Summary
Mutations of the glucokinase gene result in early-onset familial Type 2 (non-insulin-dependent) diabetes mellitus, and several members of the mutant glucokinase kindreds were originally diagnosed as having gestational diabetes. This study examined the glucokinase gene in 270 American Black women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed Type 2 diabetes after pregnancy (overt diabetes), and 99 normal control subjects who were recruited during the peripartum period. Two simple sequence repeat polymorphisms flanking either end of the glucokinase gene were evaluated. No association was found between glucokinase alleles and gestational diabetes only or overt diabetes, after adjustment for multiple comparisons. To detect single base changes, all 11 exons and proximal islet and liver promoter regions were examined by polymerase chain reaction plus single-stranded conformational polymorphism analysis in 45 gestational diabetes only patients who had not yet developed Type 2 diabetes. Nine coding region variants were identified: Ala11 (GCC) to Thr11 (ACC) in islet exon 1, and 8 variants either in untranslated regions or in the third base of a codon. Four variant sites were found in introns, but none in splicing consensus sequences. Analysis of the promoter regions revealed two common variants, G→A at islet −30 (24%), and G→A at liver −258 (42%). The frequencies of the promoter variants, determined by allele specific polymerase chain reaction analysis, did not differ among the three groups. Thus, no significant coding sequence glucokinase mutations were found in 90 alleles from 45 patients with gestational diabetes. Further studies will be required to rule out a minor role of the newly-described promoter region variants as susceptibility factors in this disorder.
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Iynedijan PB, Mobius G, Seitz HJ, Wollheim CB, Renold AE (1986) Tissue specific expression of glucokinase: identification of the gene product in liver and pancreatic islet. Proc Natl Acad Sci USA 83: 1998–2001
Matschinsky FM (1990) Glucokinase as glucose sensor and metabolic signal generator in pancreatic β-cells and hetatocytes. Diabetes 39: 647–652
Vionnet N, Stoffel M, Takeda J et al. (1992) Nonsense mutation in the glucokinase gene cause early-onset non-insulin-dependent diabetes mellitus. Nature 356: 721–722
Stoffel M, Patel P, Lo Y-MD et al. (1992) Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nature Genetics 2: 153–156
Froguel P, Zouali H, Vionnet N et al. (1993) Familial hyperglycemia due to mutation in glucokinase. New Engl J Med 328: 697–702
Gidh-Jain M, Takeda J, Xu LZ, Lange AJ, Vionney N, Stoffel M, Froguel P et al. (1993) Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Pro Natl Acad Sci USA 90: 1932–1936
Hattersley AT, Turner RC, Permutt MA et al. (1992) Linkage of type 2 diabetes to the glucokinase gene. Lancet 339: 1307–1310
Velho G, Froguel P, Clement K et al. (1992) Primary pancreatic beta-cell secretory defect caused by mutation in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 340: 444–448
Cousins L, Rigg L, Hollingsworth D, Brink G, Aurand J, Yen SSC (1980) The 24-hour excursions and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy. Am J Obstet Gynecol 136: 483–488
Cousins L (1991) Insulin sensitivity in pregnancy. Diabetes 40 [Suppl 2]: 39–41
Piscitelli J, Eden RD, Jelovsek FK, Grandis AS, Gall SA (1987) Family history of diabetes mellitus and oral glucose tolerance test criteria. Acta Obstet Gynecol Scand 66: 489–492
Matsutani A, Janssen R, Donis-Keller H, Permutt MA (1992) A polymorphic (CA)n repeat element maps the human glucokinase GCK (E.C. 2.7.1.1.) gene to chromosome 7p. Genomics 12: 319–325
Tanizawa Y, Matsutani A, Chiu KC, Permutt MA (1992) Human glucokinase gene: isolation, structural characterization, and identification of a microsatellite repeat polymorphism. Molec Endocrinol 6: 1070–1081
Acton RT, Vanichanan CJ, Perkins L et al. (1990) Immunogenetic predictors of gestational diabetes in American Blacks. In: Andreani D, Bompiaini GD, Di Mario U, Faulk WP, Galluzzo A (ed) Immunobiology of normal and diabetic pregnancy, John Wiley & Sons Ltd, New York, New York
