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Cited by 218Pancreatic function and diabetesDiabetes Treatment and ManagementDiabetes and associated disorders

Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells

Open access
Vieira, E., Salehi, A., Gylfe, E.·2007·Diabetologia
DOI 10.1007/s00125-006-0511-1
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Abstract

Aims/hypothesis The mechanisms by which glucose regulates glucagon release are poorly understood. The present study aimed to clarify the direct effects of glucose on the glucagon-releasing alpha cells and those effects mediated by paracrine islet factors.Materials and methods Glucagon, insulin and somatostatin release were measured from incubated mouse pancreatic islets and the cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) recorded in isolated mouse alpha cells.Results Glucose inhibited glucagon release with maximal effect at 7 mmol/l. Since this concentration corresponded to threshold stimulation of insulin secretion, it is unlikely that inhibition of glucagon secretion is mediated by beta cell factors. Although somatostatin secretion data seemed consistent with a role of this hormone in glucose-inhibited glucagon release, a somatostatin receptor type 2 antagonist stimulated glucagon release without diminishing the inhibitory effect of glucose. In islets exposed to tolbutamide plus 8 mmol/l K(+), glucose inhibited glucagon secretion without stimulating the release of insulin and somatostatin, indicating a direct inhibitory effect on the alpha cells that was independent of ATP-sensitive K(+) channels. Glucose lowered [Ca(2+)](i) of individual alpha cells independently of somatostatin and beta cell factors (insulin, Zn(2+) and gamma-aminobutyric acid). Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca(2+)-ATPase, which abolished the [Ca(2+)](i)-lowering effect of glucose on isolated alpha cells.Conclusions/interpretation Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion. We instead propose that glucose has a direct inhibitory effect on mouse alpha cells by suppressing a depolarising Ca(2+) store-operated current.

AI snapshot

Written from the paper’s full text.

TL;DR

Glucose directly inhibits glucagon secretion from mouse pancreatic alpha cells, with maximal inhibition at 7 mmol/l, independent of beta-cell factors and somatostatin. The effect is associated with suppression of a depolarising Ca²⁺ store-operated current and lowering of cytoplasmic Ca²⁺ concentration.

Key findings

  • Glucose inhibited glucagon release from mouse islets over 4–20 mmol/l, with maximal effect at 7 mmol/l; insulin secretion was threshold-stimulated at 7 mmol/l, making beta-cell factors unlikely mediators of glucagon inhibition up to 7 mmol/l.
  • The somatostatin receptor type 2 antagonist PRL-2903 stimulated glucagon secretion at low glucose but did not diminish maximal inhibition at 7 mmol/l glucose, arguing against somatostatin as the mediator.
  • With tolbutamide plus 8 mmol/l K⁺, glucose inhibited glucagon secretion without stimulating insulin or somatostatin release; glucose also lowered [Ca²⁺]ᵢ in individual alpha cells, including in 100% of 11 cells at 20 mmol/l glucose even after pertussis toxin and wortmannin treatment.
  • SERCA inhibitors CPA and thapsigargin raised [Ca²⁺]ᵢ, stimulated glucagon secretion, and prevented glucose inhibition; CPA reversed glucose inhibition of [Ca²⁺]ᵢ signalling in all 12 alpha cells, and 20 mmol/l glucose failed to reduce [Ca²⁺]ᵢ in 74% (5/7) of CPA-exposed and all 10 thapsigargin-exposed alpha cells.

Methods

  • Mouse C57BL/6 pancreatic islets were used for glucagon, insulin, and somatostatin secretion measurements by radioimmunoassay; isolated mouse alpha cells were loaded with fura-2 for digital imaging fluorometry of [Ca²⁺]ᵢ.
  • Secretion experiments used batches of 8–12 islets, pre-incubated for 30 min at 1 mmol/l glucose, then incubated for 1 h with different glucose concentrations and drugs including tolbutamide, K⁺, CPA, and PRL-2903.
  • Alpha cells were initially selected by small size and adrenaline-induced [Ca²⁺]ᵢ response, and only cells confirmed by positive glucagon immunostaining were analysed; statistics included ANOVA, paired/unpaired Student’s t tests, Fisher’s exact test or χ² with Yates’ correction, and Wilcoxon’s signed rank test.

