Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents

Jarrad M. Scarlett, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
Jennifer M. Rojas, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
Miles E. Matsen, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
Karl J. Kaiyala, Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, Washington, USA.
Darko Stefanovski, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Richard N. Bergman, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Hong T. Nguyen, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
Mauricio D. Dorfman, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
Louise Lantier, Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee, USA.
David H. Wasserman, Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee, USA.
Zaman Mirzadeh, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Terry G. Unterman, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA.
Gregory J. Morton, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
Michael W. Schwartz, Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.

Document Type

Article

Abstract

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.

Medical Subject Headings

Adipose Tissue (drug effects, metabolism); Animals; Blood Glucose (drug effects, metabolism); Blotting, Western; Body Composition; Brain (drug effects, metabolism); Carbon Radioisotopes; Deoxyglucose; Diabetes Mellitus, Experimental (metabolism); Diabetes Mellitus, Type 2 (metabolism); Diet, High-Fat; Disease Models, Animal; Ependymoglial Cells (drug effects, metabolism); Fibroblast Growth Factor 1 (pharmacology); Forkhead Box Protein O1 (genetics); Glucose Tolerance Test; Heart (drug effects); Heat-Shock Proteins (drug effects, metabolism); Hyperglycemia (metabolism); Hypothalamus (cytology, drug effects, metabolism); Injections, Intraventricular; Liver (metabolism); Male; Mice; Mice, Knockout; Mice, Obese; Molecular Chaperones; Muscle, Skeletal (drug effects, metabolism); Myocardium (metabolism); Neoplasm Proteins (drug effects, metabolism); Proto-Oncogene Proteins c-fos (drug effects, metabolism); Rats; Rats, Zucker; Real-Time Polymerase Chain Reaction; Receptor, Insulin (antagonists & inhibitors, genetics); Remission Induction

Publication Date

7-1-2016

Publication Title

Nature medicine

E-ISSN

1546-170X

Volume

22

Issue

7

First Page

800

Last Page

6

PubMed ID

27213816

Digital Object Identifier (DOI)

10.1038/nm.4101

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