1932

Abstract

Liver glucose metabolism is dependent on glucokinase activity. Glucokinase expression is transcriptionally regulated by hormones and metabolites of glucose, and glucokinase activity is dependent on reversible binding of glucokinase to a specific inhibitor protein, glucokinase regulatory protein (GKRP), and to other binding proteins such as 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK2/FBP2), which functions as an activator. Glucokinase is inhibited in the postabsorptive state by sequestration in the nucleus bound to GKRP, and it is activated postprandially by portal hyperglycemia and fructose through dissociation from GKRP, translocation to the cytoplasm, and binding to PFK2/FBP2. Glucagon dissociates this interaction, promoting translocation back to the nucleus. In humans, changes in glucokinase expression and activity are associated with poorly controlled type 2 diabetes and with nonalcoholic fatty liver disease, and a common variant of GKRP with altered binding affinity for glucokinase is associated with increased blood and liver lipids and other metabolic traits that implicate a role for GKRP in maintaining intrahepatic metabolite homeostasis.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-nutr-071715-051145
2016-07-17
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/nutr/36/1/annurev-nutr-071715-051145.html?itemId=/content/journals/10.1146/annurev-nutr-071715-051145&mimeType=html&fmt=ahah

Literature Cited

  1. Agius L. 1.  1994. Control of glucokinase translocation in rat hepatocytes by sorbitol and the cytosolic redox state. Biochem. J. 298:237–43 [Google Scholar]
  2. Agius L. 2.  1997. Involvement of glucokinase translocation in the mechanism by which resorcinol inhibits glycolysis in hepatocytes. Biochem. J. 325:667–73 [Google Scholar]
  3. Agius L. 3.  2008. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem. J. 414:1–18 [Google Scholar]
  4. Agius L. 4.  2013. High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload. Biochem. Pharmacol. 85:306–12 [Google Scholar]
  5. Agius L. 5.  2015. Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein. Proc. Nutr. Soc. 12:1–9 [Google Scholar]
  6. Agius L, Peak M. 6.  1993. Intracellular binding of glucokinase in hepatocytes and translocation by glucose, fructose and insulin. Biochem. J. 296:785–96 [Google Scholar]
  7. Agius L, Peak M, Newgard CB, Gomez-Foix AM, Guinovart JJ. 7.  1996. Evidence for a role of glucose-induced translocation of glucokinase in the control of hepatic glycogen synthesis. J. Biol. Chem. 271:30479–86 [Google Scholar]
  8. Agius L, Stubbs M. 8.  2000. Investigation of the mechanism by which glucose analogues cause translocation of glucokinase in hepatocytes: evidence for two glucose binding sites. Biochem. J. 346:413–21 [Google Scholar]
  9. Aiston S, Trinh KY, Lange AJ, Newgard CB, Agius L. 9.  1999. 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. J. Biol. Chem. 274:24559–66 [Google Scholar]
  10. Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJ. 10.  1997. Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 272:31515–24 [Google Scholar]
  11. Arden C, Petrie JL, Tudhope SJ, Al-Oanzi Z, Claydon AJ. 11.  et al. 2011. Elevated glucose represses liver glucokinase and induces its regulatory protein to safeguard hepatic phosphate homeostasis. Diabetes 60:3110–20 [Google Scholar]
  12. Arden C, Tudhope SJ, Petrie JL, Al-Oanzi ZH, Cullen KS. 12.  et al. 2012. Fructose 2,6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes. Biochem. J. 443:111–23 [Google Scholar]
