Re: Researchers Discover Mechanistic Link Between High-Fat Diet and Type 2 Diabetes

The following suggests a positive role for glycosylation. However, a
great many health enthusiasts are taking supplements to block
glycosylation, such as carnosine and benfotiamine. Are they wrong in
doing so?


NWCurandero wrote:
> Jamey D. Marth
>
> Howard Hughes Medical Institute researchers have discovered a molecular
> link between a high-fat, Western-style diet, and the onset of type 2
> diabetes. In studies in mice, the scientists showed that a high-fat
> diet interferes with a genetic mechanism they discovered that promotes
> insulin production, resulting in the classic signs of type 2 diabetes.
>
> In an article published in the December 29, 2005, issue of the journal
> Cell, the researchers report that knocking out a single gene encoding
> the enzyme GnT-4a glycosyltransferase (GnT-4a ) disrupts insulin
> production. Importantly, the scientists showed that a high-fat diet
> suppresses the activity of GnT-4a and leads to type 2 diabetes due to
> failure of the pancreatic beta cells.
>
> "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 Jamey Marth, a Howard Hughes
> Medical Institute investigator at the University of California, San
> Diego (UCSD). Marth and first author Kazuaki Ohtsubo at UCSD
> collaborated on the studies with researchers from the Kirin Brewery Co.
> Ltd., and the University of Fukui, both in Japan.
>
> The discovery of the link between diet and insulin production offers
> new information that may aid in the development of treatments that
> target the early stages of type 2 diabetes. In its earliest phases, the
> disease causes failure of insulin-secreting beta cells in the pancreas,
> which leads to elevated blood glucose levels. As the disease
> progresses, the insulin-secreting beta cells overcompensate for the
> elevated blood glucose, and eventually pump out too much insulin. This
> leads to insulin resistance and full-blown type 2 diabetes.
>
> Worldwide, more than 200 million people have type 2 diabetes, and close
> to 20 million people in the United States have been diagnosed with the
> disorder. The new studies suggest that people with an inherited
> predisposition to type 2 diabetes might have variations in the gene for
> GnT-4a, said the researchers.
>
> Marth and his colleagues began their studies hoping to learn more about
> the function of protein glycosylation in the pancreas. They focused on
> the function of GnT-4a, in part, because it is highly expressed in the
> pancreas. GnT-4a is a type of enzyme known as a glycosyltransferase
> that attaches sugar-like molecules called glycans to proteins in a
> process called glycosylation. Glycans are essential for the proper
> function of many proteins.
>
> GnT-4a was found to maintain glucose transporters on the surface of
> beta cells in the pancreas. Those transporters, such as Glut-2, play a
> crucial role in allowing the beta cell to sense how much glucose is in
> the blood. Transport of glucose across the cell membrane into
> pancreatic beta cells triggers insulin secretion.
>
> The new studies showed that in the absence of sufficient GnT-4a enzyme,
> Glut-2 lacks an attached glycan that is required for it to be expressed
> at the cell membrane. Without that glycan, Glut-2 leaves the cell
> surface and becomes internalized, where it can no longer transport
> glucose into the cell. In turn, this failure impairs insulin secretion,
> causing type 2 diabetes in the mice.
>
> "What was really astounding to us, however, was that when we fed
> normal mice a high-fat diet, we saw this same mechanism of pathogenesis
> with attenuation of GnT-4a enzyme levels, reduced Glut-2 glycosylation,
> and loss of cell surface Glut-2 expression," said Marth. "This
> finding may explain the loss of Glut-2 commonly observed in type 2
> diabetes. For example, transcriptional control of GnT-4a expression may
> underlie the pathogenesis of type 2 diabetes in human mature onset
> diabetes of the young (MODY), and perhaps in response to leptin
> signaling deficiency in db mice."
>
> In addition, variations in susceptibility to type 2 diabetes may result
> from inherited differences in the gene for GnT-4a that may ultimately
> affect its level or activity. These findings could have important
> clinical implications because reduced GnT-4a expression has been
> observed by other researchers in tissue samples from humans with
> diabetes. "If you could somehow stimulate production of this enzyme,
> you might be able to render animals, and perhaps humans, resistant to
> high-fat diet-induced diabetes," said Marth.
>
> To explore such possible clinical applications, Marth and his
> colleagues are now testing whether over-expression of the GnT-4a gene
> in transgenic mice makes them resistant to diabetes induced by a
> high-fat diet or by transcriptional factor mutations that cause MODY.
>
> "If our findings can be applied to humans, they should give us
> important insights into how type 2 diabetes may be prevented and
> treated," he said.
>
> While a deficiency of insulin can cause diabetes, too much insulin can
> also be harmful, and has been found to contribute to the pathogenesis
> of cancer, cardiovascular disease, ovarian diseases, and Alzheimer's
> disease. "It may be that suppressing insulin production to some
> degree could be beneficial in such disorders, and that could
> theoretically be achieved by inhibiting the GnT-4a
> glycosyltransferase," Marth said.
>
> Original Article may be found at:
>
> http://www.hhmi.org/news/marth20051229.html

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