Skip to main content

Advertisement

SpringerLink
Log in

Moving on from GWAS: Functional Studies on the G6PC2 Gene Implicated in the Regulation of Fasting Blood Glucose

  • Genetics (TM Frayling, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Genome-wide association studies (GWAS) have shown that single-nucleotide polymorphisms (SNPs) in G6PC2 are the most important common determinants of variations in fasting blood glucose (FBG) levels. Molecular studies examining the functional impact of these SNPs on G6PC2 gene transcription and splicing suggest that they affect FBG by directly modulating G6PC2 expression. This conclusion is supported by studies on G6pc2 knockout (KO) mice showing that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux and opposing the action of glucokinase. Suppression of G6PC2 activity might, therefore, represent a novel therapy for lowering FBG and the risk of cardiovascular-associated mortality. GWAS and G6pc2 KO mouse studies also suggest that G6PC2 affects other aspects of beta cell function. The evolutionary benefit conferred by G6PC2 remains unclear, but it is unlikely to be related to its ability to modulate FBG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Yaghootkar H, Frayling TM. Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits. Genome Biol. 2013;14(3):203. doi:10.1186/gb-2013-14-3-203.

    Article  PubMed  Google Scholar 

  2. Torres JM, Cox NJ, Philipson LH. Genome wide association studies for diabetes: perspective on results and challenges. Pediatr Diabetes. 2013;14(2):90–6. doi:10.1111/pedi.12015.

    Article  PubMed  CAS  Google Scholar 

  3. Bouatia-Naji N, Rocheleau G, Van Lommel L, Lemaire K, Schuit F, Cavalcanti-Proenca C, et al. A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science. 2008;320(5879):1085–8.

    Article  PubMed  CAS  Google Scholar 

  4. Chen WM, Erdos MR, Jackson AU, Saxena R, Sanna S, Silver KD, et al. Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. J Clin Invest. 2008;118:2620–8.

    PubMed  CAS  Google Scholar 

  5. Soranzo N, Sanna S, Wheeler E, Gieger C, Radke D, Dupuis J, et al. Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways. Diabetes. 2010;59(12):3229–39. doi:10.2337/db10-0502.

    Article  PubMed  CAS  Google Scholar 

  6. El-Sayed Moustafa JS, Froguel P. From obesity genetics to the future of personalized obesity therapy. Endocrinology: Nature reviews; 2013.

    Google Scholar 

  7. Droumaguet C, Balkau B, Simon D, Caces E, Tichet J, Charles MA, et al. Use of HbA1c in predicting progression to diabetes in French men and women: data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). Diabetes Care. 2006;29(7):1619–25. doi:10.2337/dc05-2525.

    Article  PubMed  CAS  Google Scholar 

  8. Abdul-Ghani MA, DeFronzo RA. Plasma glucose concentration and prediction of future risk of type 2 diabetes. Diabetes Care. 2009;32 Suppl 2:S194–8. doi:10.2337/dc09-S309.

    Article  PubMed  CAS  Google Scholar 

  9. Edelman D, Olsen MK, Dudley TK, Harris AC, Oddone EZ. Utility of hemoglobin A1c in predicting diabetes risk. J Gen Intern Med. 2004;19(12):1175–80. doi:10.1111/j.1525-1497.2004.40178.x.

    Article  PubMed  Google Scholar 

  10. Ye J. Mechanisms of insulin resistance in obesity. Front Med. 2013;7(1):14–24. doi:10.1007/s11684-013-0262-6.

    Article  PubMed  Google Scholar 

  11. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22(2):233–40.

    Article  PubMed  CAS  Google Scholar 

  12. Lawes CM, Parag V, Bennett DA, Suh I, Lam TH, Whitlock G, et al. Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care. 2004;27(12):2836–42.

    Article  PubMed  CAS  Google Scholar 

  13. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Arterioscler Thromb Vasc Biol. 2006;26(5):968–76. doi:10.1161/01.ATV.0000216787.85457.f3.

    Article  PubMed  CAS  Google Scholar 

  14. • Abdul-Ghani MA, Stern MP, Lyssenko V, Tuomi T, Groop L, Defronzo RA. Minimal contribution of fasting hyperglycemia to the incidence of type 2 diabetes in subjects with normal 2-h plasma glucose. Diabetes Care. 2010;33(3):557–61. doi:10.2337/dc09-1145. This paper challenges the long held connection between FBG and type 2 diabetes risk.