  13. Baltrusch S, Lenzen S, Okar DA, Lange AJ, Tiedge M. 13.  2001. Characterization of glucokinase-binding protein epitopes by a phage-displayed peptide library. Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase as a novel interaction partner. J. Biol. Chem. 276:43915–23 [Google Scholar]
  14. Baltrusch S, Schmitt H, Brix A, Langer S, Lenzen S. 14.  2012. Additive activation of glucokinase by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and the chemical activator LY2121260. Biochem. Pharmacol. 83:1300–6 [Google Scholar]
  15. Baraille F, Planchais J, Dentin R, Guilmeau S, Postic C. 15.  2015. Integration of ChREBP-mediated glucose sensing into whole body metabolism. Physiology (Bethesda) 30:428–37 [Google Scholar]
  16. Bécard D, Hainault I, Azzout-Marniche D, Bertry-Coussot L, Ferré P, Foufelle F. 16.  2001. Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice. Diabetes 50:2425–30 [Google Scholar]
  17. Bechmann LP, Gastaldelli A, Vetter D, Patman GL, Pascoe L. 17.  et al. 2012. Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease. Hepatology 55:1083–93 [Google Scholar]
  18. Beck T, Miller BG. 18.  2013. Structural basis for regulation of human glucokinase by glucokinase regulatory protein. Biochemistry 52:6232–39 [Google Scholar]
  19. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR. 19.  et al. 2009. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 18:4081–88 [Google Scholar]
  20. Bowler JM, Hervert KL, Kearley ML, Miller BG. 20.  2013. Small-molecule allosteric activation of human glucokinase in the absence of glucose. ACS Med. Chem. Lett. 4:7580–84 [Google Scholar]
  21. Brichard SM, Henquin JC, Girard J. 21.  1993. Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism. Diabetologia 36:292–98 [Google Scholar]
  22. Brocklehurst KJ, Davies RA, Agius L. 22.  2004. Differences in regulatory properties between human and rat glucokinase regulatory protein. Biochem. J. 378:693–97 [Google Scholar]
  23. Brocklehurst KJ, Payne VA, Davies RA, Carroll D, Vertigan HL. 23.  et al. 2004. Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. Diabetes 53:535–41 [Google Scholar]
  24. Brown KS, Kalinowski SS, Megill JR, Durham SK, Mookhtiar KA. 24.  1997. Glucokinase regulatory protein may interact with glucokinase in the hepatocyte nucleus. Diabetes 46:179–86 [Google Scholar]
  25. Caron A, Richard D, Laplante M. 25.  2015. The roles of mTOR complexes in lipid metabolism. Annu. Rev. Nutr. 35:321–48 [Google Scholar]
  26. Choi JM, Seo MH, Kyeong HH, Kim E, Kim HS. 26.  2013. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. PNAS 110:10171–76 [Google Scholar]
  27. Chu CA, Fujimoto Y, Igawa K, Grimsby J, Grippo JF. 27.  et al. 2004. Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats. Am. J. Physiol. Gastrointest. Liver Physiol. 286:G627–34 [Google Scholar]
  28. Coate KC, Kraft G, Moore MC, Smith MS, Ramnanan C. 28.  et al. 2014. Hepatic glucose uptake and disposition during short-term high-fat versus high-fructose feeding. Am. J. Physiol. Endocrinol. Metab. 307:E151–60 [Google Scholar]
  29. Cullen KS, Al-Oanzi ZH, O'Harte FP, Agius L, Arden C. 29.  2014. Glucagon induces translocation of glucokinase from the cytoplasm to the nucleus of hepatocytes by transfer between 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2 and the glucokinase regulatory protein. Biochim. Biophys. Acta 1843:1123–34 [Google Scholar]
  30. Dai W, Panserat S, Terrier F, Seiliez I, Skiba-Cassy S. 30.  2014. Acute rapamycin treatment improved glucose tolerance through inhibition of hepatic gluconeogenesis in rainbow trout (Oncorhynchus mykiss). Am. J. Physiol. Regul. Integr. Comp. Physiol. 307:R1231–38 [Google Scholar]
  31. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S. 31.  et al. 2003. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424:952–56 [Google Scholar]
