Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

Almaça, Joana; Molina, Judith; Menegaz, Danusa; Pronin, Alexey; Tamayo, Alejandro; Slepak, Vladlen Z.; Berggren, Per Olof; Caicedo, Alejandro

doi:10.1016/j.celrep.2016.11.072

Cited by 162 publications

(166 citation statements)

References 70 publications

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“…These findings do not preclude paracrine mechanisms observed in other studies; in fact, the studies of Almaca et al . () and Li et al . () were conducted in human islets – a paracrine environment very architecturally different from that of mouse islets (Brissova et al .…”

Section: Discussionmentioning

confidence: 88%

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δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

Briant

Reinbothe

Spiliotis

et al. 2017

The Journal of Physiology

129

120

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Key points We used a mouse expressing a light‐sensitive ion channel in β‐cells to understand how α‐cell activity is regulated by β‐cells.Light activation of β‐cells triggered a suppression of α‐cell activity via gap junction‐dependent activation of δ‐cells.Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by β‐cells via gap junction‐dependent activation of δ‐cells/somatostatin secretion. AbstractGlucagon, the body's principal hyperglycaemic hormone, is released from α‐cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring β‐ and δ‐cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light‐induced activation of β‐cells in mouse islets expressing the light‐gated channelrhodopsin‐2 resulted in stimulation of electrical activity in δ‐cells but suppression of α‐cell activity. Activation of the δ‐cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in α‐cells was blocked by CYN 154806, an antagonist of the somatostatin‐2 receptor. These observations indicate that optogenetic activation of the β‐cells propagates to the δ‐cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits α‐cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating α‐cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 α‐, β‐ and δ‐cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose.

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Section: Discussionmentioning

confidence: 88%

“…; Ravier & Rutter, ), serotonin (Almaca et al . ), somatostatin (Hauge‐Evans et al . ) and urocortin3 (van der Meulen et al .…”

Section: Introductionmentioning

confidence: 99%

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

Briant

Reinbothe

Spiliotis

et al. 2017

The Journal of Physiology

129

120

View full text Add to dashboard Cite

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“…), paracrine (Almaca et al. ), juxtacrine (Hutchens and Piston ), neuronal (Rosario et al. ), hormonal (Pipeleers et al.…”

Section: Discussionmentioning

confidence: 99%

“…GLP-1 infusions in nondiabetic men have demonstrated that the plasma glucose-lowering action of GLP-1 is due to both a reduction in glucagon and increase in insulin secretion (Hare et al 2010). The regulation of glucagon secretion from the pancreatic a-cells remains obscure even under healthy conditions, with evidence for intrinsic (Zhang et al 2007), paracrine (Almaca et al 2016), juxtacrine (Hutchens and Piston 2015), neuronal (Rosario et al 2016), hormonal (Pipeleers et al 1985), and hepatic (Kim et al 2017) modulation. Furthermore, our knowledge of the cellular regulation of glucagon secretion comes from studies of rodent pancreatic islets, with a limited number of studies examining human a-cells (Cabrera et al 2006;MacDonald et al 2007;Spigelman et al 2010).…”

Section: Discussionmentioning

confidence: 99%

GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca²⁺ channels

et al. 2018

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Glucagon is the body's main hyperglycemic hormone, and its secretion is dysregulated in type 2 diabetes mellitus (T2DM). The incretin hormone glucagon‐like peptide‐1 (GLP‐1) is released from the gut and is used in T2DM therapy. Uniquely, it both stimulates insulin and inhibits glucagon secretion and thereby lowers plasma glucose levels. In this study, we have investigated the action of GLP‐1 on glucagon release from human pancreatic islets. Immunocytochemistry revealed that only <0.5% of the α‐cells possess detectable GLP‐1R immunoreactivity. Despite this, GLP‐1 inhibited glucagon secretion by 50–70%. This was due to a direct effect on α‐cells, rather than paracrine signaling, because the inhibition was not reversed by the insulin receptor antagonist S961 or the somatostatin receptor‐2 antagonist CYN154806. The inhibitory effect of GLP‐1 on glucagon secretion was prevented by the PKA‐inhibitor Rp‐cAMPS and mimicked by the adenylate cyclase activator forskolin. Electrophysiological measurements revealed that GLP‐1 decreased action potential height and depolarized interspike membrane potential. Mathematical modeling suggests both effects could result from inhibition of P/Q‐type Ca2+ channels. In agreement with this, GLP‐1 and ω‐agatoxin (a blocker of P/Q‐type channels) inhibited glucagon secretion in islets depolarized by 70 mmol/L [K+]o, and these effects were not additive. Intracellular application of cAMP inhibited depolarization‐evoked exocytosis in individual α‐cells by a PKA‐dependent (Rp‐cAMPS‐sensitive) mechanism. We propose that inhibition of glucagon secretion by GLP‐1 involves activation of the few GLP‐1 receptors present in the α‐cell membrane. The resulting small elevation of cAMP leads to PKA‐dependent inhibition of P/Q‐type Ca2+ channels and suppression of glucagon exocytosis.

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“…The latter may play a role for the autoimmune attack in type-1 diabetes, the pro-inflammatory milieu associated with type-2 diabetes 83 , and βcell development during embryogenesis 84 . Finally, human β-cells also secrete serotonin (5hydroxytryptamine), which inhibits glucagon secretion from α-cells 85 . The effects of Epac activation by cAMP and sulfonylureas on fusion pore behavior are therefore likely to have profound consequences for intra-islet signaling.…”

Section: Discussionmentioning

confidence: 99%

Fusion pore regulation by Epac2/cAMP controls cargo release during insulin exocytosis

Guček

Gandasi

Omar‐Hmeadi

et al. 2018

Preprint

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Regulated exocytosis establishes a narrow fusion pore as the initial aqueous connection to the extracellular space, through which small transmitter molecules such as ATP can exit. Co-release of larger peptides and hormones like insulin requires further expansion of the pore. There is evidence that pore expansion is regulated and can fail in type-2 diabetes and neurodegenerative disease. Here we report that the cAMP-sensor Epac2 (Rap-GEF4) controls fusion pore behavior by acutely recruiting two pore-restricting proteins, amisyn and dynamin-1, to the exocytosis site in insulin-secreting beta-cells. cAMP elevation leads to pore expansion and peptide release, but not when Epac2 is inactivated pharmacologically or in Epac2 -/mice. Conversely, overexpression of Epac2 impedes pore expansion. Widely used antidiabetic drugs (GLP-1 agonists and sulfonylureas) activate this pathway and thereby paradoxically restrict hormone release. We conclude that Epac2/cAMP controls fusion pore expansion and thus the balance of hormone and transmitter release during insulin granule exocytosis.

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Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

Cited by 162 publications

References 70 publications

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca²⁺ channels

Fusion pore regulation by Epac2/cAMP controls cargo release during insulin exocytosis

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Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

Cited by 162 publications

References 70 publications

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels

Fusion pore regulation by Epac2/cAMP controls cargo release during insulin exocytosis

Contact Info

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GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca²⁺ channels