Glutamate pathways of the beta-cell and the control of insulin secretion

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Glutamate pathways of the beta-cell and the control of insulin secretion

MAECHLER, Pierre

Abstract

Pancreatic beta-cells secrete insulin in response to circulating glucose, thereby maintaining euglycemia. Inside the beta-cell, glucose is transformed into intracellular signals stimulating exocytosis. While calcium is an obligatory messenger, this ion is not sufficient to promote the full secretory response. Accordingly, glucose metabolism produces the additive factor glutamate that participates to an amplifying pathway of the calcium signal. Although intracellular glutamate potentiates insulin secretion, extracellular glutamate may activate ionotropic receptors. As a consequence of such activation, insulin exocytosis is slowed down.

Therefore, for the beta-cell glutamate is a double-edged sword, an amplifying pathway and a negative feedback, illustrating the principle of homeostasis.

MAECHLER, Pierre. Glutamate pathways of the beta-cell and the control of insulin secretion.

Diabetes Research and Clinical Practice , 2017, vol. 131, p. 149-153

DOI : 10.1016/j.diabres.2017.07.009 PMID : 28743063

Available at:

http://archive-ouverte.unige.ch/unige:99221

Disclaimer: layout of this document may differ from the published version.

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Invited review

Glutamate pathways of the beta-cell and the control of insulin secretion

Pierre Maechler

Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland

A R T I C L E I N F O Article history:

Received 20 June 2017 Accepted 4 July 2017 Available online 12 July 2017

Keywords:

Pancreatic beta-cell Insulin

Glucose Glutamate

A B S T R A C T

Pancreatic beta-cells secrete insulin in response to circulating glucose, thereby maintaining euglycemia. Inside the beta-cell, glucose is transformed into intracellular signals stimulat- ing exocytosis. While calcium is an obligatory messenger, this ion is not sufficient to pro- mote the full secretory response. Accordingly, glucose metabolism produces the additive factor glutamate that participates to an amplifying pathway of the calcium signal.

Although intracellular glutamate potentiates insulin secretion, extracellular glutamate may activate ionotropic receptors. As a consequence of such activation, insulin exocytosis is slowed down. Therefore, for the beta-cell glutamate is a double-edged sword, an ampli- fying pathway and a negative feedback, illustrating the principle of homeostasis.

Ó2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . 150

1.1. Introduction to glutamate . . . 150

1.2. Insulin and the control of glycaemia . . . 150

2. Function of the insulin-secreting cell . . . 150

2.1. The pancreaticb-cell . . . 150

2.2. Potentiating the secretory response . . . 150

3. Glutamate dehydrogenase inb-cells . . . 150

3.1. The enzyme glutamate dehydrogenase . . . 150

3.2. The pancreaticb-cell with or without GDH . . . 151

4. Preventing obesity by the limitation of insulin secretion . . . 152

5. Glutamate receptors on pancreaticb-cells . . . 152

6. Conclusions . . . 152

Conflicts of interest . . . 152

Acknowledgement . . . 152

References . . . 152

http://dx.doi.org/10.1016/j.diabres.2017.07.009 0168-8227/Ó2017 Elsevier B.V. All rights reserved.

E-mail address:pierre.maechler@unige.ch

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1. Introduction

1.1. Introduction to glutamate

Glutamate is a multiple use amino acid, the Swiss army knife of the cell in a way. On top of being one key constitutive build- ing block of all of our proteins, glutamate is the main excita- tory neurotransmitter, is at the crossroad of metabolic pathways through the TCA cycle, participates to the urea cycle, is the activator of the umami taste receptor, and plays a role as an intracellular factor regulating insulin secretion.

The present review describes the latter action of glutamate.

1.2. Insulin and the control of glycaemia

Insulin is produced and secreted by the endocrine pancreas, more specifically by the pancreaticb-cells forming the islets of Langerhans. This hormone regulates blood glucose through its action on its target tissues. Insulin induces glucose clear- ance by skeletal muscles and inhibits hepatic glucose produc- tion. As an anabolic hormone, insulin promotes the storage of lipids in general and the expansion of adipose tissue in partic- ular. In case of obesity, or even just overweight, the action of insulin becomes less efficient because of the development of insulin resistance of the target tissues. Such a resistance to the action of insulin can be counterbalanced by an increase of the production of insulin by the pancreaticb-cells. In the event of a failure of the insulin-producing cells, obesity is then accompanied by hyperglycemia, thereby characterizing type 2 diabetes[1].

2. Function of the insulin-secreting cell

Pancreaticb-cells are neuroendocrine cells with the unique feature of having the most common nutrient, glucose, as the main stimulus. Indeed, other nutrients, such as fatty acids and amino acids, made available in the post-prandial state are not bone fide stimuli for the induction of insulin secretion. This is probably because these metabolic sub- strates are efficiently recruited both in the fasting state and in case of prolonged physical exercise, two situations that should not be associated with the elevation of circulating insulin in order to avoid further hypoglycemia.

