The
Effects of Fructose on Insulin Resistance in Humans: A Systematic Review
Abstract
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.
Introduction
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.
Methods
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.
Discussion
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.
