Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion

G da Silva Xavier; H Farhan; H Kim; S Caxaria; P Johnson; S Hughes; M Bugliani; L Marselli; P Marchetti; F Birzele; G Sun; R Scharfmann; J Rutter; K Siniakowicz; G Weir; H Parker; F Reimann; F M Gribble; G A Rutter

doi:10.1007/s00125-010-2010-7

Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion

G da Silva Xavier, H Farhan, H Kim, S Caxaria, P Johnson, S Hughes, M Bugliani, L Marselli, P Marchetti, F Birzele, G Sun, R Scharfmann, J Rutter, K Siniakowicz, G Weir, H Parker, F Reimann, F M Gribble, G A Rutter

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Abstract

AIMS/HYPOTHESIS: We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion.

METHODS: mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask-/-) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK.

RESULTS: PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask-/- mice, fasted blood glucose and plasma glucagon levels were 25 ± 5% and 50 ± 8% (mean ± SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask-/- mice secreted 2.04 ± 0.2-fold (p < 0.01) more glucagon and 2.63 ± 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release.

CONCLUSIONS/INTERPRETATION: PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.

Original language	English
Pages (from-to)	819-27
Number of pages	9
Journal	Diabetologia
Volume	54
Issue number	4
DOIs	https://doi.org/10.1007/s00125-010-2010-7
Publication status	Published - Apr 2011

Keywords

Animals
Cell Line
Cells, Cultured
Diabetes Mellitus, Type 2/enzymology
Glucagon/metabolism
Glucagon-Secreting Cells/drug effects
Glucose/pharmacology
Humans
Insulin-Secreting Cells/drug effects
Islets of Langerhans/drug effects
Mice
Mice, Mutant Strains
Models, Biological
Polymerase Chain Reaction
Protein-Serine-Threonine Kinases/genetics
Rats

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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G_da_Silva_Xavier_Per-arnt-sim_(PAS)_domain-containing_protein_kinase_Diabetologia_2011
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https://link.springer.com/article/10.1007%2Fs00125-010-2010-7Licence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

Cite this

da Silva Xavier, G., Farhan, H., Kim, H., Caxaria, S., Johnson, P., Hughes, S., Bugliani, M., Marselli, L., Marchetti, P., Birzele, F., Sun, G., Scharfmann, R., Rutter, J., Siniakowicz, K., Weir, G., Parker, H., Reimann, F., Gribble, F. M., & Rutter, G. A. (2011). Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. Diabetologia, 54(4), 819-27. https://doi.org/10.1007/s00125-010-2010-7

@article{240aaee289a141a781be1f2e0ea45df6,

title = "Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion",

abstract = "AIMS/HYPOTHESIS: We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion.METHODS: mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask-/-) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK.RESULTS: PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask-/- mice, fasted blood glucose and plasma glucagon levels were 25 ± 5% and 50 ± 8% (mean ± SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask-/- mice secreted 2.04 ± 0.2-fold (p < 0.01) more glucagon and 2.63 ± 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release.CONCLUSIONS/INTERPRETATION: PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.",

keywords = "Animals, Cell Line, Cells, Cultured, Diabetes Mellitus, Type 2/enzymology, Glucagon/metabolism, Glucagon-Secreting Cells/drug effects, Glucose/pharmacology, Humans, Insulin-Secreting Cells/drug effects, Islets of Langerhans/drug effects, Mice, Mice, Mutant Strains, Models, Biological, Polymerase Chain Reaction, Protein-Serine-Threonine Kinases/genetics, Rats",

author = "{da Silva Xavier}, G and H Farhan and H Kim and S Caxaria and P Johnson and S Hughes and M Bugliani and L Marselli and P Marchetti and F Birzele and G Sun and R Scharfmann and J Rutter and K Siniakowicz and G Weir and H Parker and F Reimann and Gribble, {F M} and Rutter, {G A}",

year = "2011",

month = apr,

doi = "10.1007/s00125-010-2010-7",

language = "English",

volume = "54",

pages = "819--27",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "4",

}

da Silva Xavier, G, Farhan, H, Kim, H, Caxaria, S, Johnson, P, Hughes, S, Bugliani, M, Marselli, L, Marchetti, P, Birzele, F, Sun, G, Scharfmann, R, Rutter, J, Siniakowicz, K, Weir, G, Parker, H, Reimann, F, Gribble, FM & Rutter, GA 2011, 'Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion', Diabetologia, vol. 54, no. 4, pp. 819-27. https://doi.org/10.1007/s00125-010-2010-7

TY - JOUR

T1 - Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion

AU - da Silva Xavier, G

AU - Farhan, H

AU - Kim, H

AU - Caxaria, S

AU - Johnson, P

AU - Hughes, S

AU - Bugliani, M

AU - Marselli, L

AU - Marchetti, P

AU - Birzele, F

AU - Sun, G

AU - Scharfmann, R

AU - Rutter, J

AU - Siniakowicz, K

AU - Weir, G

AU - Parker, H

AU - Reimann, F

AU - Gribble, F M

AU - Rutter, G A

PY - 2011/4

Y1 - 2011/4

N2 - AIMS/HYPOTHESIS: We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion.METHODS: mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask-/-) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK.RESULTS: PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask-/- mice, fasted blood glucose and plasma glucagon levels were 25 ± 5% and 50 ± 8% (mean ± SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask-/- mice secreted 2.04 ± 0.2-fold (p < 0.01) more glucagon and 2.63 ± 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release.CONCLUSIONS/INTERPRETATION: PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.

AB - AIMS/HYPOTHESIS: We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion.METHODS: mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask-/-) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK.RESULTS: PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask-/- mice, fasted blood glucose and plasma glucagon levels were 25 ± 5% and 50 ± 8% (mean ± SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask-/- mice secreted 2.04 ± 0.2-fold (p < 0.01) more glucagon and 2.63 ± 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release.CONCLUSIONS/INTERPRETATION: PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.

KW - Animals

KW - Cell Line

KW - Cells, Cultured

KW - Diabetes Mellitus, Type 2/enzymology

KW - Glucagon/metabolism

KW - Glucagon-Secreting Cells/drug effects

KW - Glucose/pharmacology

KW - Humans

KW - Insulin-Secreting Cells/drug effects

KW - Islets of Langerhans/drug effects

KW - Mice

KW - Mice, Mutant Strains

KW - Models, Biological

KW - Polymerase Chain Reaction

KW - Protein-Serine-Threonine Kinases/genetics

KW - Rats

U2 - 10.1007/s00125-010-2010-7

DO - 10.1007/s00125-010-2010-7

M3 - Article

C2 - 21181396

SN - 0012-186X

VL - 54

SP - 819

EP - 827

JO - Diabetologia

JF - Diabetologia

IS - 4

ER -

Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion

Abstract

Keywords

UN SDGs

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