A transcription factor activated by too much sugar in the blood is a driver of an implacable cycle of too little insulin resulting in too much sugar in the blood that, in turn, causes failure of beta cells to make enough insulin which results in even higher blood sugar and type 2 diabetes, said researchers from Baylor College of Medicine in an online report in the journal Diabetologia.
That transcription factor – carbohydrate response element binding protein or ChREBP – offers the possibility of a target for drug treatment for the disorder that affects as many as 25 million people in the United States, said Dr. Lawrence Chan, director of the federally funded Diabetes and Endocrinology Research Center at BCM and chief of the section of diabetes, endocrinology and metabolism in the BCM departments of medicine, molecular and cellular biology and biochemistry.
Beta cells fail
Type 2 diabetes occurs when key parts of the pancreas called beta cells start to fail and cannot produce enough insulin to keep levels of the sugar in the blood in check particularly in those who have increased demands for the hormone, e.g., in obese individuals.
"We know that the inability of the beta cells in the pancreas to produce sufficient insulin leads to elevated blood sugar," said Chan. The high levels of blood sugar are actually toxic to the pancreatic beta cells that are responsible for producing insulin.
Hyperglycemia or too much sugar in the blood causes fats to build up inside beta cells, increases oxidative stress, impairs the production and secretion of insulin and promotes death of the beta cells, thus perpetuating the hyperglycemia and dooming the animal or person to progressively worsening diabetes.
In studies in mice and on mouse and human tissues, Chan and his colleagues found that the factor ChREBP is a mediator of many of these effects of too much sugar in the blood on beta cells and, in the final analysis, plays an important role in the overall health of the organism.
Useful adjunctive therapy
Chan credited his former graduate and postdoctoral student Dr. Navarat Poungvarin with doing much of the work on the pancreatic beta cells and with finding how the receptor works.
Chan does not think that a drug that targets ChREBP can reverse type 2 diabetes, but it can be a useful adjunctive therapy in slowing down the destructive cycle of the disease.
"Unfortunately, this is a progressive disease, and the cycle just gets more destructive," he said. "With proper treatment we hope to slow its progress and preserve the function of the beta cells."
Others who took part in this research include Drs. Jeong Kyung Lee, Vijay K. Yechoor, Ming V. Li, Taweevat Assavapokee, Promporn Suksaranjit, Jet John Thepsongwajja, Pradip K. Saha and Kazuhiro Oka, all of BCM. Poungvarin is also affiliated with Siriraj Hospital, Mahidol University in Bangkok, Thailand.
Funding for this work came from the National Institutes of Health, the Diabetes and Endocrinology Research Center, the Betty Rutherford Chair in Diabetes Research from St. Luke's Hospital (held by Chan) and the T.T. & W.F. Chao Global Foundation.