Mechanism of Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor 1

Abstract

The rising prevalence of type 2 diabetes mellitus (T2D) is a major health concern worldwide. Growing evidence of a role for the brain in glucose homeostasis has stimulated interest in therapeutic approaches that target the brain for the treatment of T2D. Our recent finding that a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) elicits sustained diabetes remission in rodent models of T2D supports a growing consensus that the brain is a key target for diabetes drug development. The goal of the research reported in this dissertation is to identify the brain area, signal transduction pathway, and peripheral mechanisms responsible for mediating sustained diabetes remission induced by central FGF1. We identified the hypothalamic arcuate nucleus (ARC) median eminence (ME) (ARC-ME), a brain area known to participate in glucose homeostasis, as being one of only two brain areas that show robust induction of MAP Kinase / ERK (MAPK/ERK) signaling (a marker of FGF receptor activation) following icv injection of FGF1, and that FGF1 microinjection localized to this brain area is capable of inducing sustained glucose lowering. Additionally, activation of the MAPK/ERK signaling pathway occurs in the ARC-ME for at least 24 hours post icv injection, and diabetes remission induced by the central action of FGF1 depends upon this prolonged hypothalamic MAPK/ERK signaling. Finally, in the Zucker diabetic fatty rat model of T2D, sustained glucose lowering induced by the central action of FGF1 involves both preservation of β-cell function and stimulation of hepatic glucose utilization through increased hepatic glucokinase activity. This work provides fundamental insight into mechanisms underlying the brain’s capacity to induce sustained diabetes remission.