HYPOTHALAMIC NEUROCIRCUIT REMODELING TO TREAT DIABETES - PROJECT SUMMARY Diabetes afflicts over 30 million Americans, corresponding to nearly 10% of the general population and accounting for over $320 billion per year in healthcare costs—among the most common and costly diseases in modern society. To exacerbate the problem, despite over 40 new diabetes drugs being introduced since 2005, there has not been a concomitant improvement in treatment outcomes for patients with type 2 diabetes (T2D). This paradox may reflect the need for therapeutic strategies that address the causes rather than the manifestations of T2D. A key observation is that T2D is characterized by the biological defense of an elevated level of blood glucose (BG)—that is, BG is regulated, but at a higher setpoint. From this perspective, currently available anti-diabetic drugs ameliorate hyperglycemia only transiently below this defended level (until the drug effect has worn off), require drug administration on a daily basis to stay below the defended level, and result in most patients failing to achieve target levels of glycemia in a sustained manner. Accumulating evidence implicates the brain, and hypothalamic neurocircuits in particular, in the homeostatic defense of BG, with the corollary that a defect in these circuits may be responsible for the defense of an elevated BG level in T2D. Consistent with this hypothesis, recent work shows that in rodent T2D models, remission of hyperglycemia lasting for months can be induced by a single intracerebroventricular injection of fibroblast growth factor 1 (FGF1). This “resetting” to a lower, more normal defended BG level can be recapitulated by local FGF1 micro- injection into the hypothalamic arcuate nucleus (ARC), and is accompanied by new synapse formation and widespread suppression of ARC neuronal activity, invoking neural plasticity and augmented ARC inhibitory tone as potential mechanisms for the enduring anti-diabetic effect. Furthermore, aberrant hyperactivity of a specific population of ARC neurons, co-expressing Agouti-related peptide (Agrp) and Neuropeptide Y (NPY), is consistently observed in multiple distinct rodent models of diabetes and suppression of this hyperactivity is sufficient to ameliorate hyperglycemia in these models. This proposal describes studies investigating how augmenting ARC inhibitory tone directly, via inhibitory interneuron transplantation, ameliorates hyperglycemia in rodent T2D models, the electrophysiological mechanisms and graft-host cellular connectivity underlying this effect, and whether human induced pluripotent stem cell (iPSC)-derived inhibitory interneurons can reproduce these effects as a step toward translation.
