Resetting Hypothalamic and Autonomic Neurocircuitry to Treat Diabetes
Abstract
Diabetes afflicts nearly 10% of the general U.S. population, 3% of active U.S. Service Members, and nearly 25% of U.S. Department of Veterans Affairs patients, accounting for an annual economic burden of over $404 billion per year in medical expenses and lost productivity. Despite the introduction of >40 new diabetes drugs since 2005, treatment outcomes for patients with type 2 diabetes (T2D) have not improved over the past decade. One potential reason is that these medications treat the symptoms instead of the causes of T2D, and therefore are unable to prevent progression of the disease. Based on evidence supporting a primary role for insulin secreted by the pancreas as the primary controller of blood glucose levels, our large and ever-growing toolbox of diabetes drugs has been limited to medications that either replace insulin, or increase the responsiveness of peripheral organs including the liver, muscle, and gut to insulin. Unfortunately, none of them are able to maintain stable blood glucose once the drug effect wears off, and most are associated with significant side effects including hypoglycemia, weight gain, and gastrointestinal discomfort. Recent studies in patients with T2D indicate that their elevated blood sugar levels are not due to a lack of control, but rather are being controlled at a higher, albeit abnormal set point. This type of error in regulation also occurs in patients who are hypertensive or obese as these diseases are characterized by elevated levels of blood pressure and body fat mass. Although it is widely accepted that the brain plays an active role in the control of blood pressure and body weight, only recently has it been recognized that the brain plays a key role in regulating blood glucose and that T2D may involve a defect in this system. Consistent with this idea, recent studies have demonstrated the unprecedented ability of a single dose of a brain-directed drug to induce remission of diabetes lasting for weeks or months in rodent models of T2D. The ability of this drug to induce diabetes remission appears to be achieved by rewiring neural circuits in the brain that control blood glucose levels that have become defective. To fully realize the potential of such a translational advance, an improved understanding of how the brain controls blood glucose is required, and in this proposal we describe studies aimed at understanding how neurocircuits in the brain control blood glucose, how these circuits become defective in T2D, and how brain-directed therapies can be used to repair these circuits to “re-set” the defended blood glucose level in the normal range.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110635
Entities
People
- Jarrad Scarlett
Organizations
- United States Army
- University of Washington