Limitations

  • The paper does not include a formal limitations section. It states that rat and mouse alpha cells may be differently regulated: in isolated rat alpha cells, the direct effect of glucose may stimulate secretion, and inhibition may require paracrine islet factors.
  • Evident from the text: all experiments were in vitro using mouse islets or isolated mouse alpha cells, with no in vivo or human data; alpha cell responses were heterogeneous, so results are reported as proportions of cells reacting in different ways; some [Ca²⁺]ᵢ analyses used small numbers of cells (e.g., 7–12 per condition).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00125-006-0511-1

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 32 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In presence of tolbutamide/8 mmol/l K+, glucose inhibited glucagon secretion in the 5 to 20 mmol/l range.

    “The presence of tolbutamide/8 mmol/l K + did not prevent glucose inhibition of glucagon secretion in the 5 to 20 mmol/l range, indicating involvement of a mechanism independent of the K ATP channel.”
    Quote in the paperSubstantial claim
  • Findingown data

    In alpha cells without spontaneous activity, the fraction responding to tolbutamide was only 21%.

    “However, in cells without spontaneous activity, the fraction of cells responding to tolbutamide was only 21%.”
    Quote in the paperSubstantial claim
  • Findingown data

    Raising K+ from 4.8 to 8 mmol/l caused [Ca2+]i response in 11% of silent alpha cells and 67% of those with spontaneous activity.

    “Such depolarisation caused a [Ca 2+ ] i response in 11% of the silent alpha cells and in 67% of those with spontaneous [Ca 2+ ] i activity (Fig. 2b,c).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In mouse alpha cells with spontaneous [Ca2+]i activity in 1 mmol/l glucose, 80% responded to 500 μmol/l tolbutamide by elevation of [Ca2+]i.

    “Among alpha cells with spontaneous [Ca 2+ ] i activity in 1 mmol/l glucose, 80% reacted to 500 μmol/l of the K ATP channel inhibitor tolbutamide by elevation of [Ca 2+ ] i (Fig. 2a,c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Depolarisation with 500 μmol/l tolbutamide plus 8 mmol/l K+ inhibited glucagon secretion by 30% at 1 mmol/l glucose without affecting its release at other sugar concentrations.

    “We now observed that depolarisation with 500 μmol/l tolbutamide plus 8 mmol/l K + inhibited glucagon secretion by 30% at 1 mmol/l glucose without affecting its release at other sugar concentrations (Fig. 4a).”
    Quote in the paperSubstantial claim
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    Insulin secretion from mouse islets is threshold-stimulated at 7 mmol/l glucose and maximal at 20 mmol/l.

    “The parallel measurements of insulin showed threshold stimulation at 7 mmol/l glucose with maximal secretion at 20 mmol/l (Fig. 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The L-type Ca2+ channel blocker nifedipine abolished the [Ca2+]i response induced by tolbutamide/8 mmol/l K+ in all 12 alpha cells, whereas ω-conotoxin did not affect it in any of 12 alpha cells.

    “Whereas the N-type Ca 2+ channel blocker ωconotoxin did not affect the elevation/oscillations of [Ca 2+ ] i induced by tolbutamide/8 mmol/l K + in any of 12 alpha cells, the L-type Ca 2+ channel blocker nifedipine abolished the [Ca 2+ ] i response in all 12 alpha cells (p<0.001;Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Blocking SSTR-2 with PRL-2903 stimulates glucagon secretion in low glucose without affecting maximally inhibited secretion in 7 mmol/l glucose.

    “Blocking the dominating somatostatin receptor subtype SSTR-2 in alpha cells with PRL-2903 [27] thus stimulated glucagon secretion in low glucose without affecting maximally inhibited secretion in 7 mmol/l sugar (Fig. 1d).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Cejvan K, Coy DH, Efendic S (2003) Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes 52:1176–1181 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Insulin secretion was slightly stimulated by tolbutamide/8 mmol/l K+ at all glucose concentrations.

    “Insulin secretion was slightly stimulated by tolbutamide/8 mmol/l K + at all glucose concentrations (Fig. 4b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Somatostatin release was stimulated fourfold at 1 mmol/l glucose and by 65% at 20 mmol/l by tolbutamide/8 mmol/l K+, but no effect was seen at 3 to 8 mmol/l glucose.

