Glutamate-mediated signaling in the islets of Langerhans: a thread entangled

doi:10.1016/j.tips.2003.08.002

Trends in Pharmacological Sciences

Volume 24, Issue 10, October 2003, Pages 511-517

https://doi.org/10.1016/j.tips.2003.08.002 Get rights and content

Abstract

Increasing evidence suggests that the excitatory neurotransmitter l-glutamate functions as a modulator in the islet of Langerhans, an endocrine organ involved in blood glucose homeostasis. The islet is equipped with all the elements required for l-glutamate-mediated transmission, and it has been shown that l-glutamate is co-stored and co-secreted with glucagon from α-cells following treatment with low levels of glucose, and triggers the secondary paracrine response of islet cells. In this article, we propose that l-glutamate regulates the secretion of glucagon from islets but does not affect the secretion of insulin from islets. It is suggested that the effects of glutamate are mediated by the activation of GABA_A receptors on α-cells following glutamate-mediated release of GABA from β-cells and the activation of glutamate receptors on α-cells. This novel regulatory mechanism for islet hormone secretion should provide a target for chemotherapeutics in the treatment of class II diabetes mellitus.

Section snippets

Glutamate systems in the islets of Langerhans

l-Glutamate is the major excitatory neurotransmitter in the CNS and plays important roles in many neuronal processes such as fast synaptic transmission and neuronal plasticity. To use l-glutamate as an intercellular signaling molecule, neuronal cells develop a glutamate system that includes: (i) the ability to store l-glutamate in synaptic vesicles and secrete l-glutamate by exocytosis; (ii) glutamate receptors by which signals can be transmitted intercellularly; and (iii) a plasma

Glutamate-mediated response of islets

Because islets appear to possess all the necessary components of a glutamate system, it is likely that l-glutamate acts as an intercellular transmitter of these cells. Indeed, several investigators have observed that AMPA and kainate, agonists of AMPA receptors, each stimulate insulin secretion from perfused or isolated islets or clonal islet cells in the presence of high levels of glucose 5, 6, 20, 21 (Table 1). This stimulatory effect was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione

Where, when and how is l-glutamate secreted?

Clues regarding where, when and how l-glutamate is secreted have been provided by research in neuroscience. Recent findings indicate that brain-specific Na⁺-dependent inorganic phosphate cotransporter (BNPI), a member of the Na⁺-dependent inorganic phosphate cotransporter family [35], facilitates ATP-dependent vesicular l-glutamate uptake, indicating that BNPI is in fact VGLUT itself (Figure 1) 36, 37. It has been shown that VGLUT-expressing PC12 cells can secrete l-glutamate, and that the

Role of l-glutamate as an intercellular transmitter

What is the role of l-glutamate signaling under physiological conditions? Because l-glutamate is co-secreted with glucagon, stimulation of glutamate receptors should only occur in the presence of low levels of glucose, and thus glutamate signaling is not directly involved in the regulation of insulin secretion. β-Cells store the inhibitory amino acid GABA in synaptic-like microvesicles (SLMVs), which are secretory vesicles that are distinct from insulin granules, and secrete GABA by Ca²⁺

Perspectives and concluding remarks

Understanding the sites, timing and mode of l-glutamate secretion helps to identify the complex features of the l-glutamate-mediated signaling in islets. The mode of action of l-glutamate as an intercellular transmitter is distinct from that of l-glutamate as an intracellular messenger. More importantly, the glutamate system reveals the framework of the ‘paracrine signal network’ as a novel regulatory mechanism for islet function. Very recently, it was reported that zinc ions co-released with

Acknowledgements

Thanks are due to Akitsugu Yamamoto and all the co-authors listed in our literature for their contributions.

