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Dietary advanced glycation end-product restriction for the attenuation of insulin resistance, oxidative stress and endothelial dysfunction: a systematic review
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The benefits of advanced glycation end-product (AGE)-restricted diets in humans are unclear. This review aimed to determine the
effect of dietary AGE restriction on the inflammatory profiles of healthy adults and adults with diabetes or renal failure. Eight
computer databases were searched for controlled feeding trials published in English between January 1997 and December 2012.
Human trials were included if at least one group received an AGE-restricted dietary intervention. A total of 12 trials reporting on
289 participants were included in the review. Five trials (42%) were of high methodological quality. Meta-analysis of two long-term
(16 week) trials provided evidence favoring an AGE-restricted diet for the reduction of 8-isoprostanes (standardized mean
difference 0.9; 95% confidence interval (CI): 0.3–1.5) and tumor necrosis factor-a (1.3; 95% CI: 0.6–1.9) in healthy adults.
Intermediate-term dietary AGE restriction in adults with chronic renal failure reduced serum VCAM-1 (0.9; 95% CI: 0.1–1.7).
Individual trials provided some evidence that long-term dietary AGE restriction reduces HOMA-IR (1.4; 95% CI: 0.3–2.6) and
AGE-modified low-density lipoprotein (2.7; 95% CI: 1.6–3.9) in adults with type 2 diabetes. Generalisability is limited, as 75% of
studies were of less than 6 weeks duration and more than half were of low methodological quality. Evidence quality ranged from
low to very low, limiting the conclusions that can be drawn from this review. There is currently insufficient evidence to recommend
dietary AGE restriction for the alleviation of the proinflammatory milieu in healthy individuals and patients with diabetes or renal
failure. Additional long-term high-quality RCTs with larger sample sizes measuring patient-important outcomes are required to
strengthen the evidence supporting the effects of AGE-restricted diets.
INTRODUCTION
Advanced glycation end products (AGEs) are formed endogenously
when the carbonyl groups of reducing sugars nonenzymatically
react with the free amino groups on proteins. AGEs
are generated in vivo as a normal consequence of metabolism, but
their formation is accelerated under conditions of hyperglycemia,
hyperlipidemia and increased oxidative stress.
Although glucose is relatively slow in reacting with proteins,
highly reactive dicarbonyl compounds (generated as a result of
glucose auto-oxidation, lipid peroxidation and the interruption
of glycolysis by reactive oxygen species) are capable of rapid
AGE formation. Dicarbonyls such as glyoxal, methylglyoxal and
3-deoxyglucosone interact with intracellular proteins to form
AGEs, and can also diffuse out of the cell and react with
extracellular proteins.
Excessive AGE accumulation results in significant cellular
dysfunction by inhibiting communication between cells, altering
protein structure and interfering with lipid accumulation within
the arterial wall.1 Interaction of AGEs with the receptor for AGEs
(RAGE) activates nuclear factor kB, triggering oxidative stress,
thrombogenesis, vascular inflammation and pathological angiogenesis,2
thereby contributing to many of the long-term
complications of diabetes. More recently, AGEs have been implicated
in the pathogenesis of type 2 diabetes by contributing to the development of insulin resistance and low-grade inflammation
known to precede the condition.3,4
Apart from endogenous AGE formation, AGEs and their
precursors are also absorbed by the body from exogenous
sources such as cigarette smoke and through consumption of
highly heated processed foods. Browning of food during cooking
is used to enhance the quality, flavour, color and aroma of the
diet. This process (known as the Maillard reaction) generates large
quantities of AGEs.5 Factors that enhance AGE formation in foods
include high lipid and protein content, low water content during
cooking, elevated pH and the application of high temperature
over a short time period. More AGEs are generated in foods
exposed to dry heat (grilling, frying, roasting, baking and
barbecuing) than foods cooked at lower temperatures for longer
time periods in the presence of higher water content (boiling,
steaming, poaching, stewing or slow cooking).6
Kinetic studies have demonstrated that approximately 10–30%
of dietary AGEs consumed are intestinally absorbed,7 with only
one-third of ingested AGEs excreted in urine and feces. Plasma
AGE concentration appears to be directly influenced by dietary
AGE intake and the body’s capacity for AGE elimination.8
Individuals with renal insufficiency demonstrate reduced urinary
excretion of dietary AGEs, and plasma AGE levels inversely
correlate with renal function.9
Low-AGE diets in animal studies have been shown to reverse
insulin resistance and chronic inflammation, inhibit the progression
of atherosclerosis and prevent experimental diabetic
nephropathy and neuropathy,10 but whether these results can
be translated to humans is uncertain. Cross-sectional and case–
control studies involving humans with impaired renal function or
diabetes have demonstrated associations between elevated AGE
intakes and serum biomarkers of oxidative stress, endothelial
dysfunction, inflammation, hyperlipidemia and hyperglycemia.11,12
AGEs have also recently been implicated in the dysfunction
and death of pancreatic beta cells,13 leading to the hypothesis
that excessive AGE formation and oxidative stress possibly
have a role in the development of type 1 and type 2
diabetes.14,15 Low-AGE diets have been suggested as a possible
future therapeutic option for healthy individuals at risk for the
development of type 1 or type 2 diabetes.16
Through reduced consumption of highly processed heattreated
foods, dietary AGE restriction may represent a relatively
simple, noninvasive therapy for the effective treatment of many of
the metabolic disturbances attributed to excessive AGE levels. This
systematic review sought to determine whether there is sufficient
evidence to recommend therapeutic AGE-restricted diets in
healthy or overweight individuals, people with diabetes or those
with renal impairment for the prevention or attenuation of insulin
resistance, the improvement of endothelial function and the
reduction of biomarkers of inflammation and oxidative stress.