    “Somatostatin release was stimulated fourfold at 1 mmol/l glucose and by 65% at 20 mmol/l, but no effect of tolbutamide/8 mmol/l K + was seen at 3 to 8 mmol/l glucose (Fig. 4c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Glucose inhibits glucagon release from incubated mouse pancreatic islets, with maximal effect at 7 mmol/l.

    “Glucose inhibited glucagon release with maximal effect at 7 mmol/l.”
    • Also stated in: § Relationship between glucose-regulated glucagon, insulin and somatostatin secretion · plain
      “Glucagon secretion was inhibited by glucose in the 4 to 20 mmol/l range with maximal effect at 7 mmol/l (Fig. 1a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the presence of tolbutamide plus 8 mmol/l K+, glucose induced additional inhibition of glucagon secretion, most of which occurred without accompanying changes in insulin or somatostatin release.

    “In the presence of tolbutamide plus 8 mmol/l K + glucose induced additional inhibition of glucagon secretion, most of which occurred without accompanying changes in insulin or somatostatin release.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tolbutamide plus 8 mmol/l K+ closes KATP channels.

  • May combine two claims.

    Findingown data

    Activation of store-operated mechanism by blocking SERCA pump with CPA stimulated glucagon secretion and prevented the inhibitory effect of glucose.

    “Activation of the store-operated mechanism by blocking the SERCA pump with CPA stimulated glucagon secretion and prevented the inhibitory effect of glucose (Fig. 5b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When mouse islets were exposed to tolbutamide plus 8 mmol/l K+ in 1 mmol/l glucose, partial inhibition of glucagon release occurred concomitantly with a slight increase of insulin and pronounced stimulation of somatostatin secretion.

    “When the mouse islets were exposed to tolbutamide plus 8 mmol/l K + in 1 mmol/l glucose, partial inhibition of glucagon release occurred concomitantly with a slight increase of insulin and pronounced stimulation of somatostatin secretion.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tolbutamide plus 8 mmol/l K+ closes KATP channels.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Insulin secretion was marginally enhanced when CPA was combined with tolbutamide/8 mmol/l K+ compared with CPA alone.

    “Insulin secretion was marginally enhanced when CPA was combined with tolbutamide/8 mmol/l K + compared with CPA alone, but the stimulatory effect of glucose was unaffected (Fig. 6b).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Tolbutamide plus 8 mmol/l K+ closes KATP channels.

  • May combine two claims.

    Findingown data

    Somatostatin immediately inhibited the [Ca2+]i response to tolbutamide/8K in all of six alpha cells, and this inhibition was completely prevented by PTX pre-treatment in all of seven alpha cells.

    “Although somatostatin immediately inhibited the [Ca 2+ ] i response to 500 μmol/l tolbutamide plus 8 mmol/l K + in all of six alpha cells, this inhibition was completely prevented by PTX pre-treatment in all of seven alpha cells (p<0.001,data not shown).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    1 mmol/l GABA failed to affect [Ca2+]i in all of five alpha cells exposed to 500 μmol/l tolbutamide plus 8 mmol/l K+.

    “In addition, 1 mmol/l GABA failed to affect [Ca 2+ ] i in all of five alpha cells exposed to 500 μmol/l tolbutamide plus 8 mmol/l K + (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Parallel insulin measurements showed no effect of CPA on basal secretion in 0 to 5 mmol/l glucose and moderate amplification in 8 and 20 mmol/l of the sugar.

    “Parallel insulin measurements showed no effect of CPA on basal secretion in 0 to 5 mmol/l glucose and moderate amplification in 8 and 20 mmol/l of the sugar (Fig. 5c).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    30 μmol/l Zn2+ always stimulated [Ca2+]i signalling in mouse alpha cells (nine alpha cells).

    “we found that 30 μmol/l Zn 2+ always stimulated [Ca 2+ ] i signalling (nine alpha cells, data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An increase of glucose from 1 to 20 mmol/l failed to reduce [Ca2+]i in 74% (five of seven) of alpha cells exposed to CPA and in all of ten alpha cells exposed to thapsigargin.