  32. Decaux JF, Juanes M, Bossard P, Girard J. 32.  1997. Effects of triiodothyronine and retinoic acid on glucokinase gene expression in neonatal rat hepatocytes. Mol. Cell Endocrinol. 130:61–67 [Google Scholar]
  33. de la Iglesia N, Mukhtar M, Seoane J, Guinovart JJ, Agius L. 33.  2000. The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. J. Biol. Chem. 275:10597–603 [Google Scholar]
  34. Detheux M, Vandercammen A, Van Schaftingen E. 34.  1991. Effectors of the regulatory protein acting on liver glucokinase: a kinetic investigation. Eur. J. Biochem. 200:553–61 [Google Scholar]
  35. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI. 35.  et al. 2010. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39:171–83 [Google Scholar]
  36. Farrelly D, Brown KS, Tieman A, Ren J, Lira SA. 36.  et al. 1999. Mice mutant for glucokinase regulatory protein exhibit decreased liver glucokinase: a sequestration mechanism in metabolic regulation. PNAS 96:14511–16 [Google Scholar]
  37. Fernández-Novell JM, Castel S, Bellido D, Ferrer JC, Vilaró S, Guinovart JJ. 37.  1999. Intracellular distribution of hepatic glucokinase and glucokinase regulatory protein during the fasted to refed transition in rats. FEBS Lett. 459:211–14 [Google Scholar]
  38. Fleischmann M, Iynedjian PB. 38.  2000. Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem. J. 349:13–17 [Google Scholar]
  39. Foretz M, Guichard C, Ferré P, Foufelle F. 39.  1996. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. PNAS 96:12737–42 [Google Scholar]
  40. Francini F, Massa ML, Polo MP, Villagarcía H, Castro MC, Gagliardino JJ. 40.  2015. Control of liver glucokinase activity: a potential new target for incretin hormones?. Peptides 74:57–63 [Google Scholar]
  41. Futamura M, Hosaka H, Kadotani A, Shimazaki H, Sasaki K. 41.  et al. 2006. An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. J. Biol. Chem. 281:37668–74 [Google Scholar]
  42. Ganjam GK, Dimova EY, Unterman TG, Kietzmann T. 42.  2009. FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol. J. Biol. Chem. 284:30783–97 [Google Scholar]
  43. Giménez-Cassina A, Garcia-Haro L, Choi CS, Osundiji MA, Lane EA. 43.  et al. 2014. Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab. 19:272–84 [Google Scholar]
  44. Grefhorst A, Schreurs M, Oosterveer MH, Cortés VA, Havinga R. 44.  et al. 2010. Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1. Biochem. J. 432:249–54 [Google Scholar]
  45. Gregori C, Guillet-Deniau I, Girard J, Decaux JF, Pichard AL. 45.  2006. Insulin regulation of glucokinase gene expression: evidence against a role for sterol regulatory element binding protein 1 in primary hepatocytes. FEBS Lett. 580:410–41 [Google Scholar]
  46. Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM. 46.  et al. 2000. Characterization of glucokinase regulatory protein-deficient mice. J. Biol. Chem. 275:7826–31 [Google Scholar]
  47. Guigas B, Bertrand L, Taleux N, Foretz M, Wiernsperger N. 47.  et al. 2006. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes 55:865–74 [Google Scholar]
  48. Haeusler RA, Camastra S, Astiarraga B, Nannipieri M, Anselmino M, Ferrannini E. 48.  2014. Decreased expression of hepatic glucokinase in type 2 diabetes. Mol. Metab. 4:222–26 [Google Scholar]
  49. Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C. 49.  et al. 2012. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 15:725–38 [Google Scholar]
  50. Hansmannel F, Mordier S, Iynedjian PB. 50.  2006. Insulin induction of glucokinase and fatty acid synthase in hepatocytes: analysis of the roles of sterol-regulatory-element-binding protein-1c and liver X receptor. Biochem. J. 399:275–83 [Google Scholar]