    Article  PubMed  CAS  Google Scholar 

  15. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22. doi:10.1016/S0140-6736(10)60484-9.

    Article  PubMed  CAS  Google Scholar 

  16. Cecchini KR, Raja Banerjee A, Kim TH. Towards a genome-wide reconstruction of cis-regulatory networks in the human genome. Semin Cell Dev Biol. 2009;20(7):842–8. doi:10.1016/j.semcdb.2009.06.005.

    Article  PubMed  CAS  Google Scholar 

  17. McMurray F, Moir L, Cox RD. From mice to humans. Curr Diab Rep. 2012;12(6):651–8. doi:10.1007/s11892-012-0323-2.

    Article  PubMed  Google Scholar 

  18. Frayling TM, Ong K. Piecing together the FTO jigsaw. Genome Biol. 2011;12(2):104. doi:10.1186/gb-2011-12-2-104.

    Article  PubMed  Google Scholar 

  19. Hansson O, Zhou Y, Renstrom E, Osmark P. Molecular function of TCF7L2: consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes. Curr Diab Rep. 2010;10(6):444–51. doi:10.1007/s11892-010-0149-8.

    Article  PubMed  CAS  Google Scholar 

  20. van de Bunt M, Gloyn AL. From genetic association to molecular mechanism. Curr Diab Rep. 2010;10(6):452–66. doi:10.1007/s11892-010-0150-2.

    Article  PubMed  Google Scholar 

  21. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2008;41:77–81.

    Article  PubMed  Google Scholar 

  22. Reiling E, van 't Riet E, Groenewoud MJ, Welschen LM, van Hove EC, Nijpels G, et al. Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk. Diabetologia. 2009;52:1866–70.

    Article  PubMed  CAS  Google Scholar 

  23. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42(2):105–16.

    Article  PubMed  CAS  Google Scholar 

  24. Hu C, Zhang R, Wang C, Ma X, Wang C, Fang Q, et al. A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population. Diabetologia. 2009;52(3):451–6.

    Article  PubMed  CAS  Google Scholar 

  25. Hu C, Zhang R, Wang C, Yu W, Lu J, Ma X, et al. Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose metabolism and insulin secretion. PLoS One. 2010;5(7):e11761. doi:10.1371/journal.pone.0011761.

    Article  PubMed  Google Scholar 

  26. Tam CH, Ho JS, Wang Y, Lee HM, Lam VK, Germer S, et al. Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects. PLoS One. 2010;5(7):e11428. doi:10.1371/journal.pone.0011428.

    Article  PubMed  Google Scholar 

  27. Wang Y, Martin CC, Oeser JK, Sarkar S, McGuinness OP, Hutton JC, et al. Deletion of the gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen results in a mild metabolic phenotype. Diabetologia. 2007;50:774–8.

    Article  PubMed  CAS  Google Scholar 

  28. • Pound LD, Oeser JK, O'Brien TP, Wang Y, Faulman CJ, Dadi PK, et al. G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes. 2013;62:1547–56. doi:10.2337/db12-1067. This study complements the related GWAS data by demonstrating that G6PC2 directly regulates FBG.

    Article  PubMed  CAS  Google Scholar 

  29. Bonnefond A, Bouatia-Naji N, Simon A, Saint-Martin C, Dechaume A, de Lonlay P, et al. Mutations in G6PC2 do not contribute to monogenic forms of early infancy diabetes and beta cell dysfunction. Diabetologia. 2009;52(5):982–5. doi:10.1007/s00125-009-1299-6.

    Article  PubMed  CAS  Google Scholar 

  30. Grupe A, Hultgren B, Ryan A, Ma YH, Bauer M, Stewart TA. Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. Cell. 1995;83(1):69–78.

    Article  PubMed  CAS  Google Scholar 

  31. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanne-Chantelot C, Ellard S, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30(11):1512–26. doi:10.1002/humu.21110.

    Article  PubMed  CAS  Google Scholar 

  32. Magnuson MA, She P, Shiota M. Gene-altered mice and metabolic flux control. J Biol Chem. 2003;278(35):32485–8.

    Article  PubMed  CAS  Google Scholar 

  33. Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem. 1999;274(1):305–15.

    Article  PubMed  CAS  Google Scholar 

  34. Matschinsky FM. Glucokinase, glucose homeostasis, and diabetes mellitus. Curr Diab Rep. 2005;5(3):171–6.

    Article  PubMed  CAS  Google Scholar 

  35. Mithieux G. New knowledge regarding glucose-6 phosphatase gene and protein and their roles in the regulation of glucose metabolism. Eur J Endocrinol. 1997;136(2):137–45.

