High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI

Citation
O. Massa et al., High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI, DIABETOLOG, 44(7), 2001, pp. 898-905
Citations number
48
Categorie Soggetti
Endocrynology, Metabolism & Nutrition","Endocrinology, Nutrition & Metabolism
Journal title
DIABETOLOGIA
ISSN journal
0012186X → ACNP
Volume
44
Issue
7
Year of publication
2001
Pages
898 - 905
Database
ISI
SICI code
0012-186X(200107)44:7<898:HPOGMI>2.0.ZU;2-Y
Abstract
Aims/hypothesis. The aim of this study was to assess the prevalence of gluc okinase gene mutations in Italian children with MODY and to investigate gen otype/phenotype correlations of the mutants. Methods. Screening for sequence variants in the glucokinase gene was perfor med by denaturing gradient gel electrophoresis and direct sequencing in 132 children with maturity onset diabetes of the young (MODY) and in 9 childre n with chronic fasting hyperglycaemia but without laboratory evidence for T ype I (insulin-dependent) diabetes mellitus and with normoglycaemic parents ("non-classical" MODY). Results. Altogether 54 mutations were identified in the MODY group (54/132 or 41%) and 3 among the "non-classical" MODY individuals (3/9 or 33%). Pate rnity testing indicated that the latter mutations have arisen de novo. Mean fasting plasma glucose concentrations of the children with the mutant gluc okinase was in the expected impaired fasting glucose range. In contrast, re sults of the oral glucose tolerance test showed a wide range from normal gl ucose tolerance (Group 1:2-h OGTT = 6.7 +/-1.1 mmol/l; 11 patients) to diab etes (Group 2:2-h OGTT 11.5 +/-0.5 mmol/l; 9 patients), with the remaining in the impaired glucose tolerance range. Disruptive mutations (i.e. nonsens e, frameshifts, splice-site) were equally represented in Groups 1 and 2 and were not clearly associated with an impaired first-phase insulin response. Surprisingly, 5 out of 11 children (or 45%) in Group 1 were found to be ov erweight but no children in Group 2 were overweight. Sensitivity index (SI) , calculated by a recently described method, was found to be significantly lower in Group 2 than in Group 1 (SI Group 2 = 0.0013 +/-0.0009 mi Kg(-1) m in(-1)/muU/ml: SI Group 1 = 0.0068 +/-0.0048, p < 0.0035). Conclusion/interpretation. Mutations in glucokinase are the first cause of MODY among Italian children selected through a low threshold limit of fasti ng plasma glucose (i.e. > 5.5 mmol). The lack of correlation between the mo lecular severity of glucokinase mutations, insulin secretion at intravenous glucose tolerance test and differences in glucose tolerance suggests that factors outside the beta cell are also involved in determining post-load gl ucose concentrations in these subjects. Our results seem to indicate that t he differences observed in the 2-h responses at the OGTT among children wit h MODY 2 could be related to individual differences in insulin sensitivity.