Mobbs, Charles V.
Neurons expressing D2 receptors as targets to treat diabetes
General Research Subject: Obesity
Focus: Integrated Physiology\Regulation of Food Intake, Integrated Physiology\Regulation of Glucose Kinetics, Obesity\Animal Models
Type of Grant: Clinical Scientist Training Award
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
A new treatment for diabetes based on the drug bromocriptine has just been approved, but improvements to this novel approach to treat diabetes are limited because the mechanisms by which bromocriptine improves diabetes are not know. The present proposal is based on the hypothesis that this drug acts by regulating a particular kind of neuron in the brain that has receptors known to be targets for this drug. Using a cutting edge technique called optogenetics, in the proposed studies these neurons will be modified so their regulation can be acutely regulated by light. It is anticipated that activating these neurons during consumption of a sugar solution will reduce consumption of that solution, reduce the rewarding effect of the solution, and improve control of blood sugar. Alternatively in the same area there is a set of neurons that antagonizes the neurons that are targets of bromocriptine, and it is anticipated that activating these neurons during consumption of a sugar solution will increase consumption of the sugar solution, increase reward of the sugar solution, and impair control of blood glucose. If these predictions are borne out, the proposed studies will have revealed a new pathway of regulation of blood glucose and will set the stage for much better therapeutics based on bromocriptine as a model.
Mentor: Charles Mobbs, PhD Postdoctoral Fellow: Elizabeth Schwartz
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 how the D2 receptor for dopamine controls blood glucose in patients with Type 2 diabetes. It has been known for many years that drugs such as bromocriptine, which activate the D2 receptor, improves glucose control in patients with Type 2 diabetes and in animal models of this disease. Indeed, a modified version of bromocriptine has recently been approved to treat Type 2 diabetes. Conversely, drugs that reduce activity of the D2 receptor, such as atypical antipsychotic drugs, are a major cause of Type 2 diabetes in these patients. However, the mechanism by which the D2 receptor acts to improve control of blood glucose is not known. Specifically, the identity of the cell types mediating these effects is not known. One of the best characterized type of cell that produces the D2 receptor is found in the part of the brain that regulates reward (for which dopamine is the major signal), including the reward value of food. This part of the brain is called the ventral striatum, and the D2 receptor generally appears to modulate reward. A major signal for the reward value of food is glucose itself, and glucose activates dopamine release in the part of the brain that mediates reward.
We therefore hypothesize that D2 receptors in the ventral striatum not only modulate the effects of glucose in producing food reward, but also regulate control of blood glucose. To examine this hypothesis, we propose to use recently developed technology to specifically activate or inhibit these neurons in mice with a pre-diabetic condition with or without bromocriptine. If our hypothesis is correct, we expect that activating neurons in the ventral striatum which produce the D2 receptor will improve diabetic symptoms, whereas inhibiting these neurons will worsen diabetic symptoms and even block the effect of bromocriptine in improving diabetic symptoms. If these predictions are correct, this will lay the foundations of improving therapy for Type 2 diabetes using drugs that more specifically target D2 receptors in ventral striatum neurons.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Although a modification of the D2 activator bromocriptine has been approved for use in patients with Type 2 diabetes, improved versions of this drug will require a better understanding of how this drug improves diabetic symptoms. The proposed studies would provide this much-needed understanding. The studies may also lay the foundation toward using these new technologies to replace drug therapy to treat and possibly even cure Type 2 diabetes based on regulating the activity of D2-expressing neurons in the ventral striatum.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
We have a strong commitment to translational research, which means, for us, actually curing disease, and diabetes in particular, is the goal of our research. Diabetes is increasingly a major focus of our research because it affects so many people and unfortunately the prevalence of diabetes is increasing so rapidly it is set to become the major threat to public health world-wide in the 21st century. Thus diabetes profoundly affects a large and rapidly growing patient population, and we feel committed to exploring avenues of research that can directly affect patient care as well as offer new therapeutic interventions. This award represents our own laboratory’s efforts to look for new strategies of prevention and treatment that are based on mechanisms in the brain. Our laboratory uses a wide range of techniques to assess the mechanisms by which the brain regulates glucose metabolism, a mechanism increasingly recognized as critical in diabetes. Indeed, our laboratory was the first to demonstrate that transgenic correction of neuronal gene expression in a genetic model of diabetes completely corrects peripheral glucose homeostasis, independent of food intake or body weight. The surprise is the empirical observation that drugs acting on neurons that regulate reward, including glucose-mediated food reward, appear to also regulate blood glucose independently, via the D2 receptors, which has led to the approval of a drug acting through this pathway. However, the mechanisms by which this drug corrects blood glucose are not known. Our laboratory is on the forefront in studying mechanisms by which the brain regulates blood glucose, so we are very well placed to examine these mechanisms, which nevertheless represents a new and exciting new direction for our laboratory.
In what direction do you see the future of diabetes research going?
Diabetes is one of the most significant public health problems we currently face and causes devastating complications. Although we have learned much about the mechanisms behind both the etiology and pathology of diabetes, the prevalence of diabetes for a broad range of age groups continues to remain critically high. It is now important to not only continue to probe the molecular mechanisms at work behind the peripheral complications that so significantly affect morbidity and mortality for those struggling with diabetes, but also explore new 'brain based' avenues that have the potential to lead to more effective prevention and perhaps even treatment strategies. We have learned much about how the reward value of food plays an important role in regulating energy intake, and how individual differences in these reward circuits may in fact account for variability in body mass index as well as likelihood of developing type 2 diabetes. We see the proposed project as part of a larger effort to discover ideas for new centrally based novel interventions.
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