L-Arginine is essential for pancreatic beta-cell functional integrity, metabolism and defense from inflammatory challenge

MS Krause, Neville McClenaghan, Peter Flatt, PIH de Bittencourt, C Murphy, P Newsholme

Research output: Contribution to journalArticle

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Abstract

In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of beta-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus-secretion coupling and functional integrity. Clonal BRIN-BD11 beta-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0-1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1 beta, tumour necrosis factor a and interferon gamma). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L-arginine at 1.15 mmol/l attenuated the loss of beta-cell viability observed in the presence of proinflammatory cytokines. L-Arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate beta-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of beta-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for beta-cells during inflammatory challenge. Journal of Endocrinology (2011) 211, 87-97
LanguageEnglish
Pages87-97
JournalJournal of Endrocrinology
Volume211
Issue number1
DOIs
Publication statusPublished - Oct 2011

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Insulin-Secreting Cells
Arginine
Glutathione Disulfide
Cytokines
HSP72 Heat-Shock Proteins
Insulin
Glutamic Acid
AMP-Activated Protein Kinases
Islets of Langerhans
Glucose
Antioxidants
Amino Acids
Endocrinology
Glutamine
Interleukin-1beta
Nitric Oxide Synthase
Superoxides
Interferon-gamma
Glutathione
Urea

Cite this

Krause, MS ; McClenaghan, Neville ; Flatt, Peter ; de Bittencourt, PIH ; Murphy, C ; Newsholme, P. / L-Arginine is essential for pancreatic beta-cell functional integrity, metabolism and defense from inflammatory challenge. In: Journal of Endrocrinology. 2011 ; Vol. 211, No. 1. pp. 87-97.
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abstract = "In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of beta-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus-secretion coupling and functional integrity. Clonal BRIN-BD11 beta-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0-1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1 beta, tumour necrosis factor a and interferon gamma). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L-arginine at 1.15 mmol/l attenuated the loss of beta-cell viability observed in the presence of proinflammatory cytokines. L-Arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50{\%}, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate beta-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of beta-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for beta-cells during inflammatory challenge. Journal of Endocrinology (2011) 211, 87-97",
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L-Arginine is essential for pancreatic beta-cell functional integrity, metabolism and defense from inflammatory challenge. / Krause, MS; McClenaghan, Neville; Flatt, Peter; de Bittencourt, PIH; Murphy, C; Newsholme, P.

In: Journal of Endrocrinology, Vol. 211, No. 1, 10.2011, p. 87-97.

Research output: Contribution to journalArticle

TY - JOUR

T1 - L-Arginine is essential for pancreatic beta-cell functional integrity, metabolism and defense from inflammatory challenge

AU - Krause, MS

AU - McClenaghan, Neville

AU - Flatt, Peter

AU - de Bittencourt, PIH

AU - Murphy, C

AU - Newsholme, P

PY - 2011/10

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N2 - In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of beta-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus-secretion coupling and functional integrity. Clonal BRIN-BD11 beta-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0-1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1 beta, tumour necrosis factor a and interferon gamma). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L-arginine at 1.15 mmol/l attenuated the loss of beta-cell viability observed in the presence of proinflammatory cytokines. L-Arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate beta-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of beta-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for beta-cells during inflammatory challenge. Journal of Endocrinology (2011) 211, 87-97

AB - In this work, our aim was to determine whether L-arginine (a known insulinotropic amino acid) can promote a shift of beta-cell intermediary metabolism favoring glutathione (GSH) and glutathione disulfide (GSSG) antioxidant responses, stimulus-secretion coupling and functional integrity. Clonal BRIN-BD11 beta-cells and mouse islets were cultured for 24 h at various L-arginine concentrations (0-1.15 mmol/l) in the absence or presence of a proinflammatory cytokine cocktail (interleukin 1 beta, tumour necrosis factor a and interferon gamma). Cells were assessed for viability, insulin secretion, GSH, GSSG, glutamate, nitric oxide (NO), superoxide, urea, lactate and for the consumption of glucose and glutamine. Protein levels of NO synthase-2, AMP-activated protein kinase (AMPK) and the heat shock protein 72 (HSP72) were also evaluated. We found that L-arginine at 1.15 mmol/l attenuated the loss of beta-cell viability observed in the presence of proinflammatory cytokines. L-Arginine increased total cellular GSH and glutamate levels but reduced the GSSG/GSH ratio and glutamate release. The amino acid stimulated glucose consumption in the presence of cytokines while also stimulating AMPK phosphorylation and HSP72 expression. Proinflammatory cytokines reduced, by at least 50%, chronic (24 h) insulin secretion, an effect partially attenuated by L-arginine. Acute insulin secretion was robustly stimulated by L-arginine but this effect was abolished in the presence of cytokines. We conclude that L-arginine can stimulate beta-cell insulin secretion, antioxidant and protective responses, enabling increased functional integrity of beta-cells and islets in the presence of proinflammatory cytokines. Glucose consumption and intermediary metabolism were increased by L-arginine. These results highlight the importance of L-arginine availability for beta-cells during inflammatory challenge. Journal of Endocrinology (2011) 211, 87-97

U2 - 10.1530/JOE-11-0236

DO - 10.1530/JOE-11-0236

M3 - Article

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SP - 87

EP - 97

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JF - Journal of Endrocrinology

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