    Article  PubMed  CAS  Google Scholar 

  36. Foster JD, Pederson BA, Nordlie RC. Glucose-6-phosphatase structure, regulation, and function: an update. Proc Soc Exp Biol Med. 1997;215(4):314–32.

    Article  PubMed  CAS  Google Scholar 

  37. van de Werve G, Lange A, Newgard C, Mechin MC, Li Y, Berteloot A. New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system. Eur J Biochem. 2000;267(6):1533–49.

    Article  PubMed  Google Scholar 

  38. Van Schaftingen E, Gerin I. The glucose-6-phosphatase system. Biochem J. 2002;362(Pt 3):513–32.

    Article  PubMed  Google Scholar 

  39. Hutton JC, O'Brien RM. The glucose-6-phosphatase catalytic subunit gene family. J Biol Chem. 2009;284:29241–5.

    Article  PubMed  CAS  Google Scholar 

  40. Arden SD, Zahn T, Steegers S, Webb S, Bergman B, O'Brien RM, et al. Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit-related protein. Diabetes. 1999;48(3):531–42.

    Article  PubMed  CAS  Google Scholar 

  41. Ebert DH, Bischof LJ, Streeper RS, Chapman SC, Svitek CA, Goldman JK, et al. Structure and promoter activity of an islet-specific glucose-6- phosphatase catalytic subunit-related gene. Diabetes. 1999;48(3):543–51.

    Article  PubMed  CAS  Google Scholar 

  42. Hutton JC, Eisenbarth GS. A pancreatic beta-cell-specific homolog of glucose-6-phosphatase emerges as a major target of cell-mediated autoimmunity in diabetes. Proc Natl Acad Sci U S A. 2003;100(15):8626–8.

    Article  PubMed  CAS  Google Scholar 

  43. Lieberman SM, Evans AM, Han B, Takaki T, Vinnitskaya Y, Caldwell JA, et al. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci U S A. 2003;100(14):8384–8.

    Article  PubMed  CAS  Google Scholar 

  44. Han B, Serra P, Amrani A, Yamanouchi J, Maree AF, Edelstein-Keshet L, et al. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med. 2005;11(6):645–52.

    Article  PubMed  CAS  Google Scholar 

  45. Mukherjee R, Wagar D, Stephens TA, Lee-Chan E, Singh B. Identification of CD4+ T cell-specific epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein: a novel beta cell autoantigen in type 1 diabetes. J Immunol. 2005;174(9):5306–15.

    PubMed  CAS  Google Scholar 

  46. Yang J, Danke NA, Berger D, Reichstetter S, Reijonen H, Greenbaum C, et al. Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol. 2006;176(5):2781–9.

    PubMed  CAS  Google Scholar 

  47. Jarchum I, Nichol L, Trucco M, Santamaria P, DiLorenzo TP. Identification of novel IGRP epitopes targeted in type 1 diabetes patients. Clin Immunol. 2008;127(3):359–65.

    Article  PubMed  CAS  Google Scholar 

  48. Polychronakos C, Li Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet. 2011;12(11):781–92. doi:10.1038/nrg3069.

    Article  PubMed  CAS  Google Scholar 

  49. Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, et al. A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab. 2012;16(1):122–34. doi:10.1016/j.cmet.2012.06.006.

    Article  PubMed  CAS  Google Scholar 

  50. Baerenwald DA, Bonnefond A, Bouatia-Naji N, Flemming BP, Umunakwe OC, Oeser JK, et al. Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. Diabetologia. 2013;56(6):1306–16. doi:10.1007/s00125-013-2875-3.

    Article  PubMed  CAS  Google Scholar 

  51. Matschinsky FM. Banting lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes. 1996;45(2):223–41.

    Article  PubMed  CAS  Google Scholar 

  52. Iynedjian PB. Molecular physiology of mammalian glucokinase. Cell Mol Life Sci. 2009;66(1):27–42.

    Article  PubMed  CAS  Google Scholar 

  53. Waddell ID, Burchell A. The microsomal glucose-6-phosphatase enzyme of pancreatic islets. Biochem J. 1988;255(2):471–6.

    PubMed  CAS  Google Scholar 

  54. Perales MA, Sener A, Malaisse WJ. Hexose metabolism in pancreatic islets: the glucose-6-phosphatase riddle. Mol Cell Biochem. 1991;101(1):67–71.

