Plasticity and Neurocircuit Remodeling in the Mediobasal Hypothalamus to Treat Diabetes
Abstract
Diabetes afflicts nearly 10% of the general population, close to 25% of U.S. Department of Veterans Affairs patients, and accounts for over $320 billion per year in healthcare costs. Despite the introduction of over 40 new diabetes drugs since 2005, there has been no improvement in treatment outcomes for patients with type 2 diabetes (T2D). This failure of treatment may be related to an incomplete understanding of the problem. Current drugs act primarily on peripheral organs such as the pancreas, gut, liver, and muscle to reduce high blood sugar in T2D patients. In general, these organs have a powerful ability to lower blood sugar in response. However, once the drug wears off, the blood sugar rises back to a similarly high level. Studies on T2D patients have shown that in general, their blood sugars are not “out of control,” but rather are being controlled at a higher, albeit abnormal, set point. Consequently, the rise in blood sugar after the drug wears off is, in fact, a reflection of the body and its organs wanting the blood sugar to remain high. By analogy, rather than thinking about T2D as a problem with the ventilation ducts or the air-conditioning motor, which are analogous to the peripheral organs, we need to address the regulator or thermostat, which is analogous to the brain. Increasing evidence suggests that T2D is fundamentally a problem of the brain keeping an abnormally high set point for blood sugar. Consistent with this idea, a recent breakthrough includes the ability to put diabetes into remission with a single dose of a brain-directed drug in rodent diabetic models. This drug appears to act by inducing some re-wiring of brain circuits. In this proposal, we describe studies aimed at understanding how wiring is controlled in brain areas that control blood sugar and metabolism, how this wiring is affected in rodent models of T2D, and how strategies aimed at rewiring these areas may induce lasting remission of T2D.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010250
Entities
People
- Zaman Mirzadeh
Organizations
- United States Army