Glutamate Is a Positive Autocrine Signal for Glucagon Release

Cabrera, Over; Jacques-Silva, M. Caroline; Speier, Stephan; Yang, Shao Nian; Köhler, Martin; Fachado, Alberto; Vieira, Elaine; Zierath, Juleen R.; Kibbey, Richard G.; Berman, Dora M.; Kenyon, Norma S.; Ricordi, Camillo; Caicedo, Alejandro; Berggren, Per Olof

doi:10.1016/j.cmet.2008.03.004

Cited by 196 publications

(195 citation statements)

References 45 publications

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“…In contrast, in vivo blockade of AMPA receptors on pancreatic alpha cells induces negative autocrine feedback on glucagon secretion in mice [10]. One possible mechanism behind the surprising increase in glucagon secretion in our study might be that central nervous AMPA blockade by caroverine stimulates autonomic pathways that are known to trigger glucagon release during hypoglycaemia and that such an effect overrode the presumably suppressive effect of systemic AMPA receptor blockade on glucagon secretion.…”

Section: Discussioncontrasting

confidence: 63%

Blocking AMPA receptor signalling by caroverine infusion does not affect counter-regulation of hypoglycaemia in healthy men

et al. 2009

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Aims/hypothesis Glutamatergic pathways are assumed to play a critical role in the hormonal stress response to hypoglycaemia. In rats, glutamate signalling at the amino-3-hydroxy-5-methyl-4-isoxazol propionate (AMPA) receptor contributes to hormone release induced by behavioural stressors. We hypothesised that blocking the AMPA receptor by caroverine in healthy men would impair their perception of neuroglycopenia and thereby diminish hormonal counter-regulation as well as symptoms of hypoglycaemia, as a model of stress. Methods In a balanced double-blind study, two hypoglycaemic clamp sessions (mean blood glucose 2.4 mmol/l for 50 min) were performed in ten healthy men during intravenous administration of 80 mg caroverine or placebo. We assessed concentrations of counter-regulatory hormones as well as subjective symptoms related to hypoglycaemia.Results AMPA receptor antagonisation by caroverine did not influence the perception of neuroglycopenic and autonomic hypoglycaemia-associated symptoms (p>0.39 for all). Notwithstanding, caroverine did increase basal and counter-regulatory glucagon secretion (p <0.002) and slightly enhanced counter-regulatory growth hormone concentrations (p=0.07). Counter-regulatory release of ACTH, cortisol, adrenaline (epinephrine) and noradrenaline (norepinephrine) did not differ between conditions (p>0.11 for all). Conclusions/interpretation Antagonising AMPA receptor signalling by caroverine infusion failed to diminish and even slightly amplified counter-regulatory hormone release during hypoglycaemia in healthy men. The discrepancy with previous findings in rats may be due to different dosages or administration routes and calls for further investigations on the role of AMPA receptor signalling in hypoglycaemia counter-regulation in humans.

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Section: Discussioncontrasting

confidence: 63%

Blocking AMPA receptor signalling by caroverine infusion does not affect counter-regulation of hypoglycaemia in healthy men

et al. 2009

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“…Glucagon, the functional homolog of AKH in mammals, autoregulates its own production via proliferation control of the pancreatic alpha cells (Gelling et al 2003) and via regulation of their secretory activity (Ma et al 2005;Cabrera et al 2008). Our data show that unlike its mammalian homolog, AKH does not affect the number of CC cells.…”