  51. Härndahl L, Schmoll D, Herling AW, Agius L. 51.  2006. The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism. FEBS J. 273:336–46 [Google Scholar]
  52. Hashimoto K, Matsumoto S, Yamada M, Satoh T, Mori M. 52.  2007. Liver X receptor-α gene expression is positively regulated by thyroid hormone. Endocrinology 148:4667–75 [Google Scholar]
  53. Hegarty BD, Bobard A, Hainault I, Ferré P, Bossard P, Foufelle F. 53.  2005. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c. PNAS 102:791–96 [Google Scholar]
  54. Hirota K, Sakamaki J, Ishida J, Shimamoto Y, Nishihara S. 54.  et al. 2008. A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding. J. Biol. Chem. 283:32432–41 [Google Scholar]
  55. Howell JJ, Ricoult SJ, Ben-Sahra I, Manning BD. 55.  2013. A growing role for mTOR in promoting anabolic metabolism. Biochem. Soc. Trans. 41:906–12 [Google Scholar]
  56. Iynedjian PB. 56.  2009. Molecular physiology of mammalian glucokinase. Cell Mol. Life Sci. 66:27–42 [Google Scholar]
  57. Iynedjian PB, Gjinovci A, Renold AE. 57.  1988. Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats. J. Biol. Chem. 263:740–44 [Google Scholar]
  58. Iynedjian PB, Jotterand D, Nouspikel T, Asfari M, Pilot PR. 58.  1989. Transcriptional induction of glucokinase gene by insulin in cultured liver cells and its repression by the glucagon-cAMP system. J. Biol. Chem. 264:21824–29 [Google Scholar]
  59. Iynedjian PB, Roth RA, Fleischmann M, Gjinovci A. 59.  2000. Activation of protein kinase B/cAkt in hepatocytes is sufficient for the induction of expression of the gene encoding glucokinase. Biochem. J. 351:621–27 [Google Scholar]
  60. Jetton TL, Shiota M, Knobel SM, Piston DW, Cherrington AD, Magnuson MA. 60.  2001. Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition. Int. J. Exp. Diabetes Res. 2:173–86 [Google Scholar]
  61. Jin L, Guo T, Li Z, Lei Z, Li H. 61.  et al. 2015. Role of glucokinase in the subcellular localization of glucokinase regulatory protein. Int. J. Mol. Sci. 16:7377–93 [Google Scholar]
  62. Jo SH, Kim MY, Park JM, Kim TH, Ahn YH. 62.  2013. Txnip contributes to impaired glucose tolerance by upregulating the expression of genes involved in hepatic gluconeogenesis in mice. Diabetologia 56:2723–32 [Google Scholar]
  63. Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y. 63.  2004. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 12:429–38 [Google Scholar]
  64. Kaminski MT, Schultz J, Waterstradt R, Tiedge M, Lenzen S, Baltrusch S. 64.  2014. Glucose-induced dissociation of glucokinase from its regulatory protein in the nucleus of hepatocytes prior to nuclear export. Biochim. Biophys. Acta 1843:554–64 [Google Scholar]
  65. Kim MY, Jo SH, Park JM, Kim TH, Im SS, Ahn YH. 65.  2013. Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver. Diabetologia 56:635–43 [Google Scholar]
  66. Kim SY, Kim HI, Kim TH, Im SS, Park SK. 66.  et al. 2004. SREBP-1c mediates the insulin-dependent hepatic glucokinase expression. J. Biol. Chem. 279:30823–29 [Google Scholar]
  67. Kim SY, Kim HI, Park SK, Im SS, Li T. 67.  et al. 2004. Liver glucokinase can be activated by peroxisome proliferator–activated receptor-γ. Diabetes 53:Suppl. 1S66–70 [Google Scholar]
  68. Kim TH, Kim H, Park JM, Im SS, Bae JS. 68.  et al. 2009. Interrelationship between liver X receptor α, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor γ, and small heterodimer partner in the transcriptional regulation of glucokinase gene expression in liver. J. Biol. Chem. 284:15071–83 [Google Scholar]
  69. Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S. 69.  et al. 2003. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. PNAS 100:5419–24 [Google Scholar]