Following a meal, glucose entering theb-cell should reflect the actual glycaemia and must give rise to proportionate insulin release. To this end, a cascade of biochemical reac- tions leads to the production of intracellular signals required for the coupling of glucose metabolism to the exocytosis of insulin [2]. Glucose breakdown generates ATP in the mito- chondria, which promotes the closure of the K-ATP channels on the cell membrane. This provokes the depolarization of the cell membrane and, as a result, the opening of the voltage-sensitive calcium channels (Fig. 1). The subsequent elevation of intracellular calcium triggers the exocytosis of insulin and a rapid first phase of secretion. This transient first phase is followed within a few minutes by a second sustained phase, which depends on the production of additive factors

on top of the necessary permissive cytosolic calcium concen- tration. The second phase of secretion is referred to as the amplifying pathway, pointing to a mechanism of amplifica- tion of the calcium signal[3]. Indeed, the latter is necessary for maintaining the process of exocytosis.

2.2. Potentiating the secretory response

The nature of the additional factors participating to the amplifying pathway has been the subject of numerous stud- ies, sometimes controversial, over the last two decades [4].

Seeking for those signals, we first highlighted the role of mito- chondria in the production of such factors[5], before the iden- tification of glutamate as an intracellular signal participating to the amplifying pathway[6]. Glutamate is produced by the mitochondria during glucose stimulation [6,7]. Once in the cytosolic compartment, this amino acid exerts a potentiating effect on the action of calcium, probably targeting the secre- tory granules (Fig. 1). Indeed, independent research groups reported glutamate uptake by insulin vesicles, rendering these granules exocytosis competent [2]. Interestingly, a recent study demonstrated that the action of glutamate is stimulated by cAMP, a second messenger induced by GLP-1, thereby unifying two signals controlling insulin secretion in pancreaticb-cells[8].

3. Glutamate dehydrogenase in b-cells

Glutamate metabolic pathways are closely associated with the enzyme glutamate dehydrogenase (GDH). GDH is encoded by the geneGLUD1 that is ubiquitously expressed; although mainly in the liver, the central nervous system, the kidney, and the pancreatic b-cells. This mitochondrial enzyme cat- alyzes the following reversible reaction: a-ketoglutarate + NH3+ NADHM^L-glutamate + NAD⁺. With a Delta G°being negative[9], the reaction rate is mainly driven by the respec- tive concentrations of its substrates and co-substrates. GDH is also controlled by allosteric regulation, i.e. inhibited by GTP and activated by ADP and L-leucine. In pancreatic b-cells, and in particular upon glucose stimulation, this is the cata- plerotic direction that is favored, thereby generating gluta- mate [10]. Of note, the anaplerotic direction producing a- ketoglutarate is hardly activated inb-cells, even when stimu- lated with glutamine used as a precursor for glutamate [11,12]. This preferred GDH direction, as opposed to other tis- sues, makes sense when considering the necessary basal rate of insulin secretion during prolonged fasting states or sus- tained physical exercise. As mentioned above, such condi- tions of physiological stress are associated with the recruitment of amino acids from skeletal muscles, in particu- lar glutamine and alanine, used as substrates for hepatic neoglucogenesis and not supposed to induce insulin release in a state requiring maintenance of basal insulinemia.

The pathological illustration of an undesired glutamine responsiveness is given by mutations of GDH. Indeed, a form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia is associated with dominant activat-

150

ing mutations in theGLUD1gene[13]. This is associated with increased activity of the GDH enzyme, because of either reduced GTP-mediated inhibition[14]or higher sensitivity to the allosteric activator ADP[15]. In both cases, theb-cells car- rying these mutations become responsive to glutamine and secrete insulin when exposed to this neoglucogenic amino acid[15,16].

3.2. The pancreaticb-cell with or without GDH

In a postprandial state, the rise in blood glucose stimulates insulin secretion by the pancreatic b-cells composing the islets of Langerhans. Then, circulating insulin acts on its tar- get tissues to promote glucose uptake, mainly by the skeletal muscles, bringing back glycaemia within basal levels. During this process, the contribution of the amplifying pathway of theb-cell remains unclear. In a genetically engineered mouse model, we have selectively knocked out in theb-cell theGlud1

gene encoding for GDH that is responsible for the production of glutamate upon glucose stimulation. Consequently, the optimal secretory response of theirb-cells has been reduced by half [7,17]. Nevertheless, thesebGlud1 ^/ knockout mice are asymptomatic despite a lower peak of insulinemia follow- ing glucose tolerance test, while these animals present a higher insulin sensitivity[17].