    Article  PubMed  CAS  Google Scholar 

  55. Trandaburu T. Fine structural localization of glucose-6-phosphatase activity in the pancreatic islets of two amphibian species (Salamandra salamandra L. and Rana esculenta L.). Acta Histochem. 1977;59(2):246–53.

    Article  PubMed  CAS  Google Scholar 

  56. Sweet IR, Najafi H, Li G, Grodberg J, Matschinsky FM. Measurement and modeling of glucose-6-phosphatase in pancreatic islets. Am J Physiol. 1997;272(4 Pt 1):E696–711.

    PubMed  CAS  Google Scholar 

  57. Martin CC, Bischof LJ, Bergman B, Hornbuckle LA, Hilliker C, Frigeri C, et al. Cloning and characterization of the human and rat Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein (IGRP) genes. J Biol Chem. 2001;276(27):25197–207.

    Article  PubMed  CAS  Google Scholar 

  58. Khan A, Chandramouli V, Ostenson CG, Low H, Landau BR, Efendic S. Glucose cycling in islets from healthy and diabetic rats. Diabetes. 1990;39(4):456–9.

    Article  PubMed  CAS  Google Scholar 

  59. Laybutt DR, Glandt M, Xu G, Ahn YB, Trivedi N, Bonner-Weir S, et al. Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. J Biol Chem. 2003;278(5):2997–3005.

    Article  PubMed  CAS  Google Scholar 

  60. Tokuyama Y, Sturis J, DePaoli AM, Takeda J, Stoffel M, Tang J, et al. Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. Diabetes. 1995;44(12):1447–57.

    Article  PubMed  CAS  Google Scholar 

  61. Pedersen KB, Zhang P, Doumen C, Charbonnet M, Lu D, Newgard CB, et al. The promoter for the gene encoding the catalytic subunit of rat glucose-6-phosphatase contains two distinct glucose-responsive regions. Am J Physiol Endocrinol Metab. 2007;292(3):E788–801. doi:10.1152/ajpendo.00510.2006.

    Article  PubMed  CAS  Google Scholar 

  62. Petrolonis AJ, Yang Q, Tummino PJ, Fish SM, Prack AE, Jain S, et al. Enzymatic characterization of the pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP). J Biol Chem. 2004;279:13976–83.

    Article  PubMed  CAS  Google Scholar 

  63. Ashcroft SJ, Randle PJ. Glucose-6-phosphatase activity of mouse pancreatic islets. Nature. 1968;219(5156):857–8.

    Article  PubMed  CAS  Google Scholar 

  64. Khan A, Chandramouli V, Ostenson CG, Ahren B, Schumann WC, Low H, et al. Evidence for the presence of glucose cycling in pancreatic islets of the ob/ob mouse. J Biol Chem. 1989;264(17):9732–3.

    PubMed  CAS  Google Scholar 

  65. Chandramouli V, Khan A, Ostenson CG, Berggren PO, Low H, Landau BR, et al. Quantification of glucose cycling and the extent of equilibration of glucose 6-phosphate with fructose 6-phosphate in islets from ob/ob mice. Biochem J. 1991;278(Pt 2):353–9.

    PubMed  CAS  Google Scholar 

  66. Khan A, Chandramouli V, Ostenson CG, Berggren PO, Low H, Landau BR, et al. Glucose cycling is markedly enhanced in pancreatic islets of obese hyperglycemic mice. Endocrinology. 1990;126(5):2413–6.

    Article  PubMed  CAS  Google Scholar 

  67. Jazmin LJ, Young JD. Isotopically nonstationary 13C metabolic flux analysis. Methods Mol Biol. 2013;985:367–90. doi:10.1007/978-1-62703-299-5_18.

    Article  PubMed  Google Scholar 

  68. Martin CC, Oeser JK, Svitek CA, Hunter SI, Hutton JC, O'Brien RM. Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-Phosphatase catalytic subunit-related protein. J Mol Endocrinol. 2002;29:205–22.

    Article  PubMed  CAS  Google Scholar 

  69. Li X, Shu YH, Xiang AH, Trigo E, Kuusisto J, Hartiala J, et al. Additive effects of genetic variation in Gck and G6pc2 on insulin secretion and fasting glucose. Diabetes. 2009;58:2946–53.

