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

Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion,10.1007/s0012

Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion   (Citations: 1)
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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. Scharfmannhttp://academic.research.microsoft.com/io.ashx?type=5&id=48858143&selfId1=0&selfId2=0&maxNumber=12&query=
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 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.
Journal: Diabetologia , vol. 54, no. 4, pp. 819-827, 2011
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    • ...In the present issue of Diabetologia the study by da Silva Xavier et al. [11] provides an intriguing new piece of this puzzle, and suggests a common metabolic sensing pathway may underlie not only the direct and indirect effects of glucose on glucagon, but also the pathophysiology of the alpha cell in diabetes (outlined in Fig. 7 of da Silva Xavier et al.)...
    • ...In the paper by da Silva Xavier [11], the PASK pathway is suggested as a possible pharmacological target for the treatment of type 2 diabetes...
    • ...Finally, the paper by da Silva et al. [11], in demonstrating a novel pathway regulating glucagon secretion and potentially involved in alpha cell pathophysiology, provides a strong impetus to further understand the upstream and downstream signals regulating PASK and its effects on glucagon secretion...

    P. E. MacDonaldet al. Per-arnt-sim (PAS) domain kinase (PASK) as a regulator of glucagon sec...

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