Mobbs, Charles V., PhD
Role of endogenous opioid systems in impaired responses to hypoglycemia
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\Hypoglycemia
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Diabetic patients often experience very low blood sugar due to medication. Normally the body has very robust mechanisms to prevent low blood sugar, but unfortunately these responses are often impaired in diabetic patients. Furthermore, the impairments to low blood sugar seem to themselves be caused by low blood sugar, leading to a vicious cycle. Recent clinical studies have suggested that the drug naloxone can improve these mechanisms to prevent low blood sugar, but the mechanisms mediating the effects of this drug is not clear. Specifically, this drug blocks several opioid receptors, so the specific receptor mediating the protective effect of this drug is not clear.
We have shown that naloxone also protects these mechanisms in mice to respond to low blood sugar, so we can use mice to test which opioid receptor causes the impaired responses to low blood sugar. Several lines of evidence suggest that the most likely specific receptor mediating these protective effects of naloxone is the mu opioid receptor. We therefore propose to carry out studies in which the mu opioid receptor is either genetically inactivated or is inactivated by a drug that specifically blocks the mu opioid receptor. We anticipate that both manipulations will preserve responsiveness to low blood sugar even after previous exposure to low blood sugar. These studies will pave the way for clinical trials to assess if drugs that specifically block the mu opioid receptor will minimize the risk of low blood sugar in diabetic patients.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project addresses the risk of low blood sugar in diabetic patients, which represents one of the major obstacles in optimum treatment of diabetes. Thus therapies to prevent low blood sugar could have a profound impact for all diabetic patients. Although low blood sugar occurs during treatment to reduce the high blood sugar that all diabetic patients have, the normal corrective responses that should prevent low glucose are damaged in patients with diabetes. This appears to be due to prior experience of low blood sugar. It has now been observed that a particular drug, naloxone, which is approved for use in humans, prevents the damage to the regulatory responses to low blood sugar, thus providing the opportunity to prevent low blood sugar. However, it is not known if the drug will reverse damage to regulatory responses once they have occurred, and it is not known how the drug works.
The purpose of the proposed studies is to assess if the drug reverses damage to regulatory responses after they have been produced by low blood sugar, and to examine the most likely mechanism by which the drug works. These studies will also address which specific receptors mediate the protective effects of naloxone. If successful these studies could lead to clinical trials to assess if the drug will reverse low blood sugar in patients who frequently experience this condition, and will also allow the development of even better drugs to do so. Such drugs would remove a major obstacle in optimum treatment of patients with diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Many patients with diabetes are very concerned about the problem of low blood sugar because the drugs used to treat diabetes work by reducing blood sugar, and sometimes the drugs are all too effective. Low blood sugar can cause long-term health problems and can even cause immediate loss of consciousness, potentially very dangerous if it occurs, for example, while driving. If successful the present studies could lead to the development of drugs that will reduce the danger of low blood sugar for diabetic patients.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is already one of the most common diseases in this country and its prevalence is also among the fastest growing in the country. Probably every person in the country either is diabetic or is very close to someone with the disease. Certainly this is true for me: I have several close relatives and friends with the disease. I believe with my expertise in neuroscience as well as metabolism I can be particularly helpful in developing drugs to treat the disease and its related complications, including hypoglycemia. This award is absolutely essential in carrying forward the observations we have made initially that naloxone protects against hypoglycemia. With this award I feel confident that by the end of 3 years we will have new drugs, most likely agonists of mu opioid receptors, to reduce the risk of hypoglycemia.
In what direction do you see the future of diabetes research going?
It is increasingly clear that the role of the brain in diabetes is the future of diabetes research. New hormonal pathways, including leptin, have clearly demonstrated the role of the brain in regulating blood glucose. Even the other great discovery, that bariatric surgery can "cure" some forms of diabetes, appears to implicate the brain in mediating these effects. The present studies are based on the clear evidence that the brain plays a major role in the prevention of low blood glucose, and will also undoubtedly provide evidence that the brain also plays a key role in preventing high blood glucose as well. Thus these studies may also provide new targets to not only prevent low blood glucose but high blood glucose as well.
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