals regarding high dietary fructose consumption in adults (compared to controls consuming low fructose diets) as well as measures of insulin sensitivity to determine the extent to which fructose consumption is associated with insulin resistance.

MEDLINE was searched with PubMed through March 7, 2012, using the MeSH headings “Insulin Resistance” AND “Fructose” with the limits of “Human,” “English,” and “Adults.”  This review excludes animal studies and pediatric studies, as well as reviews, commentaries, and editorials. These limits were created in order to ascertain the effects that a diet high in fructose has on the human body and on biomarkers for disease. The primary biomarker investigated here was insulin resistance because it is a primary precursor for the diseases associated with metabolic syndrome. 
A majority of studies, most of which are randomized controlled clinical trials, found a correlation between fructose intake in adults and insulin resistance, including hepatic insulin resistance, adipose tissue insulin resistance, increases in fasting glucose and fasting insulin, and decreases in EGP(8-10,12,13,15-17). Many of these studies found increases in whole-body insulin resistance, measured by HOMA indices, the HEC clamp, and ISI, which was the focus of this review(8,12,13,15-17). Much of the clinical research on this topic has only been conducted in the last decade. Since insulin resistance is considered a causal factor in the development of metabolic syndrome, it is imperative that additional studies on fructose and its effects on disease biomarkers in humans are conducted in RCCTs with sufficient statistical power to determine the exact nature of the relationship between fructose and insulin resistance.
Of the ten studies reviewed, nine are clinical intervention trials, only one of which failed to find an increase in insulin resistance in the group fed additional fructose compared to the group fed additional glucose(14). The authors of this study admit to the fact that they carried out multiple analyses, which requires a more conservative level of statistical significance. The researchers also acknowledged that their subjects “were younger and had lower BMI and therefore less metabolic risk,” their study contained a shorter fructose feeding intervention than many other studies on this topic, and that the small number of participants greatly reduced this study’s power(14).
This review has a few shortcomings, primarily the lack of human studies on this topic, as well as a lack of studies on fructose and insulin resistance published in English. The fact that this topic has only been studied in humans largely in the last decade or two, means that RCCT studies in humans with fructose consumption lasting longer than 10 weeks have not yet happened. The longest RCCT studies to date to be undertaken on fructose and insulin resistance are by Stanhope, et al. from UC Davis, because these studies have been of longer duration and with a larger dosage, evaluating the effects fructose has on the human body over a ten-week period(15-17).  Many of the studies in this review are from countries outside the U.S. that have conducted studies with a larger dosage, longer duration, and larger sample sizes than the studies from the U.S., allowing them to potentially make more reliable correlations between fructose and its effects on insulin sensitivity(8,12,13). Studies that have not been reported in English may contain necessary information to better understand the association between fructose intake and insulin resistance.
Also, a larger number of human studies in the U.S. have been conducted with fructose and biomarkers for heart disease such as the creation of VLDL in the liver as well as the effects of fructose metabolism on uric acid levels and hypertension. Less research exists describing the association between fructose and impairment in insulin and glucose regulatory systems, as well as obesity. Animal studies have been convincing as to the development of disease indicators for metabolic syndrome from high-fructose feeding(19-21), but sufficient data from human studies needed to conclusively answer the question of whether fructose intake contributes to insulin resistance is not yet available.
            Another shortcoming of this review is the lack of a clear metabolic pathway for the development of insulin resistance from the consumption of dietary fructose. Although nutritional biologists recognize that fructose is metabolized much differently than glucose, the potential pathway linking fructose intake to whole-body insulin resistance is unclear. Glucose can be used as energy by every living cell, including every organ and tissue in the human body, and also releases insulin (which is responsible for upregulating glucose receptors in peripheral tissues) but only the liver can metabolize fructose. Once the fructose reaches the liver, it is metabolized by fructokinase, which is not regulated by levels of ATP like glucose enzymes(22). When fructose levels build up in the hepatocytes, they activate de novo lipogenesis, which is linked to increases in NAFLD as well as hepatic insulin resistance(22). Whereas only 0.5% of glucose enters hepatic de novo lipogenesis pathways, up to 30% of fructose is converted into fat, leading to large increases in VLDL(23). This increased hepatic lipid accumulation leads to activation of protein kinase C (PKC), which interrupts normal insulin responses, and the increased liver fat also impairs insulin receptor substrate (IRS)-1, which decreases hepatic glycogenesis(22). It is not well understood if and how this hepatic insulin resistance leads to decreased insulin sensitivity in the peripheral tissues, especially in muscle and other organs, but it has been suggested as a causal factor in the development of whole-body insulin resistance(22,23).
Further complicating the connection between fructose, insulin resistance, and the establishment of these disease pathways is the fact that postprandial plasma insulin levels generally show decreased values following high-fructose feeding, but when researchers began to measure fasting insulin and fasting glucose after long-term high-fructose diets, they noticed that fructose feeding had detrimental effects on these biomarkers of insulin resistance(compared to glucose or another control)(23).
            Until more adequate research is conducted, with RCCTs lasting ten weeks or more, containing large enough sample sizes, and using sufficient dosages (at least the NHANES average, if not three times more to mimic upper intake ranges), these preliminary findings are not decisive enough to change current dietary recommendations. If future studies do provide conclusive evidence linking fructose to insulin resistance, both public policies and dietary recommendations should be altered in order to potentially slow the progression of insulin resistance and the numerous chronic diseases to which it is linked.