    “Moreover, an increase of glucose from 1 to 20 mmol/l failed to reduce [Ca 2+ ] i in 74% (five of seven) of alpha cells exposed to CPA and in all of ten alpha cells exposed to thapsigargin (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CPA inhibition of the SERCA pump stimulated glucagon secretion without affecting basal secretion of insulin or somatostatin.

    “Further evidence for insulin-and somatostatin-independent effects on glucagon release was obtained with the observation that CPA inhibition of the SERCA pump stimulated glucagon secretion without affecting basal secretion of insulin or somatostatin.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CPA inhibits the SERCA pump.

  • May combine two claims.

    Findingown data

    Glucose suppression of glucagon release was prevented by inhibitors of SERCA, which abolished the [Ca2+]i-lowering effect of glucose on isolated alpha cells.

    “Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca 2+ -ATPase, which abolished the [Ca 2+ ] i -lowering effect of glucose on isolated alpha cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SERCA inhibition abolished the [Ca2+]i-lowering effect of glucose in isolated alpha cells and prevented glucose inhibition of glucagon secretion from mouse islets despite the fact that glucose stimulated the release of insulin and somatostatin.

    “Moreover, SERCA inhibition abolished the [Ca 2+ ] ilowering effect of glucose in isolated alpha cells and prevented glucose inhibition of glucagon secretion from mouse islets despite the fact that the sugar stimulated the release of insulin and somatostatin.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CPA inhibits the SERCA pump.

  • May combine two claims.

    Findingown data

    Activation of the store-operated pathway by SERCA inhibition raised [Ca2+]i and stimulated glucagon release from mouse islets without affecting basal secretion of insulin or somatostatin.

    “In support of the involvement of a store-operated mechanism in the regulation of glucagon secretion, we observed that activation of the store-operated pathway by SERCA inhibition raised [Ca 2+ ] i and stimulated glucagon release from mouse islets without affecting the basal secretion of insulin or somatostatin.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CPA inhibits the SERCA pump.

  • May combine two claims.

    Interpretationcitation

    KATP channels are functionally active in mouse alpha cells and their closure tends to activate Ca2+ influx through L-type channels.

    “Taken together, these data indicated that the K ATP channels were functionally active in mouse alpha cells and that their closure tended to activate Ca 2+ influx through L-type channels [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Göpel S, Zhang Q, Eliasson L et al (2004) Capacitance measurements of exocytosis in mouse pancreatic α-, β- and δ-cells within intact islets of Langerhans. J Physiol 556:711–726 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Inhibition of glucagon secretion by tolbutamide alone or K+ concentrations up to 16 mmol/l has previously been observed in mouse islets.

    “Inhibition of glucagon secretion by tolbutamide alone or K + concentrations up to 16 mmol/l has previously been observed in mouse islets [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Gromada J, Ma X, Hoy M et al (2004) ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1−/− mouse α-cells. Diabetes 53(Suppl 3):S181–S189 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion.

    “Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion.”
    • Also stated in: § Introduction · hedged
      “Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: No beta cell or delta cell factor other than insulin, Zn2+, GABA, and somatostatin mediates glucose inhibition of glucagon secretion.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The KATP channel has a central function in glucose-stimulated insulin release, transducing an increase in ATP into depolarisation with voltage-dependent influx of Ca2+.

    “The K ATP channel has a central function in glucosestimulated insulin release, transducing an increase in ATP into depolarisation with voltage-dependent influx of Ca 2+ [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Ashcroft FM, Rorsman P (1990) ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. Biochem Soc Trans 18:109–111 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Activation of the store-operated mechanism abolishes glucose inhibition of glucagon secretion without preventing glucose stimulation of insulin and somatostatin secretion.

    “The data in Figs. 5 and 6 show that activation of the store-operated mechanism abolishes glucose inhibition of glucagon secretion without preventing glucose stimulation of insulin and somatostatin secretion.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CPA inhibits the SERCA pump.
    • Rests on an assumption: Tolbutamide plus 8 mmol/l K+ closes KATP channels.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In isolated rat alpha cells with high KATP channel density, the direct effect of glucose seems to be stimulation of secretion and the inhibitory action may require release of paracrine islet factors.

    “In isolated rat alpha cells with high K ATP channel density [43] the direct effect of glucose seems to be stimulation of secretion and the inhibitory action may require release of paracrine islet factors [46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Bokvist K, Olsen HL, Høy M et al (1999) Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells. Pflügers Arch 438:428–436

      Not checked in the free run.

    • cites [46] Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J (2005) Glucose stimulates glucagon release in single rat α-cells by mechanisms that mirror the stimulus-secretion coupling in β-cells. Endocrinology 146:4861–4870 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Neither beta cell factors nor somatostatin seem to mediate glucose inhibition of glucagon secretion.

    “However, neither beta cell factors nor somatostatin seem to mediate glucose inhibition of glucagon secretion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In isolated mouse alpha cells with low KATP channel density, the inhibitory effect of glucose dominated, although closure of the KATP channels themselves was modestly stimulatory.

    “In isolated mouse alpha cells with low K ATP channel density [13,44] the inhibitory effect of glucose dominated, although closure of the K ATP channels themselves was modestly stimulatory.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Göpel SO, Kanno T, Barg S, Weng XG, Gromada J, Rorsman P (2000) Regulation of glucagon secretion in mouse α-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol (Lond) 528:509–520 source

      Not checked in the free run.

    • cites [44] Quesada I, Nadal A, Soria B (1999) Different effects of tolbutamide and diazoxide in α-, β- and δ-cells within intact islets of Langerhans. Diabetes 48:2390–2397 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tolbutamide stimulates electrical activity and exocytosis of glucagon in isolated rat alpha cells.

    “Accordingly, tolbutamide stimulates the electrical activity [43] and exocytosis of glucagon [45] in isolated rat alpha cells”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Bokvist K, Olsen HL, Høy M et al (1999) Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells. Pflügers Arch 438:428–436

      Not checked in the free run.

    • cites [45] Høy M, Olsen HL, Bokvist K et al (2000) Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial-like ATP-sensitive K+ (KATP) conductance in rat pancreatic A-cells. J Physiol (Lond) 527:109–120 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most salient effect of knocking out the regulatory KATP channel subunit sulfonylurea receptor 1 is low glucagon secretion with absent or diminished stimulation in response to lowering of glucose.

    “The most salient effect of knocking out the regulatory K ATP channel subunit sulfonylurea receptor 1 is low glucagon secretion with absent 47] or diminished [48] stimulation in response to lowering of glucose.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Shiota C, Rocheleau JV, Shiota M, Piston DW, Magnuson MA (2005) Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor. Am J Physiol Endocrinol Metab 289:E570–E577 source

      Not checked in the free run.

    • cites [48] Muñoz A, Hu M, Hussain K, Bryan J, Aguilar-Bryan L, Rajan AS (2005) Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement. Endocrinology 146:5514–5521 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The role of glucose is to activate Ca2+ sequestration in the endoplasmic reticulum and shut off the stimulatory cascade.

    “The role of glucose is to activate Ca 2+ sequestration in the endoplasmic reticulum and shut off the stimulatory cascade.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Glucose has a direct inhibitory effect on the alpha cell by suppressing a depolarising store-operated current.

    “The data support the concept that glucose has a direct inhibitory effect on the alpha cell by suppressing a depolarising store-operated current.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CPA inhibits the SERCA pump.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glucose stimulates glucagon release from purified rat alpha cells.

    “and glucose was recently found to stimulate glucagon release from purified rat alpha cells [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J (2005) Glucose stimulates glucagon release in single rat α-cells by mechanisms that mirror the stimulus-secretion coupling in β-cells. Endocrinology 146:4861–4870 source

      Not checked in the free run.

32 of 32

  • The paper relies on this without support.

    No beta cell or delta cell factor other than insulin, Zn2+, GABA, and somatostatin mediates glucose inhibition of glucagon secretion.

    “Since glucose control of glucagon secretion has been suggested to involve paracrine release of insulin [17][18][19][20][21][22], GABA [22][23][24] and Zn 2+ [25,26] from the beta cells, and somatostatin from the delta cells [18,27], we studied how the glucose concentration affected the release of hormones from mouse islets.”

  • The paper relies on this without support.

    The isolated alpha cells used for [Ca2+]i recordings are representative of alpha cells within intact pancreatic islets with respect to glucose regulation.

    “The present study evaluated different hypotheses for the regulation of glucagon secretion by recording [Ca 2+ ] i in isolated mouse alpha cells and by parallel measurements of glucagon, insulin and somatostatin secretion from pancreatic islets.”

  • The paper relies on this without support.

    The combination of tolbutamide plus 8 mmol/l K+ does not itself alter the direct glucose-sensing mechanism in alpha cells.

    “In subsequent experiments the combination tolbutamide plus 8 mmol/l K + was used to study K ATP channel-independent effects of glucose.”

  • The paper relies on this without support.

    CPA inhibits the SERCA pump.

    “CPA inhibition of the SERCA pump stimulated glucagon secretion without affecting basal secretion of insulin or somatostatin.”

  • The paper relies on this without support.

    Tolbutamide plus 8 mmol/l K+ closes KATP channels.

    “depolarisation obtained with tolbutamideinduced closure of the K ATP channels”

  • The paper relies on this without support.

    PRL-2903 is an SSTR-2 antagonist.

    “the SSTR-2 antagonist PRL-2903”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Glucose inhibits the release of glucagon from pancreatic α-cells.

    “In parallel, glucose inhibits the release of glucagon from the pancreatic α‐cells 25, 26.”

    From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [26]

  • In isolated islets, stimulated SST secretion is initiated at glucose concentrations as low as 3 mmol/L and increases dose-dependently toward 20 mmol/L glucose, with half maximal stimulation at ∼5-6 mmol/L glucose in rodent islets and ∼10 mmol/L glucose in human islets.

    “In isolated islets, stimulated SST secretion is initiated at glucose concentrations as low as 3 mmol/L and increases dose-dependently toward 20 mmol/L glucose, with half maximal stimulation at ∼5–6 mmol/L glucose in rodent islets ( Vieira et al., 2007 ) ( Figure 2A ) and ∼10 mmol/L glucose in human islets ( Walker et al., 2011 ).”

    From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vieira et al., 2007

  • Between 1 and 20 mmol/L glucose, SST secretion increased >10-fold in mouse islets and ∼3-3.5-fold in human islets, indicating a larger magnitude response in mice.

    “Between 1 and 20 mmol/L glucose, SST secretion increased >10-fold in mouse islets ( Vieira et al., 2007 ; Vergari et al., 2020 ) and ∼3–3.5-fold in human islets ( Ramracheya et al., 2010 ; Walker et al., 2011 ; Vergari et al., 2020 ) between 1 and 20 mmol/L glucose, indicating a larger magnitude response in mice.”

    From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vieira et al., 2007

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Five of seven cells is not 74%

    Minor

    Five of seven cells is approximately 71%, not 74%.

    Reported 74 · recomputed 71.428571

1 of 1

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References 51 · Cited by 218

Authors
Vieira, E., Salehi, A., & Gylfe, E.
Affiliations
  • Uppsala University (SE)
  • Lund University (SE)
Corresponding author
Gylfe, E.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2006-11-29
Volume
50
Issue
2
Pages
370-379
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-006-0511-1
OpenAlex
W2009127988
Semantic Scholar
ae564b24b9e553d07d6b20a1e5523d3302dbb0d8
Cited by
218
References
51
Citations by year
2026: 4 · 2025: 5 · 2024: 12 · 2023: 6 · 2022: 11 · 2021: 17 · 2020: 14 · 2019: 13 · 2018: 16 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 13 · 2013: 11 · 2012: 13
FWCI
8.47
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Carl Tryggers Stiftelse för Vetenskaplig Forskning
  • Crafoordska Stiftelsen
  • Vetenskapsrådet (12X-6240)
  • Stiftelsen Familjen Ernfors Fond
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
glucose, glucagon secretion, alpha cells, somatostatin, insulin, intracellular calcium, store-operated calcium entry, sarco/endoplasmic reticulum Ca2+-ATPase, ATP-sensitive potassium channels, tolbutamide
MeSH terms
Insulin Secretion, Calcium-Transporting ATPases, Animals, Calcium, Endoplasmic Reticulum, Glucagon, Glucose, Insulin, Kinetics, Mice, Inbred C57BL, Potassium, Somatostatin, Tolbutamide, Calcium Signaling, Glucagon-Secreting Cells, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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