New Dopaminergic Mechanisms of Pancreatic Hormone Secretion and Therapeutics in Diabetes
Abstract
Topic Area: We address the Topic Area of Diabetes. We also address several Areas of Encouragement including research that: (1) identifies and evaluates new therapeutic targets and interventions to reduce metabolic dysregulation and development of diabetes among individuals that meet the clinical criteria for prediabetes; (2) offers new insights into existing interventions that treat diabetes and prevent diabetes complications; and (3) provides new biomarkers and novel insights into the heterogeneity of diabetes. Rationale: Diabetes is one of the foremost health problems faced today by active U.S. military Service Members, Veterans, their families, as well as more broadly by American society. Ten percent of people in the U.S. carry a clinical diagnosis of diabetes (33 million Americans with type 2 diabetes T2D), and 1 in 3 Americans are prediabetic. Significantly, among active and retired U.S. military Service Members, the proportion of individuals with T2D is comparable to civilians, despite fitness and weight standards. Moreover, in 2020, T2D was one of the most common diagnoses requiring hospitalization among active U.S. Armed Forces, along with ~18,000 T2D-related medical encounters affecting 6.2% of active personnel. Further, the proportion of adults with diabetes rises with age, affecting 25% of all Americans 65 years and older. Veterans are especially vulnerable as they are more than twice as likely to develop T2D and have worse overall health outcomes compared to civilians. Thus, large numbers of active and retired military personnel are susceptible to life-shortening diabetes and its complications, demonstrating a major health burden on the military. Yet, despite the many treatments for diabetes, most therapies stop working and/or have serious limitations or side effects that cause treatment discontinuation or poor compliance. Also, the ability to predict treatment response or efficacy is hampered by limited understanding of mechanisms by which T2D progresses from prediabetes, its heterogeneity, and lack of reliable biomarkers. Objectives: We have undertaken efforts to develop better, more effective therapies for T2D with fewer side effects and to identify new mechanisms for the adverse metabolic effects in diabetes. In our earlier Peer Reviewed Medical Research Program-funded work, we discovered a critical new mechanism responsible for regulating the blood levels of both insulin and glucagon, key pancreatic hormones that control blood sugar and metabolism and whose functions are often profoundly disturbed in diabetes. We showed that the neurotransmitter dopamine acts not only in the brain, but also on targets in the specific cells of the pancreas that produce insulin and glucagon to control blood sugar. Importantly, these cell targets are very susceptible to the effects of diabetes. Building on our initial findings, we have developed new drugs that modify levels of insulin and glucagon by acting through pancreatic dopamine. As a result, we have generated a new class of drugs that works specifically through the pancreatic dopamine pathway, is highly specific, and improves or even reverses the main hormonal abnormalities in T2D to improve blood sugar control, improving overall health. These new drugs have the key advantage of being excluded from the brain, in contrast to most existing diabetes drugs. This eliminates potential brain-related side effects which limit drug tolerability and compliance in patients. In extending these findings, we propose to test our new drugs in several original preclinical diabetes models and to better understand how diabetes disrupts dopamine’s actions in the pancreas to develop new diabetes biomarkers. To do so, we created new mouse models of prediabetes and T2D carrying specific mutations that target dopamine’s actions on pancreatic cells that produce insulin and glucagon as well as pancreatic islets taken from T2D and prediabetes patients. The main objectives of our proposed w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210671
Entities
People
- Zachary Freyberg
Organizations
- United States Army
- University of Pittsburgh