Skip to main content

Per-arnt-sim (PAS) domain kinase (PASK) as a regulator of glucagon secretion


The physiological and pathophysiological regulation of glucagon secretion from pancreatic alpha cells remains a hotly debated topic. The mechanism(s) contributing to the glucose sensitivity of glucagon release and its impaired regulation in diabetes remain unclear. A paper in the current issue of Diabetologia by da Silva Xavier and colleagues (doi:10.1007/s00125-010-2010-7) provides intriguing new insight into a metabolic sensing pathway mediated by the per-arnt-sim (PAS) domain kinase (PASK) that may contribute to both the paracrine and the intrinsic glucose regulation of alpha cells. Importantly, the authors show that PASK is decreased in islets from patients with type 2 diabetes, providing a potential mechanism for impaired suppression of glucagon by hyperglycaemia in this disease. Much work remains to be done to determine the exact role and mechanism of PASK in alpha and beta cells. Nevertheless, the present work introduces a new player in the metabolic regulation of glucagon secretion.

Inappropriately elevated glucagon secretion from pancreatic alpha cells has been recognised as an important contributing factor to hyperglycaemia in diabetes for more than three decades [13]. Although under-studied for some time, both the physiological mechanisms that control glucagon release and the pathophysiology that contributes to altered glucagon regulation in diabetes have seen a resurgence of interest in recent years. The importance of glucagon has recently been underscored by the potential therapeutic value of antiglucagon approaches [4] and new insights demonstrating the importance of glucagon suppression in the glucose-lowering effects of glucagon-like peptide-1 [5]. Thus, diabetes is once again recognised as a ‘bi-hormonal’ disease where impaired regulation of both insulin and glucagon contributes to elevated blood glucose levels.

One of the more intensely debated topics relating to glucagon secretion over the past few years centres on the physiological mechanism(s) regulating glucagon suppression by hyperglycaemia, and there are several schools of thought on this [6]. Glucagon is produced in pancreatic alpha cells and its release requires electrical activity and elevations in intracellular Ca2+ that trigger regulated exocytosis [7], much like that seen for insulin secretion from beta cells. It is upstream of this process where the picture becomes cloudy. There are clearly important extrinsic paracrine and neuronal inputs that control glucagon release (reviewed by Gromada et al. [6]). In addition, we have proposed [8] a direct effect of glucose to inhibit glucagon release, owing at least in part to the unique electrical properties of alpha cells in both rodents and humans [9, 10]. However, reconciling these several views and linking them to the pathophysiology of glucagon release in diabetes, particularly the effects of glucose on glucagon secretion that are direct or those that are mediated indirectly through beta cells, has been problematic. 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.).

Much recent work has examined the role of AMP-activated protein kinase (AMPK) in the regulation of insulin secretion [1214]. AMPK is a serine/threonine protein kinase that acts as a sensor and regulator of energy balance at both the cellular and whole body level [15]. An increase in intracellular AMP level activates the enzyme. Thus, when cellular energy levels fall, AMPK activity blunts insulin granule recruitment and secretion [16]. Conversely, AMPK activation upon falling cellular energy levels is suggested to augment glucagon secretion [17]. The da Silva Xavier study focuses on the per-arnt-sim (PAS) domain kinase (PASK), another serine/threonine kinase [18] implicated in the sensing of cellular energy homeostasis, the control of insulin gene expression [19] and the modulation of insulin gene expression under pathophysiological cell culture conditions [20]. However, while Pask –/– mice displayed reduced plasma insulin responses to glucose they showed normal glucose [21, 22] and insulin [21] tolerance. da Silva Xavier et al. now examine whether PASK may function as a metabolic sensor in alpha cells. Their data intriguingly suggest an underlying metabolic sensing pathway contributing to both the paracrine and intrinsic regulation of glucagon secretion from alpha cells (da Silva Xavier et al., Fig. 7). Islets from mice lacking Pask1 (Pask1 −/−) were shown to exhibit impaired glucose-dependent suppression of glucagon secretion. Furthermore, small interfering RNA (siRNA)-mediated knockdown of Pask1 in clonal alpha cells recapitulated this effect. This latter finding is consistent with a role for PASK as a metabolic sensor and potential transducer of glucose signals within the alpha cell itself. However, the relative contributions of beta cell PASK and alpha cell PASK in the intact islet remain to be determined. This is particularly important given that the Pask1 −/− islets displayed reduced insulin content, and in the intact islet this may result in a relative loss of paracrine regulation of glucagon by the beta cell. Whether the primary action of PASK on glucagon secretion is mediated through the beta cell, or through the alpha cell itself, could in part be addressed by the selective downregulation of PASK in beta and/or alpha cells.

da Silva Xavier et al. show that glucose upregulates PASK production in human islets and, perhaps more intriguingly, that PASK levels are decreased in human type 2 diabetes. The latter is consistent with in vitro work in rodent islets by Fontes et al. [20] showing reduced PASK levels in response to chronic exposure to palmitate. In that study, upregulation of PASK ameliorated the effects of palmitate to reduce insulin gene expression. 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. Some credence is lent to this idea by the demonstration that upregulating PASK production by recombinant adenovirus was able to suppress glucagon secretion in clonal alpha cells and human islets. However, it should be noted that the major effect of PASK upregulation was to suppress glucagon secretion at low glucose levels. The clinical utility of this, while promising, is unclear. The true test may be whether normalisation of PASK levels in islets from type 2 diabetic donors restores normal glucose-dependent regulation of glucagon secretion.

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. It will be critically important to determine the metabolic signal that is being sensed by PASK, which is yet to be identified. Some insight is, however, gained into the downstream mechanisms responsible for PASK effects on glucagon secretion in the da Silva Xavier study. Notably, the authors demonstrate an upregulation of the AMPK-α2 subunit, which they have recently demonstrated to stimulate glucagon release [17]. Whether this accounts for the failure of glucose to suppress glucagon secretion is also yet to be determined, and in particular the mechanism by which AMPK and PASK interact to modulate glucagon will prove particularly interesting.

How does AMPK differentially regulate glucagon secretion from that of insulin, where it exerts a negative regulation of insulin granule recruitment [13]? We proposed that differences in ion channel expression and action potential generation contribute to the opposing regulation of insulin and glucagon [10, 23]. In this context it is interesting to note that AMPK is suggested to regulate several important ion channels involved in pancreatic hormone release, including voltage-dependent Na+ channels [24], ATP-dependent K+ channels [25], KCNQ channels [26], Kv2.1 channels [27] and BK channels [28]. It is pertinent that all of these are implicated in the regulation of glucagon secretion [10, 29]. It will be interesting to determine how glucagon secretion is affected by glucose in islets obtained from patients with type 2 diabetes and whether the hypersecretion of glucagon (predicted from in vivo studies [30]) can be corrected by overproducing PASK. These are challenging experiments but they may lead to pharmacological treatments that specifically target glucagon secretion. Clearly, the study by da Silva et al. provides an exciting new piece of the glucagon puzzle—but it is not getting any easier!



AMP-activated protein kinase




PAS domain-containing protein kinase


  1. Dobbs R, Sakurai H, Sasaki H et al (1975) Glucagon: role in the hyperglycemia of diabetes mellitus. Science 187:544–547

    PubMed  Article  CAS  Google Scholar 

  2. Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM (1970) Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49:837–848

    PubMed  Article  CAS  Google Scholar 

  3. Aguilar-Parada E, Eisentraut AM, Unger RH (1969) Pancreatic glucagon secretion in normal and diabetic subjects. Am J Med Sci 257:415–419

    PubMed  Article  CAS  Google Scholar 

  4. Ali S, Drucker DJ (2009) Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes. Am J Physiol Endocrinol Metab 296:E415–E421

    PubMed  Article  CAS  Google Scholar 

  5. Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK, Holst JJ (2010) The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 59:1765–1770

    PubMed  Article  CAS  Google Scholar 

  6. Gromada J, Franklin I, Wollheim CB (2007) Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28:84–116

    PubMed  Article  CAS  Google Scholar 

  7. Barg S, Galvanovskis J, Gopel SO, Rorsman P, Eliasson L (2000) Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes 49:1500–1510

    PubMed  Article  CAS  Google Scholar 

  8. Gopel SO, Kanno T, Barg S, Weng XG, Gromada J, Rorsman P (2000) Regulation of glucagon release in mouse α-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528:509–520

    PubMed  Article  CAS  Google Scholar 

  9. MacDonald PE, de Marinis YZ, Ramracheya R et al (2007) A KATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 5:e143

    PubMed  Article  Google Scholar 

  10. Spigelman AF, Dai X, MacDonald PE (2010) Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans. Diabetologia 53:1917–1926

    PubMed  Article  CAS  Google Scholar 

  11. da Silva Xavier G, Farhan H, Kim H 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. doi:10.1007/s00125-010-2010-7

    Google Scholar 

  12. da Silva XG, Leclerc I, Varadi A, Tsuboi T, Moule SK, Rutter GA (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371:761–774

    Article  Google Scholar 

  13. Tsuboi T, da Silva XG, Leclerc I, Rutter GA (2003) 5′-AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J Biol Chem 278:52042–52051

    PubMed  Article  CAS  Google Scholar 

  14. Targonsky ED, Dai F, Koshkin V et al (2006) Alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells. Diabetologia 49:1587–1598

    PubMed  Article  CAS  Google Scholar 

  15. Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25

    PubMed  Article  CAS  Google Scholar 

  16. McDonald A, Fogarty S, Leclerc I, Hill EV, Hardie DG, Rutter GA (2009) Control of insulin granule dynamics by AMPK dependent KLC1 phosphorylation. Islets 1:198–209

    PubMed  Article  Google Scholar 

  17. Leclerc I, Sun G, Morris C, Fernandez-Millan E, Nyirenda M, Rutter GA (2010) AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells. Diabetologia 54:125–134

    PubMed  Article  Google Scholar 

  18. Schlafli P, Borter E, Spielmann P, Wenger RH (2009) The PAS-domain kinase PASKIN: a new sensor in energy homeostasis. Cell Mol Life Sci 66:876–883

    PubMed  Article  CAS  Google Scholar 

  19. da Silva XG, Rutter J, Rutter GA (2004) Involvement of Per-Arnt-Sim (PAS) kinase in the stimulation of preproinsulin and pancreatic duodenum homeobox 1 gene expression by glucose. Proc Natl Acad Sci U S A 101:8319–8324

    Article  Google Scholar 

  20. Fontes G, Semache M, Hagman DK et al (2009) Involvement of Per-Arnt-Sim kinase and extracellular-regulated kinases-1/2 in palmitate inhibition of insulin gene expression in pancreatic beta-cells. Diabetes 58:2048–2058

    PubMed  Article  CAS  Google Scholar 

  21. Hao HX, Cardon CM, Swiatek W et al (2007) PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci U S A 104:15466–15471

    PubMed  Article  CAS  Google Scholar 

  22. Borter E, Niessen M, Zuellig R et al (2007) Glucose-stimulated insulin production in mice deficient for the PAS kinase PASKIN. Diabetes 56:113–117

    PubMed  Article  CAS  Google Scholar 

  23. Rorsman P, Salehi SA, Abdulkader F, Braun M, Macdonald PE (2008) KATP-channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab 19:277–284

    PubMed  Article  CAS  Google Scholar 

  24. Light PE, Wallace CH, Dyck JR (2003) Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Circulation 107:1962–1965

    PubMed  Article  CAS  Google Scholar 

  25. Wang CZ, Wang Y, Di A et al (2005) 5-Amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by KATP channel-dependent and -independent pathways. Biochem Biophys Res Commun 330:1073–1079

    PubMed  Article  CAS  Google Scholar 

  26. Alzamora R, Gong F, Rondanino C et al (2010) AMP-activated protein kinase inhibits KCNQ1 channels through regulation of the ubiquitin ligase Nedd4-2 in renal epithelial cells. Am J Physiol Renal Physiol 299:F1308–F1319

    Google Scholar 

  27. Evans AM, Hardie DG, Peers C et al (2009) Ion channel regulation by AMPK: the route of hypoxia-response coupling in the carotid body and pulmonary artery. Ann N Y Acad Sci 1177:89–100

    PubMed  Article  CAS  Google Scholar 

  28. Dallas ML, Scragg JL, Wyatt CN et al (2009) Modulation of O2 sensitive K+ channels by AMP-activated protein kinase. Adv Exp Med Biol 648:57–63

    PubMed  Article  CAS  Google Scholar 

  29. Ramracheya R, Ward C, Shigeto M et al (2010) Membrane potential-dependent inactivation of voltage-gated ion channels in alpha-cells inhibits glucagon secretion from human islets. Diabetes 59:2198–2208

    PubMed  Article  CAS  Google Scholar 

  30. Dunning BE, Foley JE, Ahren B (2005) Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 48:1700–1713

    PubMed  Article  CAS  Google Scholar 

Download references


Research in the authors’ laboratories is supported by operating grants from the Canadian Institutes of Health Research to P. E. MacDonald and P. Rorsman and from the National Science and Engineering Council of Canada to P. E. MacDonald. P. E. MacDonald holds scholarships from the Canadian Diabetes Association and Alberta Innovates—Health Solutions, and the Canada Research Chair in Islet Biology. P. Rorsman holds the Canada Excellence Research Chair in Diabetes.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Author information

Authors and Affiliations


Corresponding author

Correspondence to P. E. MacDonald.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

MacDonald, P.E., Rorsman, P. Per-arnt-sim (PAS) domain kinase (PASK) as a regulator of glucagon secretion. Diabetologia 54, 719–721 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Alpha cells
  • Glucagon
  • Hypoglycaemia
  • Islets of langerhans
  • Metabolism
  • Paracrine
  • PASK
  • Signalling
  • Type 2 diabetes