• Obesity To Diabetes Pathway Found

      From ScienceDaily

      Newly diagnosed type 2 diabetics tend to have one thing in common: obesity. Exactly how diet and obesity trigger diabetes has long been the subject of intense scientific research. A new study led by Jamey D. Marth, Ph.D., director of the Center for Nanomedicine, a collaboration between the University of California, Santa Barbara and Sanford-Burnham Medical Research Institute (Sanford-Burnham), has revealed a pathway that links high-fat diets to a sequence of molecular events responsible for the onset and severity of diabetes.

      These findings were published online August 14 in Nature Medicine.

      In studies spanning mice and humans, Dr. Marth's team discovered a pathway to disease that is activated in pancreatic beta cells, and then leads to metabolic defects in other organs and tissues, including the liver, muscle and adipose (fat). Together, this adds up to diabetes.

      "We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes," said Dr. Marth."The observation that beta cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected. We noted, however, that studies from other laboratories published over the past few decades had alluded to this possibility."

      In healthy people, pancreatic beta cells monitor the bloodstream for glucose using glucose transporters anchored in their cellular membranes. When blood glucose is high, such as after a meal, beta cells take in this additional glucose and respond by secreting insulin in a timed and measured response. In turn, insulin stimulates other cells in the body to take up glucose, a nutrient they need to produce energy.

      In this newly discovered pathway, high levels of fat were found to interfere with two key transcription factors -- proteins that switch genes on and off. These transcription factors, FOXA2 and HNF1A, are normally required for the production of an enzyme called GnT-4a glycosyltransferase that modifies proteins with a particular glycan (polysaccharide or sugar) structure. Proper retention of glucose transporters in the cell membrane depends on this modification, but when FOXA2 and HNF1A aren't working properly, GnT-4a's function is greatly diminished. So when the researchers fed otherwise normal mice a high-fat diet, they found that the animals' beta cells could not sense and respond to blood glucose. Preservation of GnT-4a function was able to block the onset of diabetes, even in obese animals. Diminished glucose sensing by beta cells was shown to be an important determinant of disease onset and severity.

      "Now that we know more fully how states of over-nutrition can lead to type 2 diabetes, we can see more clearly how to intervene," Dr. Marth said. He and his colleagues are now considering various methods to augment beta cell GnT-4a enzyme activity in humans, as a means to prevent and possibly cure type 2 diabetes.

      "The identification of the molecular players in this pathway to diabetes suggests new therapeutic targets and approaches towards developing an effective preventative or perhaps curative treatment," Dr. Marth continued. "This may be accomplished by beta cell gene therapy or by drugs that interfere with this pathway in order to maintain normal beta cell function."

      In the United States, more than 24 million children and adults -- nearly eight percent of the population -- have diabetes. In adults, type 2 diabetes accounts for about 90 to 95 percent of all diagnosed cases of diabetes. This study was primarily funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). Co-authors of this study include Kazuaki Ohtsubo at Sanford-Burnham and Mark Z. Chen and Jerrold M. Olefsky from the University of California, San Diego.

      Story Source:
      The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Sanford-Burnham Medical Research Institute, via EurekAlert!, a service of AAAS.

      Journal Reference:
      Kazuaki Ohtsubo, Mark Z Chen, Jerrold M Olefsky, Jamey D Marth. Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport. Nature Medicine, 2011; DOI: 10.1038/nm.2414

      Source: http://www.sciencedaily.com/releases...0814141432.htm
      Comments 4 Comments
      1. bezoe's Avatar
        bezoe -
        Its long been proven that adiposity is directly linked to type II DM. What exactly did they feed the mice? It says "high fat", but if a human consumes a high fat diet with plenty of protein, an insulin spike will still occur. Also, I don't see the ramifications.. if the mice didnt eat any carbohydrates it doesnt matter if the beta cells sensations are blunted- theres no glucose in the bloodstream to cause damage. Now i can understand if a consistently high fat, no carb diet completely diminishes the function of this Gn T 4a enzyme, how things can be detrimental. Maybe I need to read the entire study.. seems like a premature declaration though.
      1. Vengeance187's Avatar
        Vengeance187 -
        Originally Posted by bezoe View Post
        theres no glucose in the bloodstream to cause damage.
        There's always glucose in the bloodstream. If you don't eat carbs it will be made from protein.

        So is this saying diabetes isn't caused mainly by simple carbs?
      1. sapentia's Avatar
        sapentia -
        Originally Posted by Vengeance187 View Post
        There's always glucose in the bloodstream. If you don't eat carbs it will be made from protein.

        So is this saying diabetes isn't caused mainly by simple carbs?
        I believe it is saying that high fat is a co-factor to excessive carbs. I remember reading a study that showed elevated blood sugar levels led to beta-cell death similar to how too much alcohol kills brain cells. So, the high fat inhibits the beta-cells from functioning properly and in conjunction the elevated blood sugar leads to cell death. As this perpetuates over time the body increasingly loses its ability to process blood sugar and to properly metabolize nutrition in a healthy manner which leads to a host of medical conditions in addition to Type II diabetes.
      1. EasyEJL's Avatar
        EasyEJL -
        Well, and keep in mind its in rats not humans so still pretty speculative. I'd like to know the total dietary macro makeup as well, and why there wasn't a control group fed balanced macros, and a control group fed high carbohydrate. Quite possible that it is a hypocaloric issue more than the particular nutrient.
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