  70. Langer S, Kaminski MT, Lenzen S, Baltrusch S. 70.  2010. Endogenous activation of glucokinase by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is glucose dependent. Mol. Endocrinol. 24:1988–97 [Google Scholar]
  71. Larion M, Miller BG. 71.  2012. Homotropic allosteric regulation in monomeric mammalian glucokinase. Arch. Biochem. Biophys. 519:103–11 [Google Scholar]
  72. Lee YK, Choi YH, Chua S, Park YJ, Moore DD. 72.  2006. Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation. J. Biol. Chem. 281:7850–55 [Google Scholar]
  73. Li S, Brown MS, Goldstein JL. 73.  2010. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. PNAS 107:3441–46 [Google Scholar]
  74. Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, Brown MS. 74.  2002. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J. Biol. Chem. 277:9520–28 [Google Scholar]
  75. Lloyd DJ, St Jean DJ Jr, Kurzeja RJ, Wahl RC, Michelsen K. 75.  et al. 2013. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature 504:437–40 [Google Scholar]
  76. Ma L, Robinson LN, Towle HC. 76.  2006. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J. Biol. Chem. 281:28721–30 [Google Scholar]
  77. Massillon D. 77.  2001. Regulation of the glucose-6-phosphatase gene by glucose occurs by transcriptional and post-transcriptional mechanisms. Differential effect of glucose and xylitol. J. Biol. Chem. 276:4055–62 [Google Scholar]
  78. Massillon D, Chen W, Barzilai N, Prus-Wertheimer D, Hawkins M. 78.  et al. 1998. Carbon flux via the pentose phosphate pathway regulates the hepatic expression of the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase genes in conscious rats. J. Biol. Chem. 273:228–34 [Google Scholar]
  79. Martinez JA, Larion M, Conejo MS, Porter CM, Miller BG. 79.  2014. Role of connecting loop I in catalysis and allosteric regulation of human glucokinase. Protein Sci. 23:915–22 [Google Scholar]
  80. Matschinsky FM. 80.  2013. GKAs for diabetes therapy: Why no clinically useful drug after two decades of trying?. Trends Pharmacol. Sci. 34:90–99 [Google Scholar]
  81. Matschinsky FM, Magnuson MA, Zelent D, Jetton TL, Doliba N. 81.  et al. 2006. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55:1–12 [Google Scholar]
  82. Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K. 82.  et al. 2002. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes 51:1672–80 [Google Scholar]
  83. Minderop RH, Hoeppner W, Seitz HJ. 83.  1987. Regulation of hepatic glucokinase gene expression. Role of carbohydrates, and glucocorticoid and thyroid hormones. Eur. J. Biochem. 164:181–87 [Google Scholar]
  84. Moore MC, Coate KC, Winnick JJ, An Z, Cherrington AD. 84.  2012. Regulation of hepatic glucose uptake and storage in vivo. Adv. Nutr. 3:286–94 [Google Scholar]
  85. Mukhtar MH, Payne VA, Arden C, Harbottle A, Khan S. 85.  et al. 2008. Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294:R766–74 [Google Scholar]
  86. Mukhtar M, Stubbs M, Agius L. 86.  1999. Evidence for glucose and sorbitol-induced nuclear export of glucokinase regulatory protein in hepatocytes. FEBS Lett. 462:453–58 [Google Scholar]
  87. Nakamura A, Terauchi Y. 87.  2015. Present status of clinical deployment of glucokinase activators. J. Diabetes Investig. 6:124–32 [Google Scholar]
  88. Narkewicz MR, Iynedjian PB, Ferre P, Girard J. 88.  1990. Insulin and tri-iodothyronine induce glucokinase mRNA in primary cultures of neonatal rat hepatocytes. Biochem. J. 271:585–89 [Google Scholar]
  89. Nelson JD, LeBoeuf RC, Bomsztyk K. 89.  2011. Direct recruitment of insulin receptor and ERK signaling cascade to insulin-inducible gene loci. Diabetes 60:127–37 [Google Scholar]