Section: Autoregulation Of the Akh Genementioning

confidence: 54%

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

et al. 2015

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Maintenance of biological functions under negative energy balance depends on mobilization of storage lipids and carbohydrates in animals. In mammals, glucagon and glucocorticoid signaling mobilizes energy reserves, whereas adipokinetic hormones (AKHs) play a homologous role in insects. Numerous studies based on AKH injections and correlative studies in a broad range of insect species established the view that AKH acts as master regulator of energy mobilization during development, reproduction, and stress. In contrast to AKH, the second peptide, which is processed from the Akh encoded prohormone [termed "adipokinetic hormone precursor-related peptide" (APRP)] is functionally orphan. APRP is discussed as ecdysiotropic hormone or as scaffold peptide during AKH prohormone processing. However, as in the case of AKH, final evidence for APRP functions requires genetic mutant analysis. Here we employed CRISPR/Cas9-mediated genome engineering to create AKH and AKH plus APRP-specific mutants in the model insect Drosophila melanogaster. Lack of APRP did not affect any of the tested steroid-dependent processes. Similarly, Drosophila AKH signaling is dispensable for ontogenesis, locomotion, oogenesis, and homeostasis of lipid or carbohydrate storage until up to the end of metamorphosis. During adulthood, however, AKH regulates body fat content and the hemolymph sugar level as well as nutritional and oxidative stress responses. Finally, we provide evidence for a negative autoregulatory loop in Akh gene regulation.KEYWORDS Drosophila; adipokinetic hormone; adipokinetic hormone precursor-related peptide; energy homeostasis; stress resistance E NERGY homeostasis requires continuous compensation for fluctuations in the energy expenditure and availability of food resources. Organisms thus build up reserves under positive energy balance and catabolize them when the balance turns negative to retain stable levels of circulating energy fuel. Insulin signaling induces the uptake of excessive circulating sugars, thus promoting reserve accumulation (reviewed, e.g., in Saltiel and Kahn 2001; Cohen 2006), whereas energy mobilization is under the control of glucagon and glucocorticoid signaling in mammals (reviewed, e.g., in Rui 2014;Charron and Vuguin 2015) and adipokinetic hormone (AKH) signaling in insects (reviewed, e.g., in Van der Horst 2003;Lorenz and Gäde 2009;Bednářová et al. 2013a). Consistent with their fundamental physiological function in energy mobilization, AKHs are found not only in insects, but are common in Protostomia, where they have been identified both in Ecdyszoa (in Arthropoda, Tardigrada, and Priapulida) and Lophotrochozoa (in Mollusca, Rotifera, and Annelida) (Gäde 2009;Hauser and Grimmelikhuijzen 2014). Nevertheless, physiological functions of AKHs have been studied mainly in Arthropoda. Similar to mammals, also insects store lipids in the form of triacylglycerides (TGs) and as carbohydrates in the form of glycogen. The main storage organ for lipid and glycogen in insects is the fat body, which can thus b...

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“…It is known that paracrine factors including insulin, zinc and GABA play important roles in modulating glucose-regulated glucagon secretion [39]. A recent study suggested that glutamate released from alpha cells exerts autocrine effects to produce adequate glucagon release under hypoglycaemic conditions [40]. Given that, physiologically, a negative feedback simultaneously occurs during a secretory process, it is possible that the HCN channel in alpha cells may function as a negative feedback modulator to prevent an 'overshooting' of glucagon secretion under glucagon-stimulatory conditions, hence to maintain the hormone at appropriate levels.…”

Section: Discussionmentioning

confidence: 99%

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

Zhang

Zhang²,

Gyulkhandanyan

et al. 2008

Diabetologia

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Aims/hypothesis The hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, discovered initially in cardiac and neuronal cells, mediate the inward pacemaker current (I f or I h ). Recently, we have demonstrated the presence of HCN channels in pancreatic beta cells. Here, we aim to examine the presence and function of HCN channels in glucagon-secreting alpha cells. Methods RT-PCR and immunocytochemistry were used to examine the presence of HCN channels in alpha cells. Whole-cell patch-clamp, calcium imaging and glucagon secretion experiments were performed to explore the function of HCN channels in alpha cells. Results HCN transcripts and proteins were detected in alpha-TC6 cells and dispersed rat alpha cells. Patch-clamp recording showed hyperpolarisation-activated currents in alpha-TC6 cells, which could be blocked by HCN channel inhibitor ZD7288. Glucagon secretion RIA studies demonstrated that at both low and high glucose concentrations (2 and 20 mmol/l), ZD7288 significantly enhanced glucagon secretion in alpha-TC6 and IN-R1-G9 cell lines. Conversely, activation of HCN channels by lamotrigine significantly suppressed glucagon secretion at the low glucose concentration. Calcium imaging studies showed that blockade of HCN channels by ZD7288 significantly increased intracellular calcium in alpha-TC6 cells, while lamotrigine or the Na + channel blocker tetrodotoxin suppressed the effect of ZD7288 on intracellular calcium. Furthermore, we found the HCN channel inhibitors ZD7288 and cilobradine both significantly increased glucagon secretion from rat islets. Conclusions/interpretation These results suggest a potential role for HCN channels in regulation of glucagon secretion via modulating Ca 2+ and Na + channel activities.

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Glutamate Is a Positive Autocrine Signal for Glucagon Release

Cited by 196 publications

References 45 publications

Blocking AMPA receptor signalling by caroverine infusion does not affect counter-regulation of hypoglycaemia in healthy men

Blocking AMPA receptor signalling by caroverine infusion does not affect counter-regulation of hypoglycaemia in healthy men

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

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