Central and Peripheral Mechanisms of FGF1-Mediated Remission of Diabetic Hyperglycemia

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Project Summary This proposal delineates a 5-year program to provide training toward the development of an independent academic research career in the study of integrated central and peripheral regulation of glucose homeostasis. The candidate has been prepared for this pathway by completing MD and PhD degrees and clinical training in Pediatrics and Gastroenterology. He has been scientifically productive at all levels of training through graduate and postdoctoral work, contributing to 15 manuscripts (7 of them first or co-first author), and successfully competing for fellowships from the American Heart Association and the NIH. The proposed research will be conducted in the laboratory of Dr. Michael Schwartz, an expert in the field of hypothalamic regulation of energy balance and glucose homeostasis. It will be overseen by an expert mentoring committee with two members of the Endocrinology Division (Dr. Gregory Morton and Dr. Joshua Thaler) as well as an external advisor (Dr. David Wasserman, Vanderbilt University). The comprehensive training plan involves continued education in the use of isotopic techniques and analytical methods to study regulation of glucose homeostasis and metabolism from the gene to the whole organism level. The proposal focuses on evidence that members of the fibroblast growth factor (FGF) family play a key role in the regulation of glucose homeostasis by targeting hypothalamic glucoregulatory neurocircuits. Using sophisticated metabolic phenotyping, the candidate demonstrated that a single central injection of FGF1 induces sustained remission of diabetic hyperglycemia in rodent models of diabetes. The anti-diabetic effect is not secondary to weight loss, and is not associated with an increase in insulin sensitivity. Furthermore, the ability of icv FGF1 to induce diabetes remission is lost in animals with severe insulin deficiency and additional preliminary data suggest that relapse of diabetes in animals previously responsive to icv FGF1 is associated with progressive pancreatic β-cell dysfunction. This research will characterize the mechanisms by which icv FGF1 induces remission of diabetic hyperglycemia through 2 specific aims. In Aim 1, we will characterize the specific receptors, intracellular signaling cascades, and synaptic changes that mediate sustained remission of diabetic hyperglycemia in response to icv FGF1. Aim 2 focuses on the requirement of an intact basal insulin signal for FGF1 to induce remission of diabetic hyperglycemia and the extent to which FGF1-induced diabetes remission is attributable to increased basal insulin secretion due to preservation of pancreatic β-cell function. The applicant's combination of expertise in neuroanatomy, molecular biology, histochemistry, pharmacology and physiology of the neural regulation of metabolism uniquely qualify him to conduct the studies in this proposal. Outcomes from these studies are expected to provide a compelling rationale for future studies investigating the mechanisms of FGF1-mediated diabetes remission, exploring the translational potential for centrally-targeted FGF1 and related peptides as anti-diabetic agents.