Type 2 diabetes (T2D) is among the most common and costly challenges confronting modern society. Although current treatment regimens can transiently normalize glycemia, lasting diabetes remission has yet to be achieved through nonsurgical means. This changed with our recent finding that central administration of fibroblast growth factor 1 (FGF1) can restore normal blood glucose levels to both rat and mouse models of T2D in a manner that is sustained for weeks or months. Our interrogation of underlying mechanisms supports the hypothesis tested in this proposal that FGF1 action in the brain of diabetic animals re-sets the defended level of glycemia to the normal range, and our preliminary data point strongly to the mediobasal hypothalamus (MBH) as a key target for this effect. The overarching goal of the proposed studies is to employ FGF1 as a tool with which to understand how glucoregulatory neurocircuits can be remodeled so as to lower the defended blood glucose level. In this context, FGF1 is used as a tool how this brain effect is achieved. Proposed studies seek to identify both the discrete MBH neurocircuits involved in this FGF1 effect and the underlying cellular and molecular mechanisms, based in part on our preliminary evidence that cross-talk between FGF receptors and integrin receptors is required for FGF1-induced diabetes remission. To delineate the specific cell types and molecular mediators involved, we will employ single cell transcriptomics, histochemistry, biochemistry, pharmacology and electrophysiology, along with established energy homeostasis and glucose metabolic phenotyping methods, in rodent models of T2D. A comprehensive understanding of how FGF1 action in the MBH induces diabetes remission will shed new light on how glucose homeostasis is controlled by the brain and on the potential of interventions that target the brain to improve treatment outcomes for patients with T2D.
Type 2 diabetes is among the most common chronic disorders affecting modern society. Work in this proposal is designed to clarify how the action of fibroblast growth factor 1 (FGF1) in the brain induces sustained remission of hyperglycemia in both rat and mouse models of T2D. By achieving a more comprehensive understanding of this action of FGF1, studies herein will both shed new light on brain control of blood glucose levels and identify novel targets for improved treatment of this disorder.
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