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Cited by 159Pancreatic function and diabetesDiabetes Treatment and ManagementDiabetes and associated disorders

Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations

Open access
Salehi, Albert, Vieira, Elaine, Gylfe, Erik·2006·Diabetes
DOI 10.2337/db06-0080
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Abstract

Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25–30 mmol/l and In-R1-G9 cells at 12–20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the α-cells. Studies of isolated mouse α-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.

AI snapshot

Written from the paper’s full text.

TL;DR

Glucose-regulated glucagon secretion from mouse pancreatic islets and hamster In-R1-G9 glucagon-releasing cells follows a U-shaped dose-response: inhibition is maximal around 7 mmol/l glucose, followed by paradoxical stimulation at high glucose (25–30 mmol/l in mouse islets; 12–20 mmol/l in In-R1-G9 cells). The stimulatory component appears to be a direct α-cell effect that does not require elevation of cytoplasmic Ca²⁺, suggesting a mechanism that may explain paradoxical hyperglucagonemia in hyperglycemia.

Key findings

  • In mouse islets, glucagon secretion was more than half-maximally inhibited by 4 mmol/l glucose, with maximal inhibition at 7–8 mmol/l; above 20 mmol/l, inhibition was reversed into small stimulation at 25–30 mmol/l. In-R1-G9 cells also showed a U-shaped response, with maximal inhibition at 7 mmol/l and significant stimulation already at 12 mmol/l. The nonmetabolizable analog 3-O-methyl glucose at 30 mmol/l was inhibitory, not stimulatory.
  • In individual mouse α-cells, 57% (8 of 14; P < 0.01) reduced [Ca²⁺]ᵢ to basal levels at 20 mmol/l glucose, and 86% (12 of 14; P < 0.001) were inhibited at 30 mmol/l. Under hyperpolarizing diazoxide, 7 mmol/l glucose reduced basal [Ca²⁺]ᵢ in 78% of α-cells (14 of 18; P < 0.001), while 30 mmol/l had no effect on α-cells but further reduced [Ca²⁺]ᵢ in 23 of 25 β-cells (P < 0.001).
  • Hyperpolarization with diazoxide reduced glucagon release at 0–1 mmol/l glucose by 70–80% of maximal glucose inhibition, but high-glucose stimulation was not diminished and even slightly exceeded control secretion at 12–30 mmol/l. Depolarization with 30 mmol/l K⁺ plus diazoxide stimulated glucagon secretion across 0–30 mmol/l; 7 mmol/l glucose failed to significantly inhibit secretion, and higher glucose still stimulated release but not more than under control or hyperpolarizing conditions.
  • In parallel insulin measurements from mouse islets, threshold insulin release was 18% at 7 mmol/l glucose and maximal at 25–30 mmol/l. In-R1-G9 cells did not secrete detectable insulin or somatostatin.

Methods

  • Mouse pancreatic islets were isolated with collagenase from C57BL/6 mice; free cells and clonal hamster In-R1-G9 glucagon-releasing cells were cultured. Secretion was measured after 60-min incubations of 8–12 islets or In-R1-G9 cells in Krebs-Ringer buffer with varying glucose, 3-O-methyl glucose, 4.8 or 30 mmol/l K⁺, and 250 µmol/l diazoxide, followed by radioimmunoassay for glucagon, insulin, and somatostatin.
  • [Ca²⁺]ᵢ was measured with fura-2 microfluorimetry in individual cells; α-cells were initially selected by small size and [Ca²⁺]ᵢ response to epinephrine and only immunostaining-confirmed α-cells were analyzed.
  • Dose-response relationships were analyzed with ANOVA and paired Student’s t test; individual α-cell reaction patterns were analyzed with two-tailed Fisher’s exact test.

Limitations

  • The paper states that the signal transduction of the glucose stimulation of glucagon secretion remains to be elucidated, and that an inhibitory effect of insulin in In-R1-G9 cells is not entirely excluded.
  • Evident from the text: the findings are from mouse islets and a hamster clonal glucagon-releasing cell line, with no direct human α-cell data; the proposed relevance to human hyperglucagonemia is presented as a possible explanation rather than a tested mechanism.

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

Integrity signals

Registry

Crossref · 10.2337/db06-0080

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Glucagon secretion in the absence of glucose is inhibited by hyperpolarization with diazoxide.