  90. Niculescu L, Veiga-da-Cunha M, Van Schaftingen E. 90.  1997. Investigation on the mechanism by which fructose, hexitols and other compounds regulate the translocation of glucokinase in rat hepatocytes. Biochem. J. 321:239–46 [Google Scholar]
  91. Nouspikel T, Iynedjian PB. 91.  1992. Insulin signalling and regulation of glucokinase gene expression in cultured hepatocytes. Eur. J. Biochem. 210:365–73 [Google Scholar]
  92. Ochiai D, Goda N, Hishiki T, Kanai M, Senoo-Matsuda N. 92.  et al. 2011. Disruption of HIF-1α in hepatocytes impairs glucose metabolism in diet-induced obesity mice. Biochem. Biophys. Res. Commun. 415:445–49 [Google Scholar]
  93. Okamoto Y, Ogawa W, Nishizawa A, Inoue H, Teshigawara K. 93.  2007. Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1. Diabetes 56:1000–9 [Google Scholar]
  94. Okar DA, Wu C, Lange AJ. 94.  2004. Regulation of the regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Adv. Enzyme Regul. 44:123–54 [Google Scholar]
  95. Ono H, Shimano H, Katagiri H, Yahagi N, Sakoda H. 95.  et al. 2003. Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. Diabetes 52:2905–13 [Google Scholar]
  96. Oosterveer MH, Mataki C, Yamamoto H, Harach T, Moullan N. 96.  et al. 2012. LRH-1-dependent glucose sensing determines intermediary metabolism in liver. J. Clin. Investig. 122:2817–26 [Google Scholar]
  97. Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D. 97.  et al. 2008. Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57:3112–21 [Google Scholar]
  98. Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G. 98.  et al. 2012. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. PNAS 109:16184–89 [Google Scholar]
  99. Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H. 99.  et al. 2007. TXNIP regulates peripheral glucose metabolism in humans. PLOS Med. 4:e158 [Google Scholar]
  100. Park JM, Kim TH, Jo SH, Kim MY, Ahn YH. 100.  2015. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity. Sci. Rep. 5:17395 [Google Scholar]
  101. Pautsch A, Stadler N, Löhle A, Rist W, Berg A. 101.  et al. 2013. Crystal structure of glucokinase regulatory protein. Biochemistry 52:3523–31 [Google Scholar]
  102. Payne VA, Arden C, Wu C, Lange AJ, Agius L. 102.  2005. Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes. Diabetes 54:1949–57 [Google Scholar]
  103. Peter A, Stefan N, Cegan A, Walenta M, Wagner S. 103.  et al. 2011. Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans. J. Clin. Endocrinol. Metab. 96:E1126–30 [Google Scholar]
  104. Peterson CW, Ayer DE. 104.  2011. An extended Myc network contributes to glucose homeostasis in cancer and diabetes. Front. Biosci. 16:2206–23 (Landmark ed.) [Google Scholar]
  105. Petrie JL, Al-Oanzi ZH, Arden C, Tudhope SJ, Mann J. 105.  et al. 2013. Glucose induces protein targeting to glycogen in hepatocytes by fructose 2,6-bisphosphate-mediated recruitment of MondoA to the promoter. Mol. Cell. Biol. 33:725–38 [Google Scholar]
  106. Petrie JL, Patman GL, Sinha I, Alexander TD, Reeves HL, Agius L. 106.  2013. The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. Am. J. Physiol. Endocrinol. Metab. 305:E1255–65 [Google Scholar]
  107. Postic C, Niswender KD, Decaux JF, Parsa R, Shelton KD. 107.  et al. 1995. Cloning and characterization of the mouse glucokinase gene locus and identification of distal liver-specific DNase I hypersensitive sites. Genomics 29:740–50 [Google Scholar]
  108. Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD. 108.  2011. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes. Metab.Suppl. 1:118–25 [Google Scholar]
  109. Rees MG, Wincovitch S, Schultz J, Waterstradt R, Beer NL. 109.  et al. 2012. Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55:114–22 [Google Scholar]
