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FGF19 action in the brain induces insulin-independent glucose lowering
Gregory J. Morton, … , David H. Wasserman, Michael W. Schwartz
Gregory J. Morton, … , David H. Wasserman, Michael W. Schwartz
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4799-4808. https://doi.org/10.1172/JCI70710.
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Research Article Metabolism

FGF19 action in the brain induces insulin-independent glucose lowering

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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.

Authors

Gregory J. Morton, Miles E. Matsen, Deanna P. Bracy, Thomas H. Meek, Hong T. Nguyen, Darko Stefanovski, Richard N. Bergman, David H. Wasserman, Michael W. Schwartz

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Figure 4

Effect of FGF19 on plasma glucagon, FFA, and lactate levels in ob/ob mice.

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Effect of FGF19 on plasma glucagon, FFA, and lactate levels in ob/ob mic...
(A) Plasma lactate levels and (B) the integrated area under the lactate curve (AUClactate) during the first 20 minutes of the same FSIGT performed in WT and ob/ob mice that received either i.c.v. vehicle or FGF19 shown in Figure 3. (C) Plasma glucagon and (D) FFA levels in ob/ob mice treated with FGF19 (1 mg/kg i.p.) or its vehicle, followed 90 minutes later by an i.p. glucose bolus. Glucagon and FFA levels were measured in plasma obtained 30 minutes after the glucose bolus. Data represent mean ± SEM. *P < 0.05 vs. WT i.c.v. vehicle; #P < 0.05 vs. ob/ob i.c.v. vehicle.

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