Uncovering the Path That Leads to Diabetes
This image obtained from confocal immunofluorescence of mouse pancreas reveals that in the islets of Langerhans (specialized cells in the pancreas that make and secrete hormones), HMGN3 protein is present in the nuclei of cells containing insulin. The red color demonstrates insulin in the cytoplasm and the green color visualizes HMGN3 in the nucleus. The blue nuclei are visualized by Hoechst DNA stain. The dotted white line outlines the pancreatic islet used to show the overlap of locations for nuclei (blue) and HMGN3 protein (green).
The origins of diabetes have been the subject of intense scientific research, but the genetic factors that cause certain people to develop the disease have remained elusive. In healthy individuals, glucose levels in the bloodstream are transiently elevated after a meal. The increase in glucose triggers β cells in the pancreatic islet to release the hormone insulin. Insulin is delivered to tissues throughout the body, and stimulates to import of glucose into cells. If a person does not produce insulin, or their cells have become insensitive to the hormone, glucose uptake does not occur and the level of glucose in the bloodstream remains elevated.
The secretion of insulin from β cells is controlled by a complex signaling pathway that starts at the cell membrane, goes through the nucleus to stimulate expression of specific genes, and ends with the release of insulin from cellular stores. The expression of the genes is controlled by many participants, including transcription factors that bind to DNA and kick-start the production of RNA, and chromatin-binding proteins that alter the structure of the DNA and help transcription factors bind.
Tetsuya Ueda, Ph.D., together with Takashi Furusawa, Ph.D., and Toshihiro Kurahashi, Ph.D., all postdoctoral fellows working with Michael Bustin, Ph.D., in the CCR Laboratory of Metabolism, recently discovered that HMGN3, a chromatin-binding protein, is involved in the regulation of insulin secretion from pancreatic cells. The study showed that HMGN3 is able to affect the expression of specific genes important in glucose-stimulated insulin secretion and thus may play a role in the development of diabetes. A report of this discovery was recently published in Molecular and Cellular Biology.
The researchers initially found high levels of HMGN3 in pancreatic β cells, leading them to think that HMGN3 might be important for regulating the secretion of insulin. They tested their hypothesis using mouse and cell culture models. Mice lacking HMGN3 had a 50 percent lower level of insulin in their bloodstream and higher glucose levels after a meal when compared to normal mice. When the HMGN3 protein was depleted from cells grown in culture, there was a reduction in glucose-stimulated insulin secretion. These observations indicate HMGN3 has a part in the release of insulin from β cells in response to glucose.
Further studies were performed to elucidate the specific role played by HMGN3. Cultured cells depleted of HMGN3 showed a change in expression of several genes important in insulin secretion. The expression of one of the genes, glucose transporter 2 (GLUT2), was reduced in both cultured cells and in the pancreatic islets of mice lacking HMGN3. GLUT2 is a membrane protein that allows glucose to enter cells, which is important for stimulating β cells to release insulin. Additional experiments revealed that HMGN3 binds cooperatively with a transcription factor called PDX1 to the region of DNA that controls the expression of GLUT2, resulting in increased GLUT2 expression.
Dr. Ueda and his colleagues have identified a new component in the pathway that regulates glucose-stimulated secretion of insulin. Further study of the role of HMGN3 in human pancreatic cells and abnormalities that can occur in its function may provide clues to the origins of diabetes.Summary Posted: 09/2009
Mol Cell Biol. 2009 Aug 3. [Epub ahead of print] PubMed Link