MATERIALS AND METHODS
Search strategy
A computer database search was undertaken for the time period between
1 January 1 1997 and 1 December 2012, using Medline, CINAHL, EMBASE,
Current Contents, PubMed, Cochrane Central Register of Controlled Trials,
Cochrane Database of Systematic Reviews and AMED. Databases were not
searched before 1997, because the potentially deleterious effects of dietary
AGE consumption was first postulated in 1997.17 Citation tracking was
performed using the ISI Web of Science for all trials identified, and the
reference lists of all identified trials were hand-searched for relevant
studies. The following search terms were used: (1) (diet$ OR food) and
(advanced glyc$ OR glycation OR Maillard OR thermal), (2) limit 1 to
year ¼ ‘1997–2012’, (3) limit 2 to humans.
Criteria for selecting trials in this review
All full reports of controlled feeding trials were eligible for inclusion if they
were published in English between 1 January 1997 and 1 December 2012.
Trials were included if they involved human participants aged X18 years
and at least one group of participants received an AGE-restricted dietary
intervention. For the purposes of this review, we defined a low-AGE dietary
intervention as one that contained 30–50% of the measured AGEs or
Maillard reaction products (MRPs) present in the standard or high-AGE
comparison diet. Trials involving dietary restriction of AGE precursors only
(such as Amadori products) were not included.
The outcomes of interest in this review were serum markers of the
following: (1) insulin resistance (HOMA-IR), (2) inflammation (tumor
necrosis factor-a (TNF-a)), (3) oxidative stress (8-isoprostane), (4) endothelial
dysfunction (VCAM-1) and (5) increased cardiovascular disease risk
(AGE-modified low-density lipoprotein (LDL)). On the basis of the duration
of low-AGE dietary interventions used in the included trials, the length of
follow-up of outcomes was categorized as short term (one meal to 6 days
after randomization), intermediate term (1–4 weeks after randomization) or
long term (more than four weeks after randomization).
Assessment of methodological quality
The two reviewers independently assessed the methodological quality of
included trials using the Heyland Methodological Quality Score18
(Supplementary Table S1). This checklist rates primary research based on
the use of allocation concealment during randomization, intention-totreat
analysis, double-blinding, patient selection with minimal risk of
bias, comparability of intervention and control groups at baseline,
100% participant follow-up, clearly described treatment protocol and well-defined outcome measurements. Trials scoring X8 out of a possible
14 points are considered to be of high methodological quality.
Disagreements between reviewers in assigning methodological quality
scores were resolved by discussion until consensus was achieved.
Data extraction and analysis
Trial information regarding the type and number of participants,
interventions used and significant findings was extracted from each study
by the first author and entered into a standardized computer spreadsheet.
As all extracted data were continuous, treatment effects and 95%
confidence intervals (CIs) were calculated using the Hedges (adjusted-g)
standardized mean difference (SMD).19 The ‘adjusted’ statistic was used
because it includes an adjustment for bias from small sample sizes. The
SMD enables comparison of effect sizes between trials that use different
outcome measures.20 SMDs were calculated from group mean results and
s.d’s) collected at the time of follow-up. When mean values were not
available, trial authors were contacted to provide the appropriate data.
When standard errors were reported, these were converted to s.d’s as per
Cochrane Collaboration Guidelines.21 SMDs were standardized so that
positive values indicated effects favoring the AGE-restricted dietary
intervention, and negative values were used to indicate effects favoring
the standard diet. SMD values of 0.2, 0.5 and 0.8 were considered to
represent small, moderate and large effect sizes, respectively.22
Data synthesis
Meta-analysis of pooled data was implemented in cases in which at least
two trials contained similar participants (health status), intervention (lowAGE
diet), comparison intervention (standard-AGE diet), outcome measures
and length of follow-up. Trials with similar characteristics were
assessed for statistical heterogeneity, which was indicated by a Po0.1 on
the w2 test and an I
2 statistic greater than 20%.23 Clinically and statistically
homogeneous trials (I
2
o20%) underwent a fixed-effects model metaanalysis
using RevMan 5.1.24
Where meta-analysis was considered not possible because of clinical or
statistical heterogeneity, effect sizes and 95% CIs were reported for
outcomes within individual trials, and a narrative analysis was performed
using the GRADE (Grades of Recommendation, Assessment, Development
& Evaluation) approach for collating evidence in systematic reviews25
(Supplementary Table S2). The GRADE criteria consider randomized
controlled trials as high-quality evidence, which can be downgraded to
moderate-, low- or very low-quality evidence in the event of limitations to
methodological quality (defined in this review as a Heyland Methodological
Quality Score o8), inconsistency of results between trials, imprecision
of results due to small sample sizes and/or wide CIs, indirectness of results
due to the measurement of secondary end points or a high probability of
reporting bias.