Such results suggest that the amplifying pathway is dis- pensable, at least under a balanced calorie intake. The bGlud1 ^/ mice lacking the glutamate-mediated amplifying pathway were also fed a high calorie diet. Whereas control mice become obese and pre-diabetic, those without GDH in theirb-cells are totally resistant to diet-induced obesity[18].

Such a resistance to weight gain is accompanied by the preservation of glucose tolerance and a better use of lipids as a source of energy compared to control mice expressing the Glud1gene encoding for GDH [18]. Even when Glud1in the b-cell is deleted following the development of obesity Fig. 1 – The action of glutamate and the regulation of insulin secretion. In the pancreaticb-cell, glucose metabolism leads to the generation of both ATP by the mitochondria and glutamate by the enzyme glutamate dehydrogenase (GDH). The thus formed ATP promotes the closure of the K-ATP channels, thereby inducing the depolarization of the plasma membrane and the opening of the voltage-sensitive calcium channels. The resulting elevation of cytosolic calcium concentration triggers insulin exocytosis, a process that is enhanced by the concomitant increases of cAMP and glutamate (green arrow). Out of the cell, glutamate released by islet cells may activate NMDA receptors on theb-cell, inducing reactivation of the K-ATP channels (red arrow). This causes the repolarization of the cell and the closure of the calcium channels, reducing the rate of insulin secretion. Therefore, glutamate plays a dual role in theb-cell as an intracellular potentiator and an extracellular inhibitor of insulin secretion. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

induced by high calorie diet, the beneficial effects on glycemic control is observed[18].

4. Preventing obesity by the limitation of insulin secretion

Obese patients with pre-diabetes exhibit hyperinsulinemia that develops as a consequence of a primary resistance of peripheral tissues to the action of insulin. Such a state may evolve towards frank diabetes in case of a failure of the pan- creatic b-cell [1]. However, it has been shown in mice that obesity is prevented by an early limitation of the full secretory potential of theb-cell, either by the reduction of insulin gene dosage[19]or by abrogation of the amplifying pathway[18].

Some available clinical data do support such observations made in rodents. Indeed, pharmacological inhibition of insu- lin secretion in obese subjects is accompanied by weight loss [20,21], although such a treatment may be associated with undesired side effects, for example hyperglycemia. Restrict- ing the inhibition of insulin secretion to the only amplifying pathway of the b-cell might potentially prevent such side effects, as demonstrated using a genetic approach[18].

The pharmacological counterpart could be achieved by tar- geting the enzyme glutamate dehydrogenase. Such an approach has been reported using epigallocatechin-3-gallate (EGCG), a molecule derived from green tea that exhibits differ- ent properties, among them to inhibit GDH in the mmolar range[22]. In human pancreatic islets stimulated with high glucose, EGCG lowers insulin secretion along with a decrease of intracellular glutamate [23]. EGCG has been shown to reduce the body weight of obese subjects[24]and of various animal models[25,26], as well as to improve glucose tolerance in diabetic db/db mice[27]. However, the poor bioavailability of EGCG may limit its use and human trials have shown some inconsistencies[26,28].

5. Glutamate receptors on pancreatic b-cells

Extracellular glutamate is well known for its role as the main excitatory neurotransmitter in the central nervous system. In pancreatic islets, insulin secretion is modulated by receptors for hormones and neurotransmitters. Among them, gluta- mate receptors might play a role, in particular the calcium- conducting ionotropic glutamate receptors, although the domain presents some controversies[29,30]. TheN-methyl- d-aspartate (NMDA) receptor is a tetramer composed of three different subunits. Binding of glycine and glutamate, along with depolarization of the cell membrane, promotes the con- ductance of the ions calcium, sodium, and potassium; accom- panied by the extrusion of magnesium from the channel pore [31]. Recent investigations have demonstrated that extracellu- lar glutamate, probably released by islet cells, may activate NMDA receptors of theb-cell[32]. Such an activation induces ion conductance through the channel of the receptor and reactivation of the K-ATP channels. This leads to repolariza- tion of the cell membrane, in turn favoring the closure of the voltage-dependent calcium channels and, consequently, the lowering of cytosolic calcium concentration reduces the rate of insulin exocytosis[32].

6. Conclusions

In the pancreaticb-cell, glutamate plays a dual role. At the intracellular level, the role of a potentiator of the calcium effect, amplifying its action on exocytosis and thereby enhancing the rate of insulin secretion. At the extracellular level, the role of a negative feedback loop by the activation of NMDA receptors and the slowdown of insulin release. By acting as a double-edged sword, glutamate illustrates the principle of homeostasis mediated by the same molecule, i.e. increasing or decreasing insulin secretion according to its localization[33].

Conflicts of interest

The author has no conflicts of interest to report.

Acknowledgement

The author thanks the long-standing support of the Swiss National Science Foundation (#146984 and #166625) and the State of Geneva; as well as all past and present members of the research group.

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