Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion.
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 tolera...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2011
|
| _version_ | 1797079877967413248 |
|---|---|
| author | 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 Rutter, G |
| author_facet | 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 Rutter, G |
| author_sort | da Silva Xavier, G |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:52:07Z |
| format | Journal article |
| id | oxford-uuid:86bee4bc-6b6e-41f6-b0dd-e9f9ba740e60 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:52:07Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:86bee4bc-6b6e-41f6-b0dd-e9f9ba740e602022-03-26T22:06:10ZPer-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:86bee4bc-6b6e-41f6-b0dd-e9f9ba740e60EnglishSymplectic Elements at Oxford2011da Silva Xavier, GFarhan, HKim, HCaxaria, SJohnson, PHughes, SBugliani, MMarselli, LMarchetti, PBirzele, FSun, GScharfmann, RRutter, JSiniakowicz, KWeir, GParker, HReimann, FGribble, FRutter, GAIMS/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. |
| spellingShingle | 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 Rutter, G Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. |
| title | Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. |
| title_full | Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. |
| title_fullStr | Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. |
| title_full_unstemmed | Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. |
| title_short | Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. |
| title_sort | per arnt sim pas domain containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion |
| work_keys_str_mv | AT dasilvaxavierg perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT farhanh perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT kimh perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT caxarias perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT johnsonp perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT hughess perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT buglianim perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT marsellil perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT marchettip perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT birzelef perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT sung perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT scharfmannr perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT rutterj perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT siniakowiczk perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT weirg perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT parkerh perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT reimannf perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT gribblef perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion AT rutterg perarntsimpasdomaincontainingproteinkinaseisdownregulatedinhumanisletsintype2diabetesandregulatesglucagonsecretion |