BOSTON -- The development of type 2 diabetes -- or at least part of it -- may be in your head, researchers here said.
BOSTON, Aug. 29 -- The development of type 2 diabetes -- or at least part of it -- may be in your head, researchers here said.
The idea of neurons as a third-party player in the pathogenesis of diabetes -- in addition to improper functioning of pancreatic beta cells and impairment of insulin activity in tissue -- was revealed today by Bradford Lowell, M.D., Ph.D., of Beth Israel Deaconess Medical Center and Harvard, and colleagues.
They have identified a population of glucose-sensing neurons in the arcuate nucleus of the hypothalamus whose function is disrupted by obesity, Dr. Lowell and colleagues reported online in Nature.
These glucose-excited pro-opiomelanocortin (POMC) neurons, they wrote:
Taken together, the evidence suggests that obesity-induced and OCP2-mediated loss of glucose sensing in the neurons "might have a pathogenic role in the development of type 2 diabetes," Dr. Lowell and colleagues postulated.
"For many years we've known that subpopulations of neurons in the brain become 'excited' by glucose," Dr. Lowell said. "But we haven't understood exactly how or why this is significant.
"With this study, we show that these neurons sense increases in glucose and then initiate responses aimed at returning blood-glucose levels to normal," they said. "This is the first demonstration that glucose-sensing by neurons plays an important role in responding to rising blood glucose levels."
In electrophysiology studies in mice, the researchers first showed that about half of the pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus become excited by surges in glucose equivalent to those seen after eating a meal.
The mechanism of excitement was thought to involve the closing of ATP mediated potassium channels, so the researchers created transgenic mice whose pro-opiomelanocortin neurons were 250 times less sensitive to ATP.
In these mice, almost none of the pro-opiomelanocortin neurons were excited by glucose, Dr. Lowell and colleagues reported.
In whole-body experiments, the researchers then showed that the transgenic mice -- although of normal weight -- had impaired glucose tolerance, compared to wild-type animals.
Another piece of the puzzle came from experiments on wild-type animals fed a normal chow diet or a high-fat diet to induce obesity for eight weeks, the researchers said.
In the chow-fed mice, 46% of pro-opiomelanocortin neurons were excited by glucose, but only 10% of the pro-opiomelanocortin neurons in the obese high-fat diet mice had the same response.
Since UCP2 is expressed in pro-opiomelanocortin neurons, the researchers hypothesized that it might play a similar role there as it does in the pancreas -- turning off glucose sensing.
To test that idea, they used a molecule dubbed genipin that blocks the activity of UCP2. Pancreatic beta-cells incubated with the molecule have their ability to secrete insulin restored.
In wild-type mice fed a normal chow diet, blocking UCP2 with genipin had no effect on the response to increased glucose. But in the same mice fed a high-fat diet -- whose glucose response was impaired -- the molecule completely remedied the defect.
In another test, they created transgenic mice lacking the gene for UCP2. The pro-opiomelanocortin neurons of these mice had a normal glucose response regardless of diet and did not respond differently when treated with genipin, the researchers said.
"An increase in the activity of the mitochondrial uncoupling protein 2 is behind the loss of glucose-sensing ability in the pro-opiomelanocortin neurons," said co-author Laura Parton, Ph.D., also of Beth Israel.
"Increased activity of UCP2 is known to cause loss of glucose-sensing and defective insulin secretion by pancreatic beta cells and this study now shows that a similar phenomenon also occurs in neurons."
The findings "add to our understanding of type 2 diabetes," Dr. Lowell said, "at a critically important time. The discovery that defects in glucose-sensing by the brain may also be contributing to Type 2 diabetes could help lead to new therapeutic strategies for this widespread problem."