    “Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide”
    • Also stated in: § RESULTS · plain
      “hyperpolarization with diazoxide reduced glucagon release at 0 -1 mmol/l glucose by 70 -80% of the maximal glucose inhibition (Fig. 4, top panel).”
    Quote in the paperSubstantial claim
  • Findingown data

    Clonal hamster In-R1-G9 glucagon-releasing cells show paradoxical stimulation of glucagon release at 12-20 mmol/l sugar.

    “In-R1-G9 cells at 12-20 mmol/l sugar.”
    • Also stated in: § RESULTS · plain
      “the stimulatory component was left-shifted with significant stimulation already at 12 mmol/l glucose.”
    Quote in the paperSubstantial claim
  • Findingown data

    Diazoxide tends to further enhance glucagon secretion stimulated by high glucose concentrations.

    “this agent tended to further enhance secretion stimulated by high concentrations of the sugar.”
    • Also stated in: § RESULTS · plain
      “Glucagon secretion at higher glucose concentrations was not diminished during hyperpolarizing conditions and even slightly exceeded control secretion in the 12-30 mmol/l range.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Mouse pancreatic islets show paradoxical stimulation of glucagon release at 25-30 mmol/l glucose.

    “we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l”
    • Also stated in: § RESULTS · plain
      “above 20 mmol/l, inhibition was dramatically reversed into a small stimulation at 25-30 mmol/l glucose.”
    Quote in the paperSubstantial claim
  • Findingown data

    After further elevation to 30 mmol/l glucose, 86% (12 of 14; P<0.001) of the alpha-cells are inhibited.

    “After further elevation to 30 mmol/l glucose, 86% (12 of 14; P Ͻ 0.001) of the ␣-cells were inhibited.”
    Quote in the paperSubstantial claim
  • May combine two claims. 27
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data

    Glucose-regulated glucagon secretion from mouse pancreatic islets has a U-shaped dose-response relationship, with maximal inhibition around 7-8 mmol/l glucose and stimulation at 25-30 mmol/l glucose.

    “Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l”
    • Also stated in: § RESULTS · plain
      “In the mouse islets, glucagon secretion was more than half-maximally inhibited by 4 mmol/l glucose, and the maximal effect was reached at 7-8 mmol/l (Fig. 1, top left panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Glucose-regulated glucagon secretion from In-R1-G9 cells has a U-shaped dose-response relationship, with maximal inhibition at 7 mmol/l glucose and significant stimulation already at 12 mmol/l glucose.

    “There was a U-shaped dose-response relationship for glucose-regulated glucagon secretion also in In-R1-G9 cells with maximal inhibition at 7 mmol/l (Fig. 1, right panel).”
    • Also stated in: § RESULTS · plain
      “the stimulatory component was left-shifted with significant stimulation already at 12 mmol/l glucose.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Further elevation of glucose to 30 mmol/l has no effect on alpha-cells but induces a more pronounced additional reduction of [Ca2+]i in 23 of 25 beta-cells (P<0.001).

    “Further elevation of glucose to 30 mmol/l had no effect on the ␣-cells but induced a more pronounced additional reduction of [Ca 2ϩ ] i in 23 of 25 ␤-cells (P Ͻ 0.001).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The additional inhibition obtained by raising the sugar concentration to 7 mmol/l remains statistically significant under hyperpolarizing conditions.

    “Nevertheless, the additional inhibition obtained by raising the sugar concentration to 7 mmol/l remained statistically significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Glucose does not affect depolarization-induced insulin secretion in the 0-7 mmol/l range, but higher concentrations of the sugar have a pronounced amplifying effect.

    “Glucose did not affect the depolarization-induced insulin secretion in the 0 -7 mmol/l range, but higher concentrations of the sugar had a pronounced amplifying effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Hyperpolarization in the absence of glucose has no effect on [Ca2+]i of resting beta-cells but lowers [Ca2+]i of oscillating alpha-cells.

    “Hyperpolarization in the absence of glucose had no effect on [Ca 2ϩ ] i of resting ␤-cells but lowered [Ca 2ϩ ] i of oscillating ␣-cells (not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the presence of diazoxide, introduction of 7 mmol/l glucose results in a small reduction of basal [Ca2+]i in 78% of alpha-cells (14 of 18; P<0.001) and all of 12 beta-cells (P<0.001).

    “In the presence of diazoxide, introduction of 7 mmol/l glucose resulted in a small reduction of basal [Ca 2ϩ ] i in 78% of the ␣-cells (14 of 18; P Ͻ 0.001) and all of 12 ␤-cells (P Ͻ 0.001; Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Higher concentrations of the sugar still stimulate glucagon release under depolarizing conditions, but this effect is not more pronounced than under control or hyperpolarizing conditions.