    Article  PubMed  CAS  Google Scholar 

  70. Rose CS, Grarup N, Krarup NT, Poulsen P, Wegner L, Nielsen T, et al. A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads. Diabetologia. 2009;52(10):2122–9.

    Article  PubMed  CAS  Google Scholar 

  71. Ingelsson E, Langenberg C, Hivert MF, Prokopenko I, Lyssenko V, Dupuis J, et al. Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes. 2010;59(5):1266–75. doi:10.2337/db09-1568.

    Article  PubMed  CAS  Google Scholar 

  72. Heni M, Ketterer C, t Hart LM, Ranta F, van Haeften TW, Eekhoff EM, et al. The impact of genetic variation in the G6PC2 gene on insulin secretion depends on glycemia. J Clin Endocrinol Metab. 2010;95:E479–84. doi:10.1210/jc.2010-0860.

    Article  PubMed  CAS  Google Scholar 

  73. Koza RA, Nikonova L, Hogan J, Rim JS, Mendoza T, Faulk C, et al. Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet. 2006;2(5):e81.

    Article  PubMed  Google Scholar 

  74. Merrins MJ, Fendler B, Zhang M, Sherman A, Bertram R, Satin LS. Metabolic oscillations in pancreatic islets depend on the intracellular Ca2+ level but not Ca2+ oscillations. Biophys J. 2010;99(1):76–84. doi:10.1016/j.bpj.2010.04.012.

    Article  PubMed  CAS  Google Scholar 

  75. Merrins MJ, Bertram R, Sherman A, Satin LS. Phosphofructo-2-kinase/fructose-2,6-bisphosphatase modulates oscillations of pancreatic islet metabolism. PLoS One. 2012;7(4):e34036. doi:10.1371/journal.pone.0034036.

    Article  PubMed  CAS  Google Scholar 

  76. Bertram R, Sherman A, Satin LS. Electrical bursting, calcium oscillations, and synchronization of pancreatic islets. Adv Exp Med Biol. 2010;654:261–79. doi:10.1007/978-90-481-3271-3_12.

    Article  PubMed  CAS  Google Scholar 

  77. Wolf BA, Colca JR, Comens PG, Turk J, McDaniel ML. Glucose 6-phosphate regulates Ca2+ steady state in endoplasmic reticulum of islets. A possible link in glucose-induced insulin secretion. J Biol Chem. 1986;261(35):16284–7.

    PubMed  CAS  Google Scholar 

  78. Jetton TL, Liang Y, Pettepher CC, Zimmerman EC, Cox FG, Horvath K, et al. Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J Biol Chem. 1994;269(5):3641–54.

    PubMed  CAS  Google Scholar 

  79. Goh BH, Khan A, Efendic S, Portwood N. Expression of glucose-6-phosphatase system genes in murine cortex and hypothalamus. Horm Metab Res. 2006;38(1):1–7.

    Article  PubMed  CAS  Google Scholar 

  80. Frigeri C, Martin CC, Svitek CA, Oeser JK, Hutton JC, Gannon M, et al. The Proximal Islet-Specific Glucose-6-Phosphatase Catalytic Subunit Related Protein (IGRP) autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo. Diabetes. 2004;53:1754–64.

    Article  PubMed  CAS  Google Scholar 

  81. Wang Y, Flemming BP, Martin CC, Allen SR, Walters J, Oeser JK, et al. Long-range enhancers are required to maintain expression of the autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein in adult mouse islets in vivo. Diabetes. 2008;57(1):133–41.

    Article  PubMed  CAS  Google Scholar 

  82. Woods SC, Lutz TA, Geary N, Langhans W. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos Trans R Soc Lond B Biol Sci. 2006;361(1471):1219–35.

    Article  PubMed  CAS  Google Scholar 

  83. Barzilai N, Rossetti L. Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin. J Biol Chem. 1993;268(33):25019–25.

    PubMed  CAS  Google Scholar 

  84. Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767–93. doi:10.1146/annurev-biochem-072909-095555.

    Article  PubMed  CAS  Google Scholar 

  85. Karunakaran U, Park KG. A systematic review of oxidative stress and safety of antioxidants in diabetes: focus on islets and their defense. Diabetes Metab J. 2013;37(2):106–12. doi:10.4093/dmj.2013.37.2.106.

    Article  PubMed  Google Scholar 

  86. Trinh K, Minassian C, Lange AJ, O'Doherty RM, Newgard CB. Adenovirus-mediated expression of the catalytic subunit of glucose-6- phosphatase in INS-1 cells. Effects on glucose cycling, glucose usage, and insulin secretion. J Biol Chem. 1997;272(40):24837–42.

