Food, not drugs?
- From: Susan <nevermind@xxxxxxxxxx>
- Date: Sun, 13 May 2007 10:58:36 -0400
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Dietary carbohydrate modification induces alterations in gene
expression in abdominal subcutaneous adipose tissue in persons with
the metabolic syndrome: the FUNGENUT Study
Kallio et al., American Journal of Clinical Nutrition, Vol. 85, No. 5,
1417-1427, May 2007
Background: Diets rich in whole-grain cereals and foods with a low
glycemic index may protect against type 2 diabetes, but the underlying
molecular mechanisms are unknown.
Objective: The main objective was to test whether 2 different
carbohydrate modifications-a rye-pasta diet characterized by a low
postprandial insulin response and an oat-wheat-potato diet
characterized by a high postprandial insulin response-affect gene
expression in subcutaneous adipose tissue (SAT) in persons with the
metabolic syndrome.
Design: We assessed the effect of carbohydrate modification on SAT
gene expression in 47 subjects [24 men and 23 women with a mean (±SD)
age of 55 ± 6 y] with the features of the metabolic syndrome in a
parallel study design. The subjects had a mean (±SD) body mass index
(kg/m2) of 32.1 ± 3.8 and a 2-h plasma glucose concentration of 8.0 ±
2.3 mmol/L. Adipose tissue biopsies were performed, and oral-glucose-
tolerance tests and other biochemical measurements were conducted
before and after the intervention.
Results: We detected 71 down-regulated genes in the rye-pasta group,
including genes linked to insulin signaling and apoptosis. In
contrast, the 12-wk oat-wheat-potato diet up-regulated 62 genes
related to stress, cytokine-chemokine-mediated immunity, and the
interleukin pathway. The insulinogenic index improved after the rye-
pasta diet (P = 0.004) but not after the oat-wheat-potato diet. Body
weight was unchanged in both groups.
Conclusions: Dietary carbohydrate modification with rye and pasta or
oat, wheat, and potato differentially modulates the gene expression
profile in abdominal subcutaneous adipose tissue, even in the absence
of weight loss.
* * *
Editorial:
Putting your genes on a diet: the molecular effects of carbohydrate
Sandra L Salsberg and David S Ludwig
(From the Division of Endocrinology, Children's Hospital Boston,
Boston, MA)
See corresponding article on page 1417.
Traditionally, food is thought to influence human health through its
nutrient content, whereas drugs are recognized to act through
molecular pathways. However, consumption of a meal stimulates the
release of numerous hormones that can powerfully affect signal
transduction and gene function. The article by Kallio et al (1) in
this issue of the Journal highlights this possibility by demonstrating
changes in gene expression in individuals consuming diets with
different effects on postprandial insulin concentrations.
The authors randomly assigned adults with features of the metabolic
syndrome to a rye-pasta (low insulin response) or an oat-wheat-potato
(high insulin response) diet for 12 wk. The diets were designed to be
similar in energy, fiber, and macronutrient contents, although modest
differences in fiber, carbohydrate, and protein contents were
documented by food records. Gene expression in subcutaneous fat was
evaluated at baseline and at 12 wk with microarrays and quantitative
polymerase chain reaction. In individuals in the low-insulin-response
group, 71 genes showed decreased expression and none showed increased
expression. Of particular interest, several down-regulated genes have
links to insulin-signaling pathways and apoptosis. In contrast, in
individuals in the high-insulin-response group, 62 genes showed
increased expression and none showed decreased expression.
Prior microarray studies found differences in gene expression between
overweight and lean individuals (2) and after energy restriction (3);
however, changes in the ratio of fat to carbohydrate did not alter
gene expression (3). The study by Kallio et al makes a significant
contribution to the literature by demonstrating the potentially major
effects of dietary composition on gene regulation, independent of
energy intake and body weight. Two specific findings concerning the
low-insulin-response diet merit particular attention: the down-
regulation of both hormone-sensitive lipase (HSL) and TCF7L2.
HSL, a key enzyme in the release of fatty acids from adipose tissue,
has been proposed to affect body weight and metabolic variables. Mice
made deficient in HSL by genetic manipulation are resistant to
genetic- or diet-induced obesity (4, 5). Women carrying an allele
associated with decreased HSL activity have lower fasting and
simulated insulin concentrations, and men with this allele have lower
nonesterified fatty acid concentrations (6). In light of these data,
proteins involved in lipolysis have become targets of drug development
for the treatment of obesity and the metabolic syndrome. Thus,
decreased HSL activity might mediate some of the purported benefits of
diets designed to lower insulin secretion.
The transcription factor TCF7L2 is the strongest known genetic
predictor of type 2 diabetes. A microsatellite within intron 3 of this
transcription factor occurs with increased frequency in individuals
with type 2 diabetes, which corresponds to an estimated population
attributable risk of 21% (7). Although the mechanisms involved in
disease risk have not been fully elucidated, TCF7L2 affects the Wnt
signaling pathway and may be critical for glucagon-like peptide 1
(GLP-1) secretion by intestinal endocrine L cells. Decreased secretion
of GLP-1 appears to play a role in the development of type 2 diabetes,
and GLP-1 agonists have recently been developed for the treatment of
diabetes.
The present study has direct implications concerning our understanding
of the dietary glycemic index (GI). The GI is a system for classifying
carbohydrate-containing foods according to how blood glucose
concentrations change in the postprandial period (reviewed in
reference 8). High-GI meals produce greater postprandial insulin
concentrations and C-peptide excretion than do nutrient-controlled low-
GI meals. Observational and interventional studies have linked GI to
the risk of obesity, diabetes, heart disease, and cancer, although the
topic remains much debated. One factor contributing to this ongoing
controversy is the relative paucity of data regarding the relevant
molecular mechanisms. If differences in insulin secretion mediate the
genetic effects observed by Kallio et al, similar effects would be
expected to occur with both low-GI and high-GI diets. This possibility
is supported by a human study and several rodent studies, which showed
potentially beneficial changes in the expression of HSL and other
relevant genes with a low-GI diet (8, 9).
Several methodologic issues should be considered in the interpretation
of this study. Microarray analyses have well-known technical
limitations and statistical problems, especially when involving small
sample sizes (10). The unidirectional change in gene expression within
each diet group provides some grounds for concern, although
confirmation with quantitative polymerase chain reaction provides
reassurance on this point. In addition, many of the observed changes
occurred in genes that have a pathophysiologically relevant relation
to diet and disease, which provides further confidence in the study.
In any event, these findings need to be confirmed and extended by
additional research.
Molecular pathways involved in hormone action have been the target of
a multibillion-dollar pharmaceutical research effort. However, many of
these pathways may normally be under dietary regulation. The results
of the present study emphasize the age-old wisdom to "use food as
medicine"-in this case, for the targeted prevention and treatment of
obesity, diabetes, and heart disease.
* * *
.
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