Somatostatin Is Only Partly Required for the Glucagonostatic Effect of Glucose but Is Necessary for the Glucagonostatic Effect of KATP Channel Blockers

Lai, Bao-Khanh; Chae, Heeyoung; Gómez-Ruiz, Ana; Cheng, Panpan; Gallo, Paola; Antoine, Nancy; Beauloye, Christophe; Jonas, Jean‐Christophe; Seghers, Victor; Seino, Susumu; Gilon, Patrick

doi:10.2337/db17-0880

Cited by 36 publications

(59 citation statements)

References 52 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine whether the reduced SST secretion explained the lack of inhibition of glucagon secretion by glucose, we compared [Ca 2+ ] i oscillatory activity in CTL and HFD mice before and after pharmacological inhibition of somatostatin signalling in the islet. Mouse alpha–cells express primarily SST receptor 2 (SSTR2; see [7] and [45]). We therefore inhibited SST signaling using the SSTR2 inhibitor CYN154806 (CYN) and measured [Ca 2+ ] i oscillation frequency.…”

Section: Resultsmentioning

confidence: 99%

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

Kellard

Rorsman

Hill

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Kellard

Rorsman

Hill

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The mechanism(s) by which glucagon secretion is controlled is a contentious topic (Gylfe, 2013;Lai et al, 2018). Based on observations in isolated (ex vivo) islets, islets have been shown to respond to hypoglycaemia (and adjust glucagon secretion accordingly) via intrinsic (Rorsman et al, 2014;Basco et al, 2018;Yu et al, 2019) and paracrine mechanisms (Briant et al, 2018;Vergari et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

Kim

Knudsen

Madara

et al. 2020

Preprint

View full text Add to dashboard Cite

Hypoglycaemia is a major barrier to the treatment of diabetes. Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon -the body's principle blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. In isolated islets, varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor that stimulates glucagon secretion in vivo remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor (V1bR). Activation of AVP neurons in vivo increased circulating AVP, stimulated glucagon release and evoked hyperglycaemia; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of dehydration and hypoglycaemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata, which are known to be activated by hypoglycaemia, drive AVP neuron activation in response to insulin-induced hypoglycaemia.Hypoglycaemia also increases circulating levels of copeptin (derived from the same pre-pro hormone as AVP) levels in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with type 1 diabetes, hypoglycaemia failed to increase both plasma copeptin and glucagon. These findings provide a new mechanism for the central regulation of glucagon secretion in both health and disease.

show abstract

“…To address this critical point, we therefore investigated the potential effects of activation/blockage of intra‐islet SST and insulin signalling, as well as the ability of glucose to inhibit glucagon secretion, when insulin/SST signalling was prevented. Double‐immunofluorescence staining suggested that SSTR‐2 and ‐5 are the most often detected subtypes in mouse and rat alpha cells, 27 and in more recent studies in mice based on pre‐glucagon promoter driven expression of fluorescent proteins, enabling alpha cell identification and sorting, SSTR‐2, ‐3 and ‐5 were found to be the most abundantly expressed subtypes, whereas SSTR‐1 and ‐4 were not detected 10,28 . Unfortunately, we have not been able to find studies on SSTR‐1, ‐5 expression in rat islets, but based on the cited mouse expression data, we included a SSTR‐3 antagonist to a mixture of SSTR‐2 and ‐5 antagonists in order to eliminate potential SST‐signalling through these receptor subtypes.…”

Section: Discussionmentioning

confidence: 76%

“…Indeed, there is data indicating that glucagon secretion from mouse and human islets is maximally inhibited already at 5‐7 mmol/L glucose, where insulin and SST secretion is usually not stimulated 3,22,23 . It is therefore unclear whether endogenous insulin or SST is involved in the physiological glucose regulation of glucagon secretion; indeed, some studies do not support this 10,12,23,24 . The primary aim of the present study was to re‐examine the role of insulin and co‐secreted GABA, as well as SST for glucose‐induced inhibition of glucagon secretion.…”

Section: Introductionmentioning

confidence: 92%

“…In all models, exogenous SST is a powerful inhibitor of glucagon secretion. Thus, SST inhibits glucagon secretion in vivo in humans, 5 dogs 6 and rodents, 7 in vitro , in isolated perfused pancreases from mouse, rat and dogs, 8‐11 and in isolated rodent islets 10‐12 . Furthermore, SST knockout mice are characterized by enhanced insulin and glucagon secretory responses, both in vivo and from perfused islets 13 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In the rat pancreas, somatostatin tonically inhibits glucagon secretion and is required for glucose‐induced inhibition of glucagon secretion

Andersen

Izarzugaza

et al. 2020

Acta Physiologica

View full text Add to dashboard Cite

Aim It is debated whether the inhibition of glucagon secretion by glucose results from direct effects of glucose on the α‐cell (intrinsic regulation) or by paracrine effects exerted by beta‐ or delta‐cell products. Methods To study this in a more physiological model than isolated islets, we perfused isolated rat pancreases and measured glucagon, insulin and somatostatin secretion in response to graded increases in perfusate glucose concentration (from 3.5 to 4, 5, 6, 7, 8, 10, 12 mmol/L) as well as glucagon responses to blockage/activation of insulin/GABA/somatostatin signalling with or without addition of glucose. Results Glucagon secretion was reduced by about 50% (compared to baseline secretion at 3.5 mmol/L) within minutes after increasing glucose from 4 to 5 mmol/L (P < .01, n = 13). Insulin secretion was increased minimally, but significantly, compared to baseline (3.5 mmol/L) at 4 mmol/L, whereas somatostatin secretion was not significantly increased from baseline until 7 mmol/L. Hereafter secretion of both increased gradually up to 12 mmol/L glucose. Neither recombinant insulin (1 µmol/L), GABA (300 µmol/L) or the insulin‐receptor antagonist S961 (at 1 µmol/L) affected basal (3.5 mmol/L) or glucose‐induced (5.0 mmol/L) attenuation of glucagon secretion (n = 7‐8). Somatostatin‐14 attenuated glucagon secretion by ~ 95%, and blockage of somatostatin‐receptor (SSTR)‐2 or combined blockage of SSTR‐2, −3 and −5 by specific antagonists increased glucagon output (at 3.5 mmol/L glucose) and prevented glucose‐induced (from 3.5 to 5.0 mmol/L) suppression of secretion. Conclusion Somatostatin is a powerful and tonic inhibitor of glucagon secretion from the rat pancreas and is required for glucose to inhibit glucagon secretion.

show abstract

Somatostatin Is Only Partly Required for the Glucagonostatic Effect of Glucose but Is Necessary for the Glucagonostatic Effect of KATP Channel Blockers

Cited by 36 publications

References 52 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

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

In the rat pancreas, somatostatin tonically inhibits glucagon secretion and is required for glucose‐induced inhibition of glucagon secretion

Contact Info

Product

Resources

About