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

Abstract

Aims/hypothesis. The aim of this study was to assess the prevalence of glucokinase gene mutations in Italian children with MODY and to investigate genotype/phenotype correlations of the mutants. Methods. Screening for sequence variants in the glucokinase gene was performed by denaturing gradient gel electrophoresis and direct sequencing in 132 children with maturity onset diabetes of the young (MODY) and in 9 children with chronic fasting hyperglycaemia but without laboratory evidence for Type I (insulin-dependent) diabetes mellitus and with normoglycaemic parents (ªnon-classicalº MODY). Results. Altogether 54 mutations were identified in the MODY group (54/132 or 41 %) and 3 among the ªnon-classicalº MODY individuals (3/9 or 33 %). Paternity testing indicated that the latter mutations have arisen de novo. Mean fasting plasma glucose concentrations of the children with the mutant glucokinase was in the expected impaired fasting glucose range. In contrast, results of the oral glucose tolerance test showed a wide range from normal glucose tolerance (Group 1: 2-h OGTT = 6.7 1.1 mmol/l; 11 patients) to diabetes (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. nonsense, 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 overweight 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 ml Kg ±1 min ±1 /mU/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 fasting plasma glucose (i. e. > 5.5 mmol). The lack of correlation between the molecular 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 glucose concentrations in these subjects. Our results seem to indicate that the differences observed in the 2-h responses at the OGTT among children with MODY 2 could be related to individual differences in insulin sensitivity. [Diabetologia (2001) 44: 898±905] Keywords MODY 2, insulin secretion, insulin sensitivity, glucokinase, BMI, Italy. Abbreviations: GK, glucokinase; HNF 4a, HNF 1a, HNF 1b; hepatocyte nuclear factor 4a, 1a, 1b; IPF-1, Insulin promoter factor 1; FPIR, first-phase insulin response; ICA, islet cell antibodies; IAA, insulin auto-antibodies; DGGE, denaturing gradient gel electrophoresis; DG-DGGE, double gradient DGGE; HOMA-IR, homeostasis model assessment index of insulin resistance.

Glucokinase Gene Mutations: Structural and Genotype-Phenotype Analyses in MODY Children from South Italy

“…This GCK MODY prevalence is in line with those detected in southern European countries, particularly in France and in Italy, namely between 8% and 56% [25]–[27]. An analysis of the 3D structure of the protein mutants yielded evidence of structural perturbations, which supports the GCK MODY-causing nature of these mutations.…”

“…Massa et al [25] did not find an association between phenotype and genotype in GCK MODY patients. Two of our unrelated patients, M001 and M006, who both carried the p.Glu290X mutation, had a low birth weight but a different diabetic phenotype as evaluated by OGTT, FPIR tests and triglyceride level.…”

“…All mutations were detected at the heterozygous state, 9 mutations were novel; 8 of them caused variations in amino acid residues well conserved among species, and one produced a truncated protein of 289 amino acids (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu). Three other GCK mutations were already known; 2 of them caused truncated proteins (p.Lys39fsX6 and p.Ser453X) [24], [25] and 1 was a missense mutation (p.Glu265Lys) (Bellané-Chantelot C et al Abstract, Diabetologia 1998; 41:A109, 423). The structural analysis of mutation sites indicated 3D clustering.…”

Maturity-Onset Diabetes of the Young in Children With Incidental Hyperglycemia:

“…Among autoantibody-negative subjects, a significant number (∼23%) met the criteria for clinical diagnosis of maturity-onset diabetes of the young (MODY), i.e., two or three consecutive generations with hyperglycemia diagnosed before age 25 years (3,4). Alterations in at least six different genes cause MODY (3), with mutations of the glucokinase ( GCK ) and hepatocyte nuclear factor 1α ( HNF