    Article  PubMed  CAS  Google Scholar 

  87. Iizuka K, Nakajima H, Ono A, Okita K, Miyazaki J, Miyagawa J, et al. Stable overexpression of the glucose-6-phosphatase catalytic subunit attenuates glucose sensitivity of insulin secretion from a mouse pancreatic beta-cell line. J Endocrinol. 2000;164(3):307–14.

    Article  PubMed  CAS  Google Scholar 

  88. Wang H, Liu L, Zhao J, Cui G, Chen C, Ding H, et al. Large scale meta-analyses of fasting plasma glucose raising variants in GCK, GCKR, MTNR1B and G6PC2 and their impacts on type 2 Diabetes Mellitus risk. PLoS One. 2013;8(6):e67665. doi:10.1371/journal.pone.0067665.

    Article  PubMed  CAS  Google Scholar 

  89. Freathy RM, Hayes MG, Urbanek M, Lowe LP, Lee H, Ackerman C, et al. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the International Association of Diabetes and Pregnancy Study Groups. Diabetes. 2010;59(10):2682–9. doi:10.2337/db10-0177.

    Article  PubMed  CAS  Google Scholar 

  90. Bouatia-Naji N, Bonnefond A, Baerenwald DA, Marchand M, Bugliani M, Marchetti P, et al. Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that strongly associate with elevated fasting glucose levels. Diabetes. 2010;59(10):2662–71. doi:10.2337/db10-0389.

    Article  PubMed  CAS  Google Scholar 

  91. Sharp PA. Split genes and RNA splicing. Cell. 1994;77(6):805–15.

    Article  PubMed  CAS  Google Scholar 

  92. Solis AS, Shariat N, Patton JG. Splicing fidelity, enhancers, and disease. Front Biosci. 2008;13:1926–42.

    Article  PubMed  CAS  Google Scholar 

  93. Dos Santos C, Bougneres P, Fradin D. An SNP in a methylatable Foxa2 binding site of the G6PC2 promoter is associated with insulin secretion in vivo and increased promoter activity in vitro. Diabetes. 2009;58:489–92.

    Article  PubMed  Google Scholar 

  94. Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, et al. Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia. 2012;55(3):707–18. doi:10.1007/s00125-011-2369-0.

    Article  PubMed  CAS  Google Scholar 

  95. Matschinsky FM. Assessing the potential of glucokinase activators in diabetes therapy. Nat Rev Drug Discov. 2009;8(5):399–416.

    Article  PubMed  CAS  Google Scholar 

  96. Jensen MV, Joseph JW, Ronnebaum SM, Burgess SC, Sherry AD, Newgard CB. Metabolic cycling in control of glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab. 2008;295(6):E1287–97.

    Article  PubMed  CAS  Google Scholar 

  97. Chen SY, Pan CJ, Nandigama K, Mansfield BC, Ambudkar SV, Chou JY. The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic. Faseb J. 2008;22:2206–13.

    Article  PubMed  CAS  Google Scholar 

  98. Wang H, Iynedjian PB. Modulation of glucose responsiveness of insulinoma beta-cells by graded overexpression of glucokinase. Proc Natl Acad Sci U S A. 1997;94(9):4372–7.

    Article  PubMed  CAS  Google Scholar 

  99. Wang H, Iynedjian PB. Acute glucose intolerance in insulinoma cells with unbalanced overexpression of glucokinase. J Biol Chem. 1997;272(41):25731–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I would like to thank Les Satin (University of Michigan) for helpful comments on the mechanism of pulsatile insulin secretion. Research in the laboratory of R.O’B. was supported by NIH grant DK92589. This review is dedicated to the memory of my long-time colleague and friend, John C. Hutton.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Richard M. O’Brien declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Richard M. O’Brien

  2. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 8415 MRB IV, 2213 Garland Ave, Nashville, TN, 37232-0615, USA

    Richard M. O’Brien

Authors
  1. Richard M. O’Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard M. O’Brien.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O’Brien, R.M. Moving on from GWAS: Functional Studies on the G6PC2 Gene Implicated in the Regulation of Fasting Blood Glucose. Curr Diab Rep 13, 768–777 (2013). https://doi.org/10.1007/s11892-013-0422-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-013-0422-8

Keywords

Search

Navigation