The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis and its deterioration during aging.
Molecular Metabolism. 2019-12-01; 30: 152-160
DOI: 10.1016/j.molmet.2019.09.011
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OBJECTIVE: Islets secrete neurotransmitters including glutamate which participate
in fine regulation of islet function. The excitatory ionotropic glutamate
receptor GluK2 of the kainate receptor family is widely expressed in brain and
also found in islets, mainly in α and γ cells. α cells co-release glucagon and
glutamate and the latter increases glucagon release via ionotropic glutamate
receptors. However, neither the precise nature of the ionotropic glutamate
receptor involved nor its role in glucose homeostasis is known. As isoform
specific pharmacology is not available, we investigated this question in
constitutive GluK2 knock-out mice (GluK2-/-) using adult and middle-aged animals
to also gain insight in a potential role during aging.
METHODS: We compared wild-type GluK2+/+ and knock-out GluK2-/- mice using adult
(14-20 weeks) and middle-aged animals (40-52 weeks). Glucose (oral OGTT and
intraperitoneal IPGTT) and insulin tolerance as well as pyruvate challenge tests
were performed according to standard procedures. Parasympathetic activity, which
stimulates hormones secretion, was measured by electrophysiology in vivo.
Isolated islets were used in vitro to determine islet β-cell electrical activity
on multi-electrode arrays and dynamic secretion of insulin as well as glucagon
was determined by ELISA.
RESULTS: Adult GluK2-/- mice exhibit an improved glucose tolerance (OGTT and
IPGTT), and this was also apparent in middle-aged mice, whereas the outcome of
pyruvate challenge was slightly improved only in middle-aged GluK2-/- mice.
Similarly, insulin sensitivity was markedly enhanced in middle-aged GluK2-/-
animals. Basal and glucose-induced insulin secretion in vivo was slightly lower
in GluK2-/- mice, whereas fasting glucagonemia was strongly reduced. In vivo
recordings of parasympathetic activity showed an increase in basal activity in
GluK2-/- mice which represents most likely an adaptive mechanism to counteract
hypoglucagonemia rather than altered neuronal mechanism. In vitro recording
demonstrated an improvement of glucose-induced electrical activity of β-cells in
islets obtained from GluK2-/- mice at both ages. Finally, glucose-induced insulin
secretion in vitro was increased in GluK2-/- islets, whereas glucagon secretion
at 2 mmol/l of glucose was considerably reduced.
CONCLUSIONS: These observations indicate a general role for kainate receptors in
glucose homeostasis and specifically suggest a negative effect of GluK2 on
glucose homeostasis and preservation of islet function during aging. Our
observations raise the possibility that blockade of GluK2 may provide benefits in
glucose homeostasis especially during aging.