Yale scientists have unlocked another piece of the diabetes puzzle through the identification of a key enzyme expressed in a specific brain region that plays a central role in regulating glucose levels. The researchers are hopeful that with further characterization, the discovery could eventually yield novel treatments for type 2 diabetes. The study has been published in Proceedings of the National Academy of Sciences.
Diabetes mellitus, or diabetes, is a disease in which sufferers cannot control blood sugar (glucose) levels. Normally, a hormone called insulin which is secreted by the pancreas regulates blood glucose levels, but this system is disrupted in diabetes sufferers. In individuals with Type 1 diabetes, pancreatic cells fail to produce sufficient insulin. In Type 2 diabetes, however, cells in the body do not respond to insulin properly, which is known as insulin resistance. This may eventually lead on to pancreatic cells also failing to produce insulin.
It is known that a brain region called the ventromedial nucleus of the hypothalamus (VMH) plays important roles in the regulation of feeding and glucose metabolism. Contained within the VMH are cells that are capable of sensing glucose levels. Importantly, these cells express an enzyme called prolyl endopeptidase (PREP). While it was known that PREP plays various neuronal functions, whether it was involved in glucose regulation was unknown.
To find out more, the researchers genetically engineered mice so that they did not express PREP. They found that these mice essentially became diabetic. They were glucose intolerant and demonstrated reduced glucose-induced insulin production when compared with controls. Furthermore, when they gave normal mice a substance that inhibited PREP, similar effects were observed. In a final elegant experiment, the researchers used a virus to express PREP in the genetically engineered mice which reversed their glucose intolerance.
According to the researchers, PREP is responsible for glucose sensitivity in VMH cells. Cells expressing PREP detect increases in glucose levels and then spark a cascade of events that ultimately lead to the release of insulin from the pancreas. Insulin then causes cells to absorb glucose, thus reducing blood glucose levels.
The researchers would like to take this work forward by identifying the targets of PREP and deciphering how this enzyme assists in glucose sensing. According to lead researcher Sabrina Diano, if they are successful in this it may eventually lead to the development of methods to regulate the secretion of insulin and thus a mechanism to treat type 2 diabetes, but they are a long way off yet.