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