  110. Ribaux PG, Iynedjian PB. 110.  2003. Analysis of the role of protein kinase B (cAKT) in insulin-dependent induction of glucokinase and sterol regulatory element-binding protein 1 (SREBP1) mRNAs in hepatocytes. Biochem. J. 376:697–705 [Google Scholar]
  111. Rizza RA. 111.  2010. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes 59:2697–707 [Google Scholar]
  112. Romaguera D, Norat T, Wark PA, Vergnaud AC, Schulze MB. 112.  et al. 2013. Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabetologia 56:1520–30 [Google Scholar]
  113. Roth U, Curth K, Unterman TG, Kietzmann T. 113.  2004. The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 279:2623–31 [Google Scholar]
  114. Roth U, Jungermann K, Kietzmann T. 114.  2002. Activation of glucokinase gene expression by hepatic nuclear factor 4α in primary hepatocytes. Biochem. J. 365:223–28 [Google Scholar]
  115. Roth U, Jungermann K, Kietzmann T. 115.  2004. Modulation of glucokinase expression by hypoxia-inducible factor 1 and upstream stimulatory factor 2 in primary rat hepatocytes. Biol. Chem. 385:239–47 [Google Scholar]
  116. Sakamoto E, Seino Y, Fukami A, Mizutani N, Tsunekawa S. 116.  et al. 2012. Ingestion of a moderate high-sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon-like peptide-1 secretion. J. Diabetes Investig. 3:432–40 [Google Scholar]
  117. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI. 117.  et al. 2007. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–36 [Google Scholar]
  118. Shin JS, Torres TP, Catlin RL, Donahue EP, Shiota M. 118.  2007. A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292:R1381–90 [Google Scholar]
  119. Shiota C, Coffey J, Grimsby J, Grippo JF, Magnuson MA. 119.  1999. Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase. J. Biol. Chem. 274:37125–30 [Google Scholar]
  120. Simmgen M, Knauf C, Lopez M, Choudhury AI, Charalambous M. 120.  et al. 2006. Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice. Diabetologia 49:552–61 [Google Scholar]
  121. Stoeckman AK, Towle HC. 121.  2002. The role of SREBP-1c in nutritional regulation of lipogenic enzyme gene expression. J. Biol. Chem. 277:27029–35 [Google Scholar]
  122. Sugiyama Y, Shimura Y, Ikeda H. 122.  1989. Derangement in hepatic enzymes caused by sucrose-drinking and its implication for the development of hyperglycemia in female Wistar fatty rats. Endocrinol. Jpn. 36:245–51 [Google Scholar]
  123. Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH. 123.  et al. 2014. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat. Struct. Mol. Biol. 21:36–42 [Google Scholar]
  124. Tappy L, Dussoix P, Iynedjian P, Henry S, Schneiter P. 124.  1997. Abnormal regulation of hepatic glucose output in maturity-onset diabetes of the young caused by a specific mutation of the glucokinase gene. Diabetes 46:204–8 [Google Scholar]
  125. Towle HC. 125.  2005. Glucose as a regulator of eukaryotic gene transcription. Trends Endocrinol. Metab. 16:489–94 [Google Scholar]
  126. Toyoda Y, Ito Y, Tanigawa K, Miwa I. 126.  2000. Impairment of glucokinase translocation in cultured hepatocytes from OLETF and GK rats, animal models of type 2 diabetes. Arch. Histol. Cytol. 63:243–48 [Google Scholar]
  127. Toyoda Y, Miwa I, Kamiya M, Ogiso S, Nonogaki T. 127.  et al. 1994. Evidence for glucokinase translocation by glucose in rat hepatocytes. Biochem. Biophys. Res. Commun. 204:252–56 [Google Scholar]
  128. Toyoda Y, Miwa I, Satake S, Anai M, Oka Y. 128.  1995. Nuclear location of the regulatory protein of glucokinase in rat liver and translocation of the regulator to the cytoplasm in response to high glucose. Biochem. Biophys. Res. Commun. 215:467–73 [Google Scholar]