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A growing body of evidence suggests that glutamate, the major excitatory neurotransmitter in the central nervous system, acts as a signalling molecule in peripheral tissues [4–6]. In the cells of the endocrine pancreas, glutamate is stored in glucagon or insulin-containing granules [7,8] and, once secreted, acts extracellularly to regulate hormone secretion [9,10]. Various reports suggest that glutamate stimulates insulin release in rat pancreas, by acting on excitatory AMPA receptor subtypes [11,12].
Pancreatic islets, particularly insulin-secreting β cells, share common characteristics with neurons. Glutamate is one of the major excitatory neurotransmitter in the brain and pancreas, and its action is mediated through glutamate receptors. In the present work, we analysed the role of vitamin D₃ in the modulation of AMPA receptor subunit and their functional role in insulin release. Radio receptor binding study in diabetic rats showed a significant increase in AMPA receptor density. Insulin AMPA colabelling study showed an altered AMPA GluR2 and GluR4 subunit expression in the pancreatic beta cells. We also found lowered IP3 content and decreased IP3 receptor in pancreas of diabetic rats. The alterations in AMPA and IP3 receptor resulted in reduced cytosolic calcium level concentration, which further blocks Ca²⁺-mediated insulin release. Vitamin D₃ supplementation restored the alteration in vitamin D receptor expression, AMPA receptor density and AMPA and IP3 receptor expression in the pancreatic islets that helps to restore the calcium-mediated insulin secretion. Our study reveals the antidiabetic property of vitamin D₃ that is suggested to have therapeutic role through regulating glutamatergic function in diabetic rats.
Proteome analysis and conditional deletion of the EAAT2 glutamate transporter provide evidence against a role of EAAT2 in pancreatic insulin secretion in mice
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Islet function is incompletely understood in part because key steps in glutamate handling remain undetermined. The glutamate (excitatory amino acid) transporter 2 (EAAT2; Slc1a2) has been hypothesized to (a) provide islet cells with glutamate, (b) protect islet cells against high extracellular glutamate concentrations, (c) mediate glutamate release, or (d) control the pH inside insulin secretory granules. Here we floxed the EAAT2 gene to produce the first conditional EAAT2 knock-out mice. Crossing with Nestin-cyclization recombinase (Cre) eliminated EAAT2 from the brain, resulting in epilepsy and premature death, confirming the importance of EAAT2 for brain function and validating the genetic construction. Crossing with insulin-Cre lines (RIP-Cre and IPF1-Cre) to obtain pancreas-selective deletion did not appear to affect survival, growth, glucose tolerance, or β-cell number. We found (using TaqMan RT-PCR, immunoblotting, immunocytochemistry, and proteome analysis) that the EAAT2 levels were too low to support any of the four hypothesized functions. The proteome analysis detected more than 7,000 islet proteins of which more than 100 were transporters. Although mitochondrial glutamate transporters and transporters for neutral amino acids were present at high levels, all other transporters with known ability to transport glutamate were strikingly absent. Glutamate-metabolizing enzymes were abundant. The level of glutamine synthetase was 2 orders of magnitude higher than that of glutaminase. Taken together this suggests that the uptake of glutamate by islets from the extracellular fluid is insignificant and that glutamate is intracellularly produced. Glutamine synthetase may be more important for islets than assumed previously.
Paracrine and autocrine interactions in the human islet: More than meets the eye
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The pancreatic islet secretes the hormones insulin and glucagon to regulate glucose metabolism. To generate an adequate secretory response, islet endocrine cells must receive multiple regulatory signals relaying information about changes in the internal and external environments. Islet cells also need to be made aware about the functional status of neighboring cells through paracrine interactions. All this information is used to orchestrate a hormonal response that contributes to glucose homeostasis. Several neurotransmitters have been proposed to work as paracrine signals in the islet. Most of these, however, have yet to meet the criteria to be considered bona fide paracrine signals, in particular in human islets. Here, we review recent findings describing autocrine and paracrine signaling mechanisms in human islets. These recent results are showing an increasingly complex picture of paracrine interactions in the human islet and emphasize that results from other species cannot be readily extrapolated to the human context. Investigators are unveiling new signaling mechanisms or finding new roles for known paracrine signals in human islets. While it is too early to provide a synthesis, the field of islet research is defining the paracrine and autocrine components that will be used to generate models about how islet function is regulated. Meanwhile, the identified signaling pathways can be proposed as therapeutic targets for treating diabetes, a devastating disease affecting millions worldwide.
Podocytes: A new player for glutamate signaling
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In the renal glomerulus, podocytes envelop the external side of the capillary basement membrane with their intertwining ramifications, and ensure elimination of metabolic waste within the urine, while proteins and important blood components are retained into the circulation.
To preserve the integrity of the glomerular filter, which is constantly exposed to a high variety of stimuli, podocytes need to communicate by rapid and precise signaling, likely similar to that used by neuronal cells.
