Document Type

Journal Article

Date of this Version

11-1-2013

Publication Source

Journal of Clinical Investigation

Volume

123

Issue

11

Start Page

4799

Last Page

4808

DOI

10.1172/JCI70710

Abstract

Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain’s capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal.

Comments

At the time of publication, author Darko Stefanovski was affiliated with the Diabetes and Obesity Research Institute. Currently, he is a faculty member at the University of Pennsylvania's School of Veterinary Medicine.

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Date Posted: 22 December 2016

This document has been peer reviewed.