  129. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. 129.  2002. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem. 277:27975–81 [Google Scholar]
  130. Ueta K, O'Brien TP, McCoy GA, Kim K, Healey EC. 130.  et al. 2014. Glucotoxicity targets hepatic glucokinase in Zucker diabetic fatty rats, a model of type 2 diabetes associated with obesity. Am. J. Physiol. Endocrinol. Metab. 306:E1225–38 [Google Scholar]
  131. Unger RH, Cherrington AD. 131.  2012. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Investig. 122:4–12 [Google Scholar]
  132. Vandercammen A, Van Schaftingen E. 132.  1991. Competitive inhibition of liver glucokinase by its regulatory protein. Eur. J. Biochem. 200:545–51 [Google Scholar]
  133. Vandercammen A, Van Schaftingen E. 133.  1993. Species and tissue distribution of the regulatory protein of glucokinase. Biochem. J. 294:551–56 [Google Scholar]
  134. van Dijk TH, van der Sluijs FH, Wiegman CH, Baller JF, Gustafson LA. 134.  et al. 2001. Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats. A pharmacological study with the chlorogenic acid derivative S4048. J. Biol. Chem. 276:25727–35 [Google Scholar]
  135. Van Schaftingen E. 135.  1989. A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose1-phosphate. Eur. J. Biochem. 179:179–84 [Google Scholar]
  136. Van Schaftingen E, Veiga-da-Cunha M, Niculescu L. 136.  1997. The regulatory protein of glucokinase. Biochem. Soc. Trans. 25:136–40 [Google Scholar]
  137. Veiga-da-Cunha M, Sokolova T, Opperdoes F, Van Schaftingen E. 137.  2009. Evolution of vertebrate glucokinase regulatory protein from a bacterial N-acetylmuramate 6-phosphate etherase. Biochem. J. 423:323–32 [Google Scholar]
  138. Velho G, Petersen KF, Perseghin G, Hwang JH, Rothman DL. 138.  1996. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J. Clin. Investig. 98:1755–61 [Google Scholar]
  139. Wang ZY, Jin L, Tan H, Irwin DM. 139.  2013. Evolution of hepatic glucose metabolism: liver-specific glucokinase deficiency explained by parallel loss of the gene for glucokinase regulatory protein (GCKR). PLOS ONE 8:e60896 [Google Scholar]
  140. Watanabe F, Furuya E. 140.  2010. Quantitative image analysis reveals that phosphorylation of liver-type isozyme of fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase does not affect nuclear translocation of glucokinase in rat primary hepatocytes. J. Biochem. 148:713–19 [Google Scholar]
  141. Weedon MN, Clark VJ, Qian Y, Ben-Shlomo Y, Timpson N. 141.  et al. 2006. A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses. Am. J. Hum. Genet. 79:991–1001 [Google Scholar]
  142. Whittington AC, Larion M, Bowler JM, Ramsey KM, Brüschweiler R, Miller BG. 142.  2015. Dual allosteric activation mechanisms in monomeric human glucokinase. PNAS 112:11553–58 [Google Scholar]
  143. Xiong X, Tao R, DePinho RA, Dong XC. 143.  2013. Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis. PLOS ONE 8:e74340 [Google Scholar]
  144. Yki-Järvinen H. 144.  2010. Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data. Curr. Opin. Clin. Nutr. Metab. Care 13:709–14 [Google Scholar]
  145. Zain SM, Mohamed Z, Mohamed R. 145.  2015. Common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: a meta-analysis. J. Gastroenterol. Hepatol. 30:21–27 [Google Scholar]
  146. Zelent B, Raimondo A, Barrett A, Buettger CW, Chen P. 146.  et al. 2014. Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence. Biochem. J. 459:551–64 [Google Scholar]
/content/journals/10.1146/annurev-nutr-071715-051145
Loading
/content/journals/10.1146/annurev-nutr-071715-051145
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error