Roseman JM, Go RPC, Perkins LL et al. (1991) Gestational diabetes mellitus among African-American Women. Diabetes Metab Rev 7: 93–104
O'Sullivan JB, Mahan CM (1964) Criteria for the oral glucose tolerance test in pregnancy. Diabetes 13: 278–285
National Diabetes Data Group (1979) Classification and diagnosis of diabetes and other categories of glucose intolerance. Diabetes 28: 1039–1057
Kunkel LM, Smith RD, Soyer SH et al. (1977) Analysis of human Y chromosome specific reiterated DNA in chromosome variants. Proc Natl Acad Sci 74: 1245–1249
Chiu KC, Province MA, Permutt MA (1992) Glucokinase gene is genetic marker for NIDDM in American Blacks. Diabetes 41: 843–849
Chiu KC, Tanizawa Y, Permutt MA (1993) Glucokinase variants in the common form of NIDDM. Diabetes 42: 579–582
Chiu KC, Province MA, Dowse GK et al. (1992) A genetic marker at the glucokinase gene locus for type 2 (non-insulindependent) diabetes mellitus in Mauritian Creoles. Diabetologia 35: 632–638
Tukey J (1977) Some thoughts on clinical trials, especially problems of multiplicity. Science 198: 679–684
Tanizawa Y, Koranyi LI, Welling C, Permutt MA (1991) Human liver glucokinase gene: cloning and sequence determination of two alternative spliced cDNAs. Proc Natl Acad Sci USA 88: 7294–7297
Koranyi L, Tanizawa Y, Welling C, Rabin DU, Permutt MA (1992) Human glucokinase gene: isolation and sequence analysis of a full length islet cDNA. Diabetes 41: 807–811
Magnuson MA, Shelton KD (1989) An alternative promoter in the glucokinase gene is active in the pancreatic β-cell. J Biol Chem 264: 15 936–15 942
Iynedjian PB, Gjinovci A, Renold AE (1988) Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats. J Biol Chem 263: 740–744
Iynedjian PB, Pilot P -R, Nouspikel T, Milburn JL, Quaade C, Hughes S et al. (1989) Differential expression and regulation of the glucokinase gene in liver and islet of Langerhans. Proc Natl Acad Sci 86: 7838–7842
Magnuson MA, Shelton KD (1989) An alternative promoter in the glucokinase gene is active in the pancreatic β-cell. J Biol Chem 264: 15 936–15 942
Rothman KJ (1990) No adjustments are needed for multiple comparison. Epidemiology 1: 43–46
Cox NJ, Bell GI (1989) Disease associations: chance, artifact, or susceptibility genes? Diabetes 38: 947–950
Acton RT, Roseman J, Bell D et al. (1993) Association of HLA-DR2 and autoantibodies with gestational and non-insulin-dependent diabetes in African American women. In: American Diabetes Association Research Symposium, 12th International Immunology and Diabetes Workshop. American Diabetes Association, Alexandria, Virginia, USA, p 52
Shelton KD, Franklin AJ, Khoor A, Beechem J, Magnuson MA (1992) Multiple elements in the upstream glucokinase promoter contribute to transcription in insulinoma cells. Molec Cell Biol 12: 4578–4589
Magnuson MA, Andreone TL, Printz RL, Koch S, Granner DK (1989) Rat glucokinase gene: structure and regulation by insulin. Proc Natl Acad Sci USA 86: 4838–4842
O'Brien RM, Lucas PC, Forest CD, Magnuson MA, Granner DK (1990) Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. Science 249: 533–537
Jeunemaitre X, Soubrier F, Koteletsev YV, Lifton RP, Williams CS, Charru A, et al. (1992) Molecular basis of human hypertension: role of angiotensigen. Cell 71: 169–180
Sheffield VC, Beck JS, Kwitek AE, Sandstrom DW, Stone EM (1993) The sensitivity of single-strain conformation polymorphism analysis for the detection of single base substitutions. Genomics 16: 325–332
Olansky L, Janssen R, Welling C, Permutt MA (1992) Variation of the insulin gene in American Blacks with NIDDM. Diabetes 41: 742–749
Olansky L, Welling C, Giddings S, Adler S, Bourey R, Dowse G et al. (1992) A variant insulin promoter in non-insulin-dependent diabetes mellitus. J Clin Invest 89: 1596–1602
Stoffel M, Bell KL, Blackburn CL, Powell KL, Seo TS, Takeda J et al (1993) Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes 42: 937–940
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Chiu, K.C., Go, R.C.P., Aoki, M. et al. Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning. Diabetologia 37, 104–110 (1994). https://doi.org/10.1007/BF00428785
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DOI: https://doi.org/10.1007/BF00428785