Summary
Skeletal muscle and adipose tissue hexokinase II is a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the association of alleles at four polymorphic loci in this gene with NIDDM and insulin resistance in 110 Finnish diabetic patients with NIDDM and in 97 Finnish control subjects with normal glucose tolerance and a negative family history of diabetes. The four polymorphic nucleotide substitutions (silent) in the coding region of the hexokinase II gene were: GAC 251 GAT (exon 7), AAC 692 AAT and CCG 736 CCC (exon 15), and CTG 766 CTA (exon 16). Allele frequencies of each of these polymorphisms did not differ between patients with NIDDM and control subjects. In addition, subjects who were homozygous for the less frequent allele of each of the four polymorphisms had a similar degree of insulin resistance, as determined by the euglycaemic clamp technique, as did the subjects who were homozygous for the common allele in both control subjects and in patients with NIDDM. In conclusion, polymorphisms in the hexokinase II gene are not associated with the risk of NIDDM or insulin resistance in the Finnish population.
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Abbreviations
- HKII:
-
Hexokinase II
- NIDDM:
-
non-insulin-dependent diabetes mellitus
- PCR:
-
polymerase chain reaction
- SSCP:
-
single-strand conformation polymorphism
- Ra :
-
rate of glucose appearance
- Rd :
-
rate of glucose disappearance
References
Froguel P, Zouali H, Vionnet N et al. (1993) Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. New Engl J Med 328: 697–702
Steiner DF, Tager HS, Chan J, Nanjo K, Sanke T, Rubenstein AH (1990) Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care 13: 600–609
Taylor SI (1992) Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 41: 1473–1490
Ballinger SW, Shoffner JM, Hedaya EV et al. (1992) Maternally transmitted diabetes and deafness associate with a 10.4 kb mitochondrial DNA deletion. Nature Genetics 1: 11–15
Thelen AP, Wilson JE (1991) Complete amino acid sequence of the type II isoenzyme of rat hexokinase, deducted from the cloned cDNA: comparison with a hexokinase from Novikoff ascites tumor. Arch Biochem Biophys 286: 645–651
Printz RL, Koch S, Potter LR et al. (1993) Hexokinase II mRNA and gene structure, regulation by insulin, and evolution. J Biol Chem 268: 5209–5219
Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG (1990) Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322: 223–229
Malkki M, Laakso M, Deeb SS (1994) Structure of the human hexokinase II gene. Biochem Biophys Res Comm 205: 490–496
Sarlund H, Laakso M, Voutilainen E, PenttilÄ I, PyörÄlÄ K (1991) Familial aggregation of non-insulin-dependent diabetes and coronary heart disease are accompanied by different effects on serum lipids, lipoproteins and apolipoproteins. Atherosclerosis 31: 17–29
Laakso M, Rönnemaa T, PyörÄlÄ K, Kallio V, Puukka P, PenttilÄ I (1988) Atherosclerotic vascular disease and its risk factors in non-insulin-dependent diabetic and non-diabetic subjects in Finland. Diabetes Care 11: 449–463
Laakso M, Sarlund H. Salonen R et al. (1991) Asymptomatic atherosclerosis and insulin resistance. Arterioscl Thromb 11: 1068–1076
World Health Organization (1985) Diabetes mellitus: report of a WHO Study Group. Geneva, World Health Org (Tech Rep Ser, no. 727)
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E214-E223
KarhapÄÄ P, Uusitupa M, Voutilainen E, Laakso M (1992) Effects of bezafibrate on insulin sensitivity and glucose tolerance in subjects with combined hyperlipidemia. Clin Pharmacol Ther 52: 620–626
Steele R (1959) Influence of glucose loading and of injected insulin on hepatic glucose production. Ann NY Acad Sci 82: 420–430
Cobelli C, Mari A, Ferrannini E (1987) Non-steady state: error analysis of Steele's model and development for glucose kinetics. Am J Physiol 252: E679-E689
Bergman RN, Finegood DT, Ader M (1985) Assessment of insulin sensitivity in vivo. Endocrinol Rev 5: 45–86
Laakso M, Uusitupa M, Takala J, Majander H, Reijonen T, PenttilÄ I (1988) Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects. Metabolism 37: 1092–1100
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5: 874–879
Reina M, Brunzell JD, Deeb SS (1992) Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C genes. J Lipid Res 33: 1823–1832
Nevin DN, Brunzell JD, Deeb SS (1994) The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. Arterioscl Thromb 14: 869–873
Kretz KA, Carson GS, O'Brien JS (1989) Direct sequencing from low-melt agarose with Sequenase. Nucl Acid Res 17: 5864
Lehto M, Xiang K, Stoffel M et al. (1993) Human hexokinase II: localization of the polymorphic gene to chromosome 2. Diabetologia 36: 1299–1302
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Laakso, M., Malkki, M., KekÄlÄinen, P. et al. Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance. Diabetologia 38, 617–622 (1995). https://doi.org/10.1007/BF00400733
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DOI: https://doi.org/10.1007/BF00400733