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  • 1
    Electronic Resource
    Electronic Resource
    Assessment of insulin sensitivity in glucokinase-deficient subjects (1996)
    Springer
    Diabetologia 39 (1996), S. 82-90 
    Details
    ISSN: 1432-0428
    Keywords: Insulin resistance ; glucokinase mutation ; MODY ; glucose clamp
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The chronic hyperglycaemia of glucokinase-deficient diabetes results from a glucose-sensing defect in pancreatic beta cells and abnormal hepatic glucose phosphorylation. We have evaluated the contribution of insulin resistance to this form of chronic hyperglycaemia. Insulin sensitivity, assessed by the homeostasis model assessment (HOMA) method in 35 kindreds with glucokinase mutations, was found to be significantly decreased in 125 glucokinase-deficient subjects as compared to 141 unaffected first-degree relatives. Logistic regression analysis showed that in glucokinase-deficient subjects a decrease in insulin sensitivity was associated with deterioration of the glucose tolerance status. A euglycaemic hyperin-sulinaemic clamp was performed in 14 glucokinase-deficient subjects and 12 unrelated control subjects. In six patients and six control subjects the clamp was coupled to dideutero-glucose infusion to measure glucose turnover. Average glucose infusion rates (GIR) at 1 and 5 mU · kg body weight · min−1 insulin infusion rates were significantly lower in (the glucokinase-deficient) patients than in control subjects. Although heterogeneous results were observed, in 8 out of the 14 patients GIRs throughout the experiment were lower than 1 SD below the mean of the control subjects. Hepatic glucose production at 1 mU · kg body weight−1 · min−1 insulin-infusion rate was significantly higher in patients than in control subjects. In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes. Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency. Insulin resistance might also result from interactions between the unbalanced glucose metabolism and susceptibility gene(s) to low insulin sensitivity likely to be present in this population.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400417
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  • 2
    Electronic Resource
    Electronic Resource
    Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families (1997)
    Springer
    Diabetologia 40 (1997), S. 217-224 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Diabetes mellitus ; MODY ; glucokinase mutations ; insulin secretion ; genetics.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. We screened members of 35 families with features of maturity-onset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. They included 14 new mutations in the glucokinase gene: 9 missense mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L and V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nucleotide resulting in a frameshift (V401del1); a substitution of a conserved nucleotide at a splice acceptor site (L122-1G → T); and a 10 base pair deletion that removed the GT of the splice donor site and the following eight nucleotides (K161 + 2del10). In addition, we found two previously identified mutations: R186X and G261R. Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM). Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50 % of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro- and macro-vascular complications of diabetes. Obesity, arterial hypertension and dyslipidaemia are also uncommon in this form of NIDDM. [Diabetologia (1997) 40: 217–224]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050666
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  • 3
    Electronic Resource
    Electronic Resource
    Mutation screening in 18 Caucasian families suggest the existence of other MODY genes (1998)
    Springer
    Diabetologia 41 (1998), S. 1017-1023 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Genetics ; MODY ; glucokinase gene ; HNF-1α ; HNF-4α ; HNF-1β ; IPF1 ; transcription factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4 α/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7 p, hepatocyte nuclear factor-1 alpha (HNF-1 α/MODY3/TCF1) on chromosome 12 q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13 q and hepatocyte nuclear factor-1 beta (HNF-1 β/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4 α, HNF-1 α and HNF-1 β genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T→A) and one deletion mutation (P379fsdelT) were found in the HNF-1 α gene, but no MODY-associated mutations were found in the HNF-4 α and HNF-1 β genes. Of 67 French MODY families that we have now studied, 42 (63 %) have mutations in the glucokinase gene, 14 (21 %) have mutations in the HNF-1 α gene, and 11 (16 %) have no mutations in the HNF-4 α, IPF1 and HNF-1 β genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additionnal locus that can cause MODY. [Diabetologia (1998) 41: 1017–1023]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051025
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus (1992)
    [s.l.] : Nature Publishing Group
    Nature 356 (1992), S. 162-164 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Although clinical and metabolic profiles of families with maturity-onset diabetes of the young (MODY) are diverse5, most MODY patients present a decreased insulin response to glucose, suggesting a primary pancreatic /3-cell defect6. Genes whose products seem to be involved in insulin secretion ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/356162a0
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    Paper (German National Licenses)
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