Newcastle University

Roles and Responsibilities

Principal Investigator: The Research group comprises three postdoctoral fellows, one research associate and four postgraduate students.

Qualifications

D.Sc. Oxon, 2003
D.Phil. Oxon, 1981
M.Sc. University of Malta, 1978
B.Sc. University of Malta, 1977

Previous Positions

1978 - 81: Commonwealth Scholar, University of Oxford
1981 - 82: Postdoctoral Fellow, State University of Utrecht
1982 - 86: Postdoctoral Fellow, University of Newcastle
1986 - 91: Lecturer, University of Newcastle
1991 - 94: Senior Lecturer, University of Newcastle
1994 - 03: Reader, University of Newcastle

Memberships

Diabetes UK,
European Association for the Study of Diabetes,
American Diabetes Association,
Biochemical Society

Research Interests

Liver biochemistry, glucose and glycogen metabolism, regulation by insulin and neurotransmitters; regulation of glucokinase and glycogen phosphorylase, application of metabolic control analysis, metabolite control of gene expression.

Other Expertise

Mechanism of action of anti-hyperglycaemic compounds and development of in vitro methods for screening mode of action.

Future Research

Mechanisms of hepatic insulin resistance

Research Roles

Principal Investigator on two Project Grants (MRC and Diabetes UK) and three PhD studentships.

Funding

Current Research Funding is from:
The Medical Research Council
Diabetes UK

Undergraduate Teaching

MBBS Stage I, NME2
MBBS, Accelerator Course (Case 8 and Case 18)