In the last years, we and others have shown that podocytes are indeed molecularly equipped for communicating in a synaptic-like way, where glutamate and its receptors seem to have a pivotal role, because altering glutamatergic communication leads to podocyte damage and increased filter permeability. Major components of glutamatergic signaling are organized at foot process junctions by adhesion molecules, chiefly by nephrin, and are connected to the actin cytoskeleton, that governs the health of podocytes.
Further advances in understanding podocyte physiological behavior and signaling properties have the potential to improve the knowledge of podocyte diseases, first among them idiopathic focal segmental glomerulosclerosis that still needs more precise molecular-based diagnosis and targeted treatment.
Effects of topiramate on diabetes mellitus induced by streptozotocin in rats
2012, European Journal of Pharmacology
Citation Excerpt :
The pancreatic islet secretes neurotransmitters and modulates hormone secretion (Suckow et al., 2006) for regulating blood glucose. Islet cells are composed of at least four kinds of cells: glucagon-secreting alpha-cells, insulin-secreting beta-cells, somatostatin-secreting delta-cells, and pancreatic polypeptide-secreting F-cell (Kanno et al., 2002; Maechler and Wollheim, 2001; Moriyama and Hayashi, 2003). In β-cells, GABA an inhibitory neurotransmitter is stored in synaptic-like secretory microvesicles, distinct from insulin granules (Garry et al., 1986) and secreted through exocytosis (Chessler et al., 2002).
Topiramate currently approved for marketing as antiepileptic drug also possesses anti-diabetic activity. The aim of this study was to determine the antidiabetic effect of topiramate in a rat model of diabetes mellitus. Diabetes was induced by a single injection of streptozotocin to fasted rats. Diabetic animals were divided into untreated; insulin treated; topiramate treated with 25, 50 and 100 mg/kg; and combined insulin plus topiramate treatment in the previous doses. All medications were given once daily started after the rise of blood glucose for three weeks. Control rats were divided into untreated; vehicle treated and rats given topiramate in the previous doses. Body weight, blood-glucose and insulin levels were measured. Histopathological examination, immunohistochemical and morphometric studies of islets of the pancreas were done. Topiramate 50 and 100 mg/kg resulted in a significant decrease in the blood glucose and increase in the insulin levels as well as the number of islets and the count and mass of beta cells. Combined treatment to diabetic rats with insulin and topiramate induced a better response than either alone. Further experimental and clinical studies are needed to explore the different mechanisms of action of topiramate as antidiabetic both in insulin dependent and non-insulin-dependent diabetes mellitus.
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2011, Molecular and Cellular Endocrinology
Citation Excerpt :
Functional intercellular glutamate signalling requires a glutamate system, comprised of the following components: (I) vesicular glutamate transporters (VGLUT 1–3) to store glutamate in synaptic vesicles, (II) glutamate receptors to bind the amino acid and transmit the signal, and (III) an electrogenic plasma membrane glutamate transport system mediated by excitatory amino acid transporters (EAATs 1–5) for the reuptake of the transmitter. These transporters maintain extra-cellular glutamate concentrations low and terminate the process of synaptic transmission (Moriyama and Hayashi, 2003). Except for EAAT expression in α- and β-cells, all the components necessary for extra-cellular glutamate signalling have been described in pancreatic islets (Inagaki et al., 1995; Weaver et al., 1996, 1998; Storto et al., 2006; Cabrera et al., 2008).
Glutamate is generated during nutrient stimulation of pancreatic islets and has been proposed to act both as an intra- and extra-cellular messenger molecule. We demonstrate that glutamate is not co-secreted with the hormones from intact islets or purified α- and β-cells. Fractional glutamate release was 5–50 times higher than hormone secretion. Furthermore, various hormone secretagogues did not elicit glutamate efflux. Interestingly, epinephrine even decreased glutamate release while increasing glucagon secretion. Rather than being co-secreted with hormones, we show that glutamate is mainly released via plasma membrane excitatory amino acid transporters (EAAT) by uptake reversal. Transcripts for EAAT1, 2 and 3 were present in both rat α- and β-cells. Inhibition of EAATs by l-trans-pyrrolidine-2,4-dicarboxylate augmented intra-cellular glutamate and α-ketoglutarate contents and potentiated glucose-stimulated insulin secretion from islets and purified β-cells without affecting glucagon secretion from α-cells. In conclusion, intra-cellular glutamate-derived metabolite pools are linked to glucose-stimulated insulin but not glucagon secretion.

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Trends in Pharmacological Sciences

Glutamate-mediated signaling in the islets of Langerhans: a thread entangled

Abstract

Section snippets

Glutamate systems in the islets of Langerhans

Glutamate-mediated response of islets

Where, when and how is l-glutamate secreted?

Role of l-glutamate as an intercellular transmitter

Perspectives and concluding remarks

Acknowledgements

Neurosci. Res.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

Biochem. Pharmacol.

FEBS Lett.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Res.

Neurotransmitters and their receptors in the islets of Langerhans of the pancreas

Endocrine

Autonomic regulation of islet hormone secretion – implications for health and disease

Diabetologia

Mitochondrial function in normal and diabetic beta-cells

Nature

Expression and role of ionotropic glutamate receptors in pancreatic islet cells

FASEB J.

Pharmacological and molecular characterization of glutamate receptors in the MIN6 pancreatic beta-cell line

Neurol. Res.

Activation of glycine and glutamate receptors increases intracellular calcium in cells derived from the endocrine pancreas

Mol. Pharmacol.

AMPA receptor-mediated regulation of a Gi-protein in cortical neurons

Nature

Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets

Am. J. Physiol. Endocrinol. Metab.

Metabotropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells

Diabetologia