    “Higher concentrations of the sugar still stimulated glucagon release, but this effect was not more pronounced than under control or hyperpolarizing conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Glucagon secretion at higher glucose concentrations is not diminished during hyperpolarizing conditions and even slightly exceeds control secretion in the 12-30 mmol/l range.

    “Glucagon secretion at higher glucose concentrations was not diminished during hyperpolarizing conditions and even slightly exceeded control secretion in the 12-30 mmol/l range.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Somatostatin secretion is stimulated by glucose and is significantly higher at 30 than at 20 mmol/l sugar.

    “Separate control measurements under identical conditions revealed that somatostatin secretion was stimulated by glucose and significantly higher at 30 than at 20 mmol/l sugar (data not shown)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mouse islets, glucagon secretion is more than half-maximally inhibited by 4 mmol/l glucose, and the maximal effect is reached at 7-8 mmol/l glucose.

    “In the mouse islets, glucagon secretion was more than half-maximally inhibited by 4 mmol/l glucose, and the maximal effect was reached at 7-8 mmol/l (Fig. 1, top left panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Basal insulin secretion at 0-7 mmol/l glucose is unaffected by hyperpolarization, whereas insulin secretion at 12-30 mmol/l glucose is reduced by about 70% compared with control.

    “Basal insulin secretion at 0 -7 mmol/l glucose was unaffected by the hyperpolarization (Fig. 4, bottom panel), whereas insulin secretion at 12-30 mmol/l glucose was reduced by ϳ70% compared with control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In-R1-G9 cells do not secrete detectable amounts of insulin or somatostatin.

    “The In-R1-G9 cells did not secrete detectable amounts of insulin or somatostatin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In parallel insulin measurements from the same mouse islets, threshold stimulation of insulin release (18%) is obtained at 7 mmol/l glucose and maximal secretion at 25-30 mmol/l sugar.

    “In parallel insulin measurements from the same islets, threshold stimulation of insulin release (18%) was obtained at 7 mmol/l glucose and maximal secretion at 25-30 mmol/l sugar (Fig. 1, bottom left panel).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Subsequent introduction of 3 mmol/l glucose causes a small reduction of [Ca2+]i in 3 of 19 alpha-cells, but there is no change when increasing glucose from 0 to 3, 7, and 30 mmol/l in the remaining 16 alpha-cells.

    “Subsequent introduction of 3 mmol/l glucose caused a small reduction of [Ca 2ϩ ] i in 3 of 19 ␣-cells, but there was no change of [Ca 2ϩ ] i when increasing the glucose concentration from 0 to 3, 7, and 30 mmol/l in the remaining 16 ␣-cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    High glucose concentrations stimulate glucagon secretion under hyperpolarizing conditions, although [Ca2+]i of the alpha-cells is lowered below basal levels.

    “2) High glucose concentrations stimulated glucagon secretion under hyperpolarizing conditions, although [Ca 2ϩ ] i of the ␣-cells was lowered below basal levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Glucagon secretion occurs in response to hypoglycemia and is inhibited already when the glucose concentration reaches 4-6 mmol/l.

    “Secretion occurs in response to hypoglycemia and is inhibited already when the glucose concentration reaches 4 -6 mmol/l (7,8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Gerich JE, Charles A, Grodsky GM: Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. J Clin Invest 54:833–841,1974 source

      Not checked in the free run.

    • cites [8] Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J: Glucose stimulates glucagon release in single rat α-cells by mechanisms that mirror the stimulus-secretion coupling in β-cells. Endocrinology 146:4861–4870,2005 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Stimulation of glucagon release by high glucose concentrations does not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion.

    “However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca 2؉ , indicating involvement of novel mechanisms in glucose regulation of glucagon secretion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Depolarization by tolbutamide-induced closure of KATP channels increases electrical activity, [Ca2+]i, exocytosis, and secretion in rat alpha-cells.

    “Depolarization by tolbutamideinduced closure of the K ATP channels thus increases the electrical activity (24), [Ca 2ϩ ] i (8), exocytosis (28), and secretion (8) in rat ␣-cells”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Bokvist K, Olsen HL, Høy M, Gotfredsen CF, Holmes WF, Buschard K, Rorsman P, Gromada J: Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells. Pflügers Arch 438:428–436,1999 source

      Not checked in the free run.

    • cites [8] Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J: Glucose stimulates glucagon release in single rat α-cells by mechanisms that mirror the stimulus-secretion coupling in β-cells. Endocrinology 146:4861–4870,2005 source

      Not checked in the free run.

    • cites [28] Høy M, Olsen HL, Bokvist K, Buschard K, Barg S, Rorsman P, Gromada J: Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial-like ATP-sensitive K+ (KATP) conductance in rat pancreatic A-cells. J Physiol (Lond) 527:109–120,2000 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Glucose stimulation of glucagon secretion from mouse islets occurs independent of KATP channels and does not require elevation of [Ca2+]i.

    “glucose stimulation of glucagon secretion from mouse islets occurred independent of K ATP channels and did not require elevation of [Ca 2ϩ ] i .”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Increased metabolism can stimulate insulin release independent of [Ca2+]i elevation.

    “In addition, there is evidence that increased metabolism can stimulate insulin release independent of [Ca 2ϩ ] i elevation (36,37).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Westerlund J, Hellman B, Bergsten P: Pulsatile insulin release from mouse islets occurs in the absence of stimulated entry of Ca2+. J Clin Invest 97:1860–1863,1996 source

      Not checked in the free run.

    • cites [37] Ravier MA, Gilon P, Henquin JC: Oscillations of insulin secretion can be triggered by imposed oscillations of cytoplasmic Ca2+ or metabolism in normal mouse islets. Diabetes 48:2374–2382,1999 source

      Not checked in the free run.

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

    Premisecitation

    Initiation of insulin secretion is generally attributed to depolarization with increase of [Ca2+]i after closure of KATP channels.

    “Initiation of secretion is generally attributed to depolarization with increase of [Ca 2ϩ ] i after closure of K ATP channels (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Ashcroft FM, Rorsman P: ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. Biochem Soc Trans 18:109–111,1990 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Only alpha-cells confirmed by immunostaining were included in the analyses.

    “Only ␣-cells confirmed by immunostaining were included in the analyses (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Liu YJ, Vieira E, Gylfe E: A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Cell Calcium 35:357–365,2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Alpha-cells can sense high concentrations of glucose despite expressing low Km GLUT1 but lacking high Km GLUT2.

    “It may seem surprising that the ␣-cells can sense high concentrations of glucose because they express low K m glucose transporter GLUT1 but lack high K m GLUT2 (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Heimberg H, De Vos A, Pipeleers DG, Thorens B, Schuit FC: Differences in glucose transporter gene expression between rat pancreatic α- and β-cells are correlated to differences in glucose transport but not in glucose utilization. J Biol Chem 270:8971–8975,1995 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Somatostatin secretion is undetectable in In-R1-G9 cells, indicating that maximal theoretical secretion of this hormone corresponds to 0.5-4% of glucagon secretion, much lower than in mouse islets.

    “Also, somatostatin secretion was undetectable, indicating that maximal theoretical secretion of this hormone corresponded to 0.5-4% of glucagon secretion, which is much lower than in the mouse islets (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    A similar regulation of human alpha-cells may explain why diabetic patients with hyperglycemia display paradoxical hyperglucagonemia and why a further glucose challenge has been found to stimulate glucagon release.

    “A similar regulation of human ␣-cells may explain why diabetic patients with hyperglycemia display paradoxical hyperglucagonemia and why a further glucose challenge has been found to stimulate glucagon release (9 -11).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Buchanan KD, McCarroll AM: Abnormalities of glucagon metabolism in untreated diabetes mellitus. Lancet 300:1394–1395,1972 source

      Not checked in the free run.

    • cites [10] Ohneda A, Watanabe K, Horigome K, Sakai T, Kai Y, Oikawa S: Abnormal response of pancreatic glucagon to glycemic changes in diabetes mellitus. J Clin Endocrinol Metab 46:504–510,1978 source

      Not checked in the free run.

    • cites [11] Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J: Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381–1390,1990 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The presently observed stimulatory effect of glucose on glucagon secretion from mouse islets does not depend on the [Ca2+]i level of the alpha-cells, indicating that glucose initiates rather than amplifies secretion.

    “However, the presently observed stimulatory effect of glucose on glucagon secretion from mouse islets did not depend on the [Ca 2ϩ ] i level of the ␣-cells, indicating that glucose initiates rather than amplifies secretion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Glucose increases electrical activity and [Ca2+]i of rat alpha-cells.

    “whereas glucose increases the electrical activity and [Ca 2ϩ ] i of rat ␣-cells (24)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Bokvist K, Olsen HL, Høy M, Gotfredsen CF, Holmes WF, Buschard K, Rorsman P, Gromada J: Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells. Pflügers Arch 438:428–436,1999 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    It seems unlikely that phenotypic diversity among In-R1-G9 cells explains inhibitory or stimulatory effects of glucose by paracrine routes, but an inhibitory effect of insulin is not entirely excluded.

    “It seems unlikely that phenotypic diversity among the In-R1-G9 cells explains inhibitory or stimulatory effects of glucose by paracrine routes, but an inhibitory effect of insulin is not entirely excluded.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Glucose hyperpolarizes mouse alpha-cells and lowers [Ca2+]i.

    “the sugar hyperpolarizes mouse ␣-cells (14,27,29) and, as now confirmed, lowers [Ca 2ϩ ] i (14).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Liu YJ, Vieira E, Gylfe E: A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Cell Calcium 35:357–365,2004 source

      Not checked in the free run.

    • cites [27] Barg S, Galvanovskis J, Göpel SO, Rorsman P, Eliasson L: Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting α-cells. Diabetes 49:1500–1510,2000 source

      Not checked in the free run.

    • cites [29] Hjortoe GM, Hagel GM, Terry BR, Thastrup O, Arkhammar PO: Functional identification and monitoring of individual α and β cells in cultured mouse islets of Langerhans. Acta Diabetol 41:185–193,2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Glucose transport via GLUT1 is not rate limiting in these cases, and the sensing is explained by the presence of the high Km glucokinase.

    “Apparently glucose transport via GLUT1 is not rate limiting in these cases, and the sensing is explained by the presence of the high K m glucokinase (39,40).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] De Vos A, Heimberg H, Quartier E, Huypens P, Bouwens L, Pipeleers D, Schuit F: Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression. J Clin Invest 96:2489–2495,1995 source

      Not checked in the free run.

    • cites [40] Heimberg H, De Vos A, Moens K, Quartier E, Bouwens L, Pipeleers D, Van Schaftingen E, Madsen O, Schuit F: The glucose sensor protein glucokinase is expressed in glucagon-producing α-cells. Proc Natl Acad Sci U S A 93:7036–7041,1996 source

      Not checked in the free run.

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

    Study design and conductnone given

    Local ethics committees approved the experimental procedures.

    “Local ethics committees approved the experimental procedures.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The lower duodenal part of the pancreas was rejected to avoid islets with cells producing pancreatic polypeptide.

    “The lower duodenal part of the pancreas was rejected to avoid islets with cells producing pancreatic polypeptide (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Liu YJ, Hellman B, Gylfe E: Ca2+ signaling in mouse pancreatic polypeptide cells. Endocrinology 140:5524–5529,1999 source

      Not checked in the free run.

33 of 33

  • The paper relies on this without support.

    The mechanisms underlying hyperglucagonemia in diabetes have not been fully elucidated.

    “the mecha-nisms underlying the hyperglucagonemia have not been fully elucidated.”
    “The mechanism underlying this phenomenon is unclear.”

  • The paper relies on this without support.

    Rise of cytoplasmic Ca2+ is the most important trigger of pancreatic islet hormone secretion.

    “Rise of [Ca 2ϩ ] i is probably the most important trigger of pancreatic islet hormone secretion.”
2 of 2

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Authors
Salehi, A., Vieira, E., & Gylfe, E.
Affiliations
  • Department of Clinical Science, Clinical Research Center, Malmö University Hospital, Malmö, Sweden
  • Uppsala University (SE)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2006-08-01
Volume
55
Issue
8
Pages
2318-2323
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db06-0080
OpenAlex
W2138968093
Semantic Scholar
3a406c4dfd3544fbed8b575ec5f8effd18979832
Cited by
159
References
42
Citations by year
2026: 5 · 2025: 4 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 13 · 2020: 11 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 12 · 2013: 9 · 2012: 6
FWCI
9.49
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • UCLA - Biblioteca de Ciencias de la Salud (submittedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • Lund University Publications (Lund University) (submittedVersion)
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
glucagon secretion, high glucose, alpha cells, glucose homeostasis, hyperglucagonemia, diazoxide, intracellular calcium, U-shaped dose-response
MeSH terms
Insulin Secretion, Animals, Calcium, Cell Line, Cells, Cultured, Clone Cells, Cytoplasm, Dose-Response Relationship, Drug, Glucagon, Glucose, Cricetinae, Insulin, Islets of Langerhans, Mice, Inbred C57BL, Mice

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