August 15, 2011
Genetic Reasons For Link Between Obesity, Diabetes
Obesity and type 2 diabetes have long been linked, but a new study has discovered exactly how high-fat diets serve as a catalyst for a sequence of events that ultimately lead to the onset of the disease.
Researchers, including Jamey D. Marth, Ph.D., the director of the Center for Nanomedicine, studied both humans and mice, and "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."The results of the study were published online August 14 in Nature Medicine.
"We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes," Dr. Marth said in a statement Sunday."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."
According to the scientists, the pancreatic beta cells of healthy individuals help monitor the bloodstream for glucose using special glucose transporters embedded in their cell membranes. When those glucose levels are high, beta cells assimilate the extra glucose and respond by secreting insulin in what they refer to as "a timed and measured response." That stimulates other cells to also take in glucose, which they can then use 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," they reported in a press release on Sunday. 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," they added. "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."
Thus, they report that preserving GnT-4a function can help prevent the onset of diabetes, even in obese subjects, and that beta cells that have diminished glucose sensing capabilities can play an important role in determining the onset and severity of diabetes.
"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. "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"¦ 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."
The Center for Nanomedicine is a collaborative effort between the University of California, Santa Barbara and Sanford-Burnham Medical Research Institute. According to the press release, the two educational institutions are working together to help establish "the next generation of effective disease diagnostics and therapeutics."
On the Net:
- Center for Nanomedicine
- Nature Medicine
- University of California, Santa Barbara
- Sanford-Burnham Medical Research Institute