Elsevier

Molecular Metabolism

Volume 4, Issue 8, August 2015, Pages 561-568
Molecular Metabolism

Brief communication
Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response

https://doi.org/10.1016/j.molmet.2015.05.005Get rights and content
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open access

Highlights

  • icv FGFR antagonist causes glucose intolerance in rats.

  • This effect is associated with robust sympathoadrenal activation.

  • The sympathoadrenal response is rapid in onset, but clears rapidly.

  • Reduced insulin secretion contributes to FGFR inhibitor-induced glucose intolerance.

Abstract

Objective

Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs.

Methods

Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection.

Results

Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus.

Conclusions

The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.

Keywords

Central FGF receptors
FGF receptor inhibitor PD173074
Frequently sampled intravenous glucose tolerance test
Sympathoadrenal response
Minimal model
Glucose metabolism

Abbreviations

AIRg
acute insulin response to glucose
AUC
area under the curve
Ibasal
basal insulin
BIE
basal insulin effect
CNS
central nervous system
DI
disposition index
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FGF19
Fibroblast growth factor-19
FGFRi
FGFR inhibitor
FSIGT
frequently sampled intravenous glucose tolerance test
GE
glucose effectiveness
GEZI
glucose effectiveness at zero insulin
icv
intracerebroventricular
Kg
glucose disappearance constant
NEFA
non-esterified free fatty acids
SG
glucose effectiveness at basal insulin
SI
insulin sensitivity

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