Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells

Vergari, Elisa; Denwood, Geoffrey; Salehi, Albert; Zhang, Quan; Adam, Julie; Alrifaiy, Ahmed; Asterholm, Ingrid Wernstedt; Benrick, Anna; Chibalina, Margarita V.; Eliasson, Lena; Guida, Claudia; Hill, Thomas J.; Hamilton, Alexander; Ramracheya, Reshma; Reimann, Frank; Rorsman, Nils J.G.; Spilliotis, Ioannis; Tarasov, Andrei I.; Walker, Jonathan N.; Rorsman, Patrik; Briant, Linford J.B.

doi:10.1038/s42255-019-0158-0

Cited by 30 publications

(45 citation statements)

References 34 publications

(50 reference statements)

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“…A recent study suggested that delta-cell [Ca 2+ ] i oscillatory activity is reduced after HFD feeding [49], in keeping with the reduction of somatostatin secretion we observe. We note that the effects of HFD on somatostatin secretion – when mice remain largely normoglycaemic – are different from those observed once hyperglycaemia has developed [50]. Not only was somatostatin secretion reduced in HFD mice, their alpha-cells were also much less sensitive to SST in the present study, with Ca 2+ oscillation frequency persisting in HFD islet when exposed to SST.…”

Section: Discussioncontrasting

confidence: 64%

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

Kellard

Rorsman

Hill

et al. 2020

Preprint

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Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here we explored alpha-cell function in female mice fed a high fat diet (HFD) – a widely used mouse model of pre-diabetes. In vivo, HFD-fed mice have increased fed plasma glucagon levels that are unaffected by elevation of plasma glucose. To explore the underlying mechanisms, we conducted experiments on isolated islets and in the perfused pancreas. In both experimental models, glucagon secretion under both hypo- and hyperglycaemic conditions was elevated. Because Ca2+ is an important intracellular regulator of glucagon release in alpha-cells, we fed mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells the HFD. In mice fed a control (CTL) diet, increasing glucose reduced intracellular Ca2+ ([Ca2+]i) (oscillation frequency and amplitude). This effect was not observed in HFD mice where both the frequency and amplitude of the [Ca2+]i oscillations were higher than in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD mice was reduced but exogenous SST also failed to suppress glucagon secretion and Ca2+ activity from HFD alpha-cells, in contrast to observations in CTL mice. These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cell sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD.

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Section: Discussioncontrasting

confidence: 64%

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

Kellard

Rorsman

Hill

et al. 2020

Preprint

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“…Earlier work in rat islets showed that DA inhibits SST secretion via its actions on D 2 -like receptors 92 . This raises the possibility that the DA synthesized by αand β-cells also locally activates δ-cell D2R to inhibit SST secretion and thus removes SSTmediated inhibition of insulin and glucagon release 32,91,[93][94][95][96][97][98] . Such paracrine DA signaling that involves α-, β-, and δ-cells may offer an additional dimension to our understanding of the intra-islet regulation of hormone secretion.…”

Section: Discussionmentioning

confidence: 99%

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

et al. 2021

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Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.

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“…Interestingly, the somatostatin receptor (SSTR) antagonist CYN154806 restores glucagon secretion at 1 m m glucose in diabetic mice and in some islet preparations from donors with T2D (Vergari et al . 2020). In such patients, blocking the K ATP channel component, low‐dose SUs might lower the resting K + conductance sufficiently to stimulate secretion at 1 m m glucose but it would not correct the suppression due to inhibition of exocytosis.…”

Section: Islet Katp Channels and Diabetes: Pathophysiological And Thementioning

confidence: 99%

“…5E). Indeed, T2D is associated with hypersecretion of somatostatin at low glucose (Vergari et al 2020). Somatostatin inhibits glucagon secretion by several mechanisms including the activation of G protein-coupled inward-rectifying K + channels (GIRK) and a direct effect on exocytosis (Rorsman & Huising, 2018).…”

Section: Effects Of Tolbutamide and Diazoxide On Glucagon Secretionmentioning

confidence: 99%

“…Somatostatin inhibits glucagon secretion by several mechanisms including the activation of G protein-coupled inward-rectifying K + channels (GIRK) and a direct effect on exocytosis (Rorsman & Huising, 2018). Interestingly, the somatostatin receptor (SSTR) antagonist CYN154806 restores glucagon secretion at 1 mM glucose in diabetic mice and in some islet preparations from donors with T2D (Vergari et al 2020). In such patients, blocking the K ATP channel component, low-dose SUs might lower the resting K + conductance sufficiently to stimulate secretion at 1 mM glucose but it would not correct the suppression due to inhibition of exocytosis.…”

Section: Effects Of Tolbutamide and Diazoxide On Glucagon Secretionmentioning

confidence: 99%

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‘Resistance is futile?’ – paradoxical inhibitory effects of K_ATP channel closure in glucagon‐secreting α‐cells

Zhang

Dou

Rorsman

2020

The Journal of Physiology

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By secreting insulin and glucagon, the β‐ and α‐cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP‐regulated potassium (KATP) channels that are regulated by the intracellular ATP/ADP ratio. In β‐cells, KATP channels are active at low (non‐insulin‐releasing) glucose concentrations. An increase in glucose leads to KATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+]i and initiation of exocytosis of the insulin‐containing secretory granules. The α‐cells are also equipped with KATP channels but they are under strong tonic inhibition at low glucose, explaining why α‐cells are electrically active under hypoglycaemic conditions and generate large Na+‐ and Ca2+‐dependent action potentials. Closure of residual KATP channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage‐dependent inactivation of the Na+ channels involved in action potential generation. Exocytosis in α‐cells is tightly linked to the opening of voltage‐gated P/Q‐type Ca2+ channels, the activation of which is steeply voltage‐dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion.

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Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells

Cited by 30 publications

References 34 publications

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

‘Resistance is futile?’ – paradoxical inhibitory effects of K_ATP channel closure in glucagon‐secreting α‐cells

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Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells

Cited by 30 publications

References 34 publications

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

‘Resistance is futile?’ – paradoxical inhibitory effects of KATP channel closure in glucagon‐secreting α‐cells

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Product

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‘Resistance is futile?’ – paradoxical inhibitory effects of K_ATP channel closure in glucagon‐secreting α‐cells