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Last Updated: Dec 27th, 2006 - 19:07:47 |
Fatty diets have been widely recognized as a risk factor for type 2 diabetes. A new U.S. study, published in the Dec. 29 issue of the journal Cell, suggests that a high fat diet or Western diet may cause type 2 diabetes in humans by disrupting insulin production.
In the study, Professor Jamey Marth and first author Kazuaki Ohtsubo of the University of California, San Diego (UCSD) School of Medicine and the Howard Hughes Medical Institute and colleagues identified a gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a), which enables the pancreatic beta cell to sense blood glucose levels and appropriately produce insulin.
The study, funded by a grant from the National Institutes of Health (NIH) and an Investigator award from the Howard Hughes Medical Institute, demonstrated that in mice a high-fat diet suppressed the GnT-4a enzyme production leading to pancreatic beta cell. This failed to produce the hormone insulin, resulting in type 2 diabetes.
"We have discovered a mechanistic explanation for beta cell failure in response to a high-fat diet and obesity, a molecular trigger which begins the chain of events leading from hyperglycemia to insulin resistance and type 2 diabetes," said Marth.
"This finding suggests new approaches to the prevention and treatment of diabetes."
The findings resulted from studying glycosylation, the process that controls the formation on proteins of sugar linkages called glycans. The glycans link to proteins by a number of related enzymes such as GnT-4a.
The GnT-4a enzyme maintains glucose transporters in place on the surface of the beta cell similar to when glucose is elevated after a meal, they transport glucose and trigger the beta cell to secrete insulin. Proper insulin secretion is essential for normal glucose metabolism. Excessive glucose can cause a myriad of diseases including cancer, cardiovascular disease, and stroke.
In the study, the researchers found mice lacking the GnT4a gene tended to have high blood sugar, which is the first measure and diagnosis of diabetes. The condition can worsen as the beta cell fails to normally secrete insulin, resulting in full blown type 2 diabetes.
In normal mice, the researchers tested a high-fat chow diet consisting of 16.4 percent protein, 25.5 percent carbohydrates, and 58 percent fat (mostly hydrogenated coconut oil and a small portion of soybean oil) with 5.56 kcal/g. They found that the high fat diet reduced GnT-4a gene expression leading to low counts of the GnT-4a enzyme and removal of the glucose transporter from the cell surface. This resulted in failure of the cell to sense and respond to the blood sugar level and cause the development of type 2 diabetes in the mice.
"Our findings suggest that the current human epidemic in type 2 diabetes may be a result of GnT-4a enzyme deficiency," said Marth.
"The GnT4a enzyme is required to synthesize a glycan structure that holds the glucose transporter in place at the beta cell surface. The loss of this key transporter is directly linked to reduced GnT-4a protein glycosylation, a high fat diet, and type 2 diabetes."
The authors believe that a high fat diet affects certain transcription factors that regulate GnT-4a gene expression in type 2 diabetes. Ohtsubo and Marth have observed that some of these transcription factors also cause another form of type 2 diabetes in humans, known as Mature Onset Diabetes of the Young (MODY).
"It is possible that human MODY is due to the loss of GnT-4a expression.” said Marth.
"In some forms of MODY including the most common (MODY-3), these transcription factors may bind to the GnT4a gene and enhance GnT-4a enzyme levels."
The results indicate that approaches to elevating GnT-4a levels may boost glucose transporter expression enough to prevent type 2 diabetes, a possibility that Marth and Ohtsubo are currently testing. In certain cases, however, inhibition of GnT-4a expression and attenuation of insulin may reduce the risk of certain diseases otherwise imposed by high levels of insulin.
It is unclear how the high fat diet affects the transcription factors if they are truly affected by the high fat foods as the researchers believe. Previous studies may have provided an explanation.
A study by Oana Sandu and colleagues of Mount Sinai School of Medicine found dietary advanced glycosylation end products (AGEs) in a high fat diet play a role in the progression of insulin resistance. In the study, normal mice were randomly assigned a high fat diet (35 percent fat) with high AGEs (1000 units/mg) or with low AGEs (330 units/mg) for six months.
At the end of study, 75 percent of mice fed high AGEs were found diabetic, displaying impaired glucose and insulin responses. None of the mice on the low AGEs high fat diet were diabetic, although both groups of mice gained body weight and raised plasma lipids, meaning the effect of fatty foods may depend on how they are prepared. A high temperature and long time process may generate high levels of AGEs.
The authors concluded, "the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets." The findings were published in Diabetes 54:2314-2319, 2005.
The diet in the current study is relatively simple in terms of its fat composition. A human diet may have a far more complex profile of fatty acids. The study did not intend to reveal how different types of fatty acids such as trans, polyunsaturated, saturated, and omega-3 fatty acids affect the risk of type 2 diabetes.
Many studies have been conducted to examine the effect of the type of fat on type 2 diabetes. Findings were often inconsistent and confusing.
A 14-year study titled "Dietary Fat Intake and Risk of Type 2 Diabetes in Women", conducted by Jorge Salmeron and colleagues (published in the June 2001 issue of American Journal of Clinical Nutrition) found that neither total fat intake, saturated fat nor monounsaturated fat were associated with risk of type 2 diabetes. However, five percent of energy from polyunsaturated fat reduced the risk by 37 percent while a two percent increase in energy from trans fat increased the risk by 39 percent. When two percent of energy from trans fat was replaced with polyunsaturated fatty acids, the risk was reduced by 40 percent.
The study examined 84,000 women aged 34 to 59 with no known diabetes, cardiovascular disease or cancer for their dietary information when they entered the study in 1980, subsequently in 1984, 1986, and 1990. During the 14-year follow-up, 2,507 incident cases of type 2 diabetes were reported.
Ron van Dam and colleagues of the Harvard School of Public Health reported their study titled "Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men" in a 2002 issue of Diabetes Care that showed those with highest intakes of total fat were 27 percent more likely to have type 2 diabetes compared with those with lowest intakes. For saturated fat, the highest intake quintile was 34 percent more likely to have the condition. When body mass index (BMI) was considered, the association disappeared.
Intakes of oleic acid, trans fat, long-chain omega-3 fat, and alpha-linolenic acid were not associated with diabetes risk after multivariate adjustment. Linoleic acid was associated with a 26 percent lower risk of type 2 diabetes in men aged 65.
The study involved 42,504 males aged 40 to 75 without known diabetes, cardiovascular disease and cancer, who participated in the Health Professionals Follow-Up Study in 1986. Dietary habits were surveyed at baseline and updated in 1990 and 1994. During the 12-year follow-up, 1,321 incident cases of types 2 diabetes were recorded.
The inconsistency of the conclusions is understandable considering that possible errors or bias may have been introduced in the study design and data collection. Most of the studies relied on statistical analysis in which risk factors were considered arbitrarily, which caused variation of the weight of a particular variate.
Regardless of how the dietary fat influences the type 2 diabetes risk, it is well accepted that a high fat diet can contribute to the development of obesity and type 2 diabetes in humans and animals. An increase in dietary fat has been shown to produce obesity and diabetes in mice while such diet-induced diabetes can be reversed by reducing the fat in the diet. In humans, evidence shows that a low-fat diet can produce acute improvements in blood sugar control in type 2 diabetes, even in the absence of weight loss.
It remains unknown whether the improvement is due to lower calories or low fat in a low fat diet. Duke University is currently recruiting type 2 diabetes patients for a trial to assess acute glycermic effects of a low fat diet.
Diabetics or not, people may consider using a low fat diet to prevent or control type 2 diabetes. Both trans fat and saturated fat may raise the risk of the disease, Professor Marth told foodconsumer.org.
In the U.S., more than 20 million men and women have type 2 diabetes compared to the population of 200 million in the world.
© 2004-2005 by foodconsumer.org unless otherwise specified
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