Farhan, H.Caxaria, S.Bugliani, M.Marselli, L.Marchetti, P.Birzele, F.Scharfmann, R.Rutter, J.Siniakowicz, K.Reimann, F.Gribble, F. M.Rutter, G. A.Kim, H.Johnson, P.Weir, GordonHughes, S.Sun, G.Parker, H.2011-10-252010da Silva Xavier, Gabriela, Hatem Farhan, Hyeonjung Kim, S. Caxaria, Phil Johnson, Shannon Hughes, Marco Bugliani, et al. 2010. Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. Diabetologia 54(4): 819-827.0012-186Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5311763Aims/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 quanti- tative 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 regu- lation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.en-USalpha cellsglucagon secretionhuman islets of Langerhansknockout mousePASKJournal Article2011-10-2510.1007/s00125-010-2010-7