Postgraduate Teaching

MRES

• Arden C, Trainer A, De La Iglesia N, Scougall KT, Gloyn AL, Lange AJ, Shaw J, Matschinsky FM, Agius L. Cell biology assessment of glucokinase mutations V62M and G72R in pancreatic β-cells: Evidence for cellular instability of catalytic activity. Diabetes 2007, 56(7), 1773-1782.
• Brocklehurst KJ, Payne VA, Davies RA, Carroll D, Vertigan HL, Wightman HJ, Aiston S, Waddell ID, Leighton B, Coghlan MP, Agius L. Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators. Diabetes 2004, 53(3), 535-541.
• Green AR, Aiston S, Greenberg CC, Freeman S, Poucher SM, Brady MJ, Agius L. The glycogenic action of protein targeting to glycogen in hepatocytes involves multiple mechanisms including phosphorylase inactivation and glycogen synthase translocation. Journal of Biological Chemistry 2004, 279(45), 46474-46482.
• Payne VA, Arden C, Wu C, Lange AJ, Agius L. Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes. Diabetes 2005, 54(7), 1949-1957.
• Hampson LJ, Agius L. Increased potency and efficacy of combined phosphorylase inactivation and glucokinase activation in control of hepatocyte glycogen metabolism. Diabetes 2005, 54(3), 617-623.
• Aiston S, Hampson L, Gomez-Foix AM, Guinovart JJ, Agius L. Hepatic glycogen synthesis is highly sensitive to phosphorylase activity: Evidence from metabolic control analysis. Journal of Biological Chemistry 2001, 276(26), 23858-23866.
• Hampson LJ, Mackin P, Agius L. Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs. Diabetologia 2007, 50(8), 1743-1751.
• Payne VA, Arden C, Lange AJ, Agius L. Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zucker fa/fa rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology 2007, 293(2), R618-R625.
• Hampson LJ, Arden C, Agius L, Ganotidis M, Kosmopoulou MN, Tiraidis C, Elemes Y, Sakarellos C, Leonidas DD, Oikonomakos NG. Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site. Bioorganic and Medicinal Chemistry 2006, 14(23), 7835-7845.
• Arden C, Baltrusch S, Agius L. Glucokinase regulatory protein is associated with mitochondria in hepatocytes. FEBS Letters 2006, 580(8), 2065-2070.
• Oikonomakos NG, Tiraidis C, Leonidas DD, Zographos SE, Kristiansen M, Jessen CU, Norskov-Lauritsen L, Agius L. Iminosugars as potential inhibitors of glycogenolysis: Structural insights into the molecular basis of glycogen phosphorylase inhibition. Journal of Medicinal Chemistry 2006, 49(19), 5687-5701.
• Arden C, Green AR, Hampson LJ, Aiston S, Harndahl L, Greenberg CC, Brady MJ, Freeman S, Poucher SM, Agius L. Increased sensitivity of glycogen synthesis to phosphorylase-a and impaired expression of the glycogen-targeting protein R6 in hepatocytes from insulin-resistant Zucker fa/fa rats. FEBS Journal 2006, 273(9), 1989-1999.
• Harndahl L, Schmoll D, Herling AW, Agius L. The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism. FEBS Journal 2006, 273(2), 336-346.
• Aiston S, Hampson LJ, Arden C, Iynedjian PB, Agius L. The role of protein kinase B/Akt in insulin-induced inactivation of phosphorylase in rat hepatocytes. Diabetologia 2006, 49(1), 174-182.
• Brocklehurst KJ, Davies RA, Agius L. Differences in regulatory properties between human and rat glucokinase regulatory protein. Biochemical Journal 2004, 378(2), 693-697.
• Arden C, Harboottle A, Baltrusch S, Tiedge M, Agius L. Glucokinase is an integral component of the insulin granules in glucose-responsive insulin secretory cells and does not translocate during glucose stimulation. Diabetes 2004, 53(9), 2346-2352.
• Aiston S, Green A, Mukhtar M, Agius L. Glucose 6-phosphate causes translocation of phosphorylase in hepatocytes and inactivates the enzyme synergistically with glucose. Biochemical Journal 2004, 377(1), 195-204.
• Aiston S, Andersen B, Agius L. Glucose 6-phosphate regulates hepatic glycogenolysis through inactivation of phosphorylase. Diabetes 2003, 52(6), 1333-1339.
• Aiston S, Coghlan MP, Agius L. Inactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesis. European Journal of Biochemistry 2003, 270(13), 2773-2781.
• Tavridou A, Agius L. Phosphorylase regulates the association of glycogen synthase with a proteoglycogen substrate in hepatocytes. FEBS Letters 2003, 551(1-3), 87-91.
• W. Lowes, M. Walker, K. Alberti and L. Agius. Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis. Biochimica Et Biophysica Acta-General Subjects 1998, 1379, 134-142.
• G. H. Thoresen, T. K. Guren, D. Sandnes, M. Peak, L. Agius and T. Christoffersen. Response to transforming growth factor or (TGF alpha) and epidermal growth factor (EGF) in hepatocytes: Lower EGF receptor affinity of TGF alpha is associated with more sustained activation of p42/p44 mitogen-activated protein kinase and greater efficacy in stimulation of DNA synthesis. Journal of Cellular Physiology 1998, 175, 10-18.
• L. Agius. The physiological role of glucokinase binding and translocation in hepatocytes. Advances in Enzyme Regulation, Vol 38 1998, 38, 303-331.
• L. Agius. Involvement of glucokinase translocation in the mechanism by which resorcinol inhibits glycolysis in hepatocytes. Biochemical Journal 1997, 325, 667-673.
• L. Agius, M. Peak, C. B. Newgard, A. M. GomezFoix and J. J. Guinovart. Evidence for a role of glucose-induced translocation of glucokinase in the control of hepatic glycogen synthesis. Journal of Biological Chemistry 1996, 271, 30479-30486.
• L. Agius. Substrate modulation at aldolase B binding in hepatocytes. Biochemical Journal 1996, 315, 651-658.
• Petrie JL, Al-Oanzi ZH, Arden C, Tudhope SJ, Mann J, Kieswich J, Yaqoob MM, Towle HC, Agius L. Glucose induces protein targeting to glycogen in hepatocytes by fructose 2,6-bisphosphate-mediated recruitment of MondoA to the promoter. Molecular and Cellular Biology 2013, 33(4), 725-738.
• Agius L. High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload. Biochemical Pharmacology 2013, 85(3), 306-312.
• Bechmann LP, Vetter D, Ishida J, Hannivoort RA, Lang UE, Kocabayoglu P, Fiel MI, Muñoz U, Patman GL, Ge F, Yakar S, Li X, Agius L, Lee YM, Zhang W, Hui KY, Televantou D, Schwartz GJ, Leroith D, Berk PD, Nagai R, Suzuki T, Reeves HL, Friedman SL. Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. Journal of Hepatology 2013, 58(5), 1000-1006.
• Tudhope SJ, Wang CC, Petrie JL, Potts L, Malcomson F, Kieswich J, Yaqoob MM, Arden C, Hampson LJ, Agius L. A Novel Mechanism for Regulating Hepatic Glycogen Synthesis Involving Serotonin and Cyclin-Dependent Kinase-5. Diabetes 2012, 61(1), 49-60.
• Agius L. Comment on: Stefanovski et al. Estimating Hepatic Glucokinase Activity Using a Simple Model of Lactate Kinetics. Diabetes Care 2012;35: 1015-1020. Diabetes Care 2012, 35(12), E90-E90.
• Arden C, Tudhope SJ, Petrie JL, Al-Oanzi ZH, Cullen KS, Lange AJ, Towle HC, Agius L. Fructose 2,6-bisphosphate is essential for glucose-regulated genetranscription of glucose-6-phosphatase and other ChREBP target genes inhepatocytes. Biochemical Journal 2012, 443(1), 111-123.
• Marin de Mas I, Selivanov VA, Marin S, Roca J, Oresic M, Agius L, Cascante M. Compartmentation of glycogen metabolism revealed from 13C isotopologuedistributions. BMC Systems Biology 2011, 5(1), 175.
• Arden C, Petrie JL, Tudhope SJ, Al-Oanzi Z, Claydon AJ, Beynon RJ, Towle HC, Agius L. Elevated glucose represses liver glucokinase and induces its regulatory protein to safeguard hepatic phosphate homeostasis. Diabetes 2011, 60(12), 3110-3120.
• Cullen KS, Matschinsky FM, Agius L, Arden C. Susceptibility of Glucokinase-MODY Mutants to Inactivation by Oxidative Stress in Pancreatic β-Cells. Diabetes 2011, 60(12), 3175-3185.
• Bechmann LP, Vetter D, Hannivoort RA, Patman G, Lee UE, Fiel MI, Agius L, Reeves H, Friedman SL. Liver-specific deletion of KLF6 uncovers novel transcriptional pathways linked to lipid and glucose homeostasis. In: 61st Annual Meeting of the American Association for the Study of Liver Diseases. 2010, Boston, MA: Hepatology: Wiley-Blackwell.
• Latsis T, Andersen B, Agius L. Diverse effects of two allosteric inhibitors on the phosphorylation state of glycogen phosphorylase in hepatocytes. Biochemical Journal 2002, 368, 309-316.
• Agius L, Centelles J, Cascante M. Multiple glucose 6-phosphate pools or channelling of flux in diverse pathways?. In: Biochemical Society Transactions: Meeting on High-Throughput Screening - The Way Ahead. 2002, Bedford, UK: Portland Press Ltd.
• De Atauri P, Acerenza L, Kholodenko BN, De La Iglesia N, Guinovart JJ, Agius L, Cascante M. Occurrence of paradoxical or sustained control by an enzyme when overexpressed: Necessary conditions and experimental evidence with regard to hepatic glucokinase. Biochemical Journal 2001, 355(3), 787-793.
• Aiston S, Peak M, Agius L. Impaired glycogen synthesis in hepatocytes from Zucker fatty fa/fa rats: The role of increased phosphorylase activity. Diabetologia 2000, 43(5), 589-597.
• Agius L, Stubbs M. Investigation of the mechanism by which glucose analogues cause translocation of glucokinase in hepatocytes: Evidence for two glucose binding sites. Biochemical Journal 2000, 346(2), 413-421.
• Stubbs M, Aiston S, Agius L. Subcellular localization, mobility, and kinetic activity of glucokinase in glucose-responsive insulin-secreting cells. Diabetes 2000, 49(12), 2048-2055.
• Agius L, Aiston S, Newgard CB. The control strength of glucokinase in hepatocytes: A predictor of metabolic defects in maturity onset diabetes of the young, type 2. In: NATO Advanced Research Workshop on Technological and Medical Implications of metabolic Control Analysis. 2000, Visegrad, Hungary: Springer.
• De La Iglesia N, Mukhtar M, Seoane J, Guinovart JJ, Agius L. The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. Journal of Biological Chemistry 2000, 275(14), 10597-10603.
• Cascante M, Centelles JJ, Agius L. Use of α-toxin from Staphylococcus aureus to test for channelling of intermediates of glycolysis between glucokinase and aldolase in hepatocytes. Biochemical Journal 2000, 352(3), 899-905.
• Mukhtar M, Stubbs M, Agius L. Evidence for glucose and sorbitol-induced nuclear export of glucokinase regulatory protein in hepatocytes. FEBS LETTERS 1999, 462(3), 453-458.
• Aiston S, Trinh KY, Lange AJ, Newgard CB, Agius L. Glucose-6-phosphatase overexpression lowers glucose 6-phosphate and inhibits glycogen synthesis and glycolysis in hepatocytes without affecting glucokinase translocation. Evidence against feedback inhibition of glucokinase. Journal of Biological Chemistry 1999, 274(35), 24559-24566.
• Dixon M, Agius L, Yeaman SJ, Day CP. Inhibition of rat hepatocyte proliferation by transforming growth factor beta and glucagon is associated with inhibition of ERK2 and p70 S6 kinase. Hepatology 1999, 29(5), 1418-1424.
• Aiston S, Agius L. Leptin enhances glycogen storage in hepatocytes by inhibition of phosphorylase and exerts an additive effect with insulin. Diabetes 1999, 48(1), 15-20.
• Agius L. The role of glucokinase translocation in the hepatocyte in the control of glucose metabolism. In: FASEB Journal. 1999, Federation of American Societies for Experimental Biology.
• Agius L. The hepatocyte cytoskeleton. Biochemical, physiological, and pathological aspects. In: John E. Hesketh and Ian F. Pryme, ed. Cytoskeleton in Specialized Tissues and in Pathological States. London: JAI Press, 1996, pp.71-106.