Writing in Cell Metabolism, Professor Gerald Shulman and his co-workers report that a gene called transcriptional coactivator PPAR-gamma coactivator-1 beta (PGC-1b) appears to play a central role in the development of insulin resistance.
Insulin resistance, whereby insufficient insulin is released to produce a normal glucose response from fat, muscle and liver cells, was prevented when the researchers used mice with the PGC-1b knocked out.
In an accompanying editorial in the same journal, Carlos Hernandez and Jiandie Lin of the University of Michigan Medical Center said the new study has “revealed the transcriptional coactivator PGC-1b as a missing link between fructose intake and metabolic disorders”.
"The findings …support the emerging role of gene/environment interaction in modulating the metabolic phenotype and disease pathogenesis. Thus, perturbations of the same regulatory motif may produce vastly different metabolic responses, depending on the specific combinations of dietary nutrients," they added.
Fructose and HFCS
The Yale researchers make the link between the findings and observations from human populations concerning rocketing numbers of people suffering from the metabolic syndrome and type-2 diabetes.
“Both have reached epidemic proportions worldwide with the global adoption of the westernized diet along with increased consumption of fructose, stemming from the wide and increasing use of high-fructose corn syrup sweeteners,” they wrote.
The research looks set to heap even more misery on high fructose corn syrup (HFCS), an ingredient extensively used to sweeten soft drinks.
Campaigners against HFCS point to epidemiological studies that have linked the consumption of sweetened beverages and obesity, as well as some science that claims that the body processes the syrup differently than other sugars due to the fructose content, leading to greater fat storage.
However, industry associations like the Corn Refiners Association (CRA) have repeatedly claimed there is no scientific evidence to suggest that HFCS is uniquely responsible for people becoming obese.
In an interview with FoodNavigator.com in March 2007, Audrae Erickson, president of the CRA stated that it is not justified to directly liken HFCS to fructose as HFCS consists of 55 per cent fructose and 42 per cent glucose. "HFCS contains about 50 per cent glucose, which acts as a moderator to fructose," she said.
However, in response to these statements, Prof Shulman said he is “unaware of any data to suggest the presence of glucose along with fructose blunts the metabolic effects of fructose on lipid metabolism.
“Indeed the combination of glucose, which will stimulate insulin secretion more potently than fructose, along with fructose, which is metabolized very rapidly and differently than glucose, might promote more lipogenesis than either one alone. We are currently examining this hypothesis,” he added.
The Yale researchers built on previous studies that implicated a gene known as SREBP-1 to be a master regulator of lipid manufacture in the liver. For the new study, Shulman and his co-workers focused on PGC-1b because it is known to boost SREBP-1 levels.
To test its role in the effects of fructose, the researchers blocked its activity in mice fed a diet high in fructose for four weeks. Mice with PGC-1b knocked out were found to have improved metabolic profiles with lower levels of SREBP-1 and other fat-building genes in their livers. The mice also showed a reversal of their fructose-induced insulin resistance and a threefold increase in glucose uptake in their fat tissue.
Normal dietary intakes and a lack of moderation
In response to the findings of this and other recent studies, the CRA stated: “Recent studies using pure fructose that purport to show that the body processes high fructose corn syrup differently than other sugars due to fructose content are a classic example of this problem because pure fructose cannot be extrapolated to high fructose corn syrup. The abnormally high levels of pure fructose used in these studies are not found in the human diet.
“Fructose consumption at normal human dietary levels and as part of a balanced diet has not been shown to yield such results. Moreover, human fructose intake is nearly always accompanied by the simultaneous and equivalent intake of glucose - a critical and distinguishing factor from pure fructose used in these studies.”
Prof. Shulman told this website: “In moderation I believe all of these sugars (HFCS, fructose, sucrose, glucose), are perfectly safe for most healthy individuals and will not get them into trouble with medical problems such as hyperlipidemia or non-alcoholic fatty liver disease.
“The concern that I have is the amount of these sugars that adults and especially children are ingesting these days, which I believe may be contributing to the obesity and diabetes epidemic that we are now experiencing.”
Source: Cell Metabolism
4 March 2009, Volume 9, Issue 3, Pages 252-264
“The Role of Peroxisome Proliferator-Activated Receptor gamma Coactivator-1 beta in the Pathogenesis of Fructose-Induced Insulin Resistance”
Authors: Y. Nagai, S. Yonemitsu, D.M. Erion, T. Iwasaki, R. Stark, et al.
James Rippe, MD, a cardiologist at the Rippe Lifestyle Institute responded to our coverage with concerns over links between pure fructose and HFCS:
"The animal study by Shulman, et al, in the journal Cell Metabolism employed high levels of pure fructose. The metabolic response in human beings to High Fructose Corn Syrup is very different than pure fructose.
My research laboratory has been a leading source of information comparing the real world situation of High Fructose Corn Syrup versus sucrose when both of these substances are consumed by humans in the context of mixed nutrient meals (1-8).
Our studies were launched after a publication by Teff, et al, which employed a model comparing pure fructose versus pure glucose and reported that there were significant differences in insulin, leptin, ghrelin and blood sugar in this model (9).
Studies conducted in my laboratory have shown that by every parameter yet measured in human beings including insulin, blood sugar, leptin, ghrelin, glucose, uric acid, post prandial triglycerides, appetite and calories consumed there is no difference between High Fructose Corn Syrup and sucrose. Furthermore, we have not observed values in any of these parameters outside of the normal range. These findings stand in contrast to the prior findings by Teff, et al, and point to the danger in extrapolating from a pure fructose model to a model which utilizes the real world situation of High Fructose Corn Syrup versus sucrose. Other researchers have shown similar findings to ours (10, 11).
As a cardiologist, I am concerned that comments from Dr. Shulman extrapolate from an animal model using enormous doses of pure fructose to make assertions about nutrition parameters related to HFCS in humans. The medical literature is littered with instances where animal work does not apply to humans. Pure fructose is rarely found in the human diet.
The American Medical Association studied the issue of whether or not High Fructose Corn Syrup is related to obesity for over a year and concluded last summer that “High Fructose Corn Syrup does not contribute to obesity more than other calorie sweeteners."
The causes of obesity are well known including the over consumption of calories from all sources and decreased physical activity. Obesity is strongly linked to both Type 2 diabetes and the metabolic syndrome. It is important for all of us who care about these issues not to distract people, particularly when extrapolations from a pure fructose model in animals to human nutrition practices rest on such uncertain scientific ground."
James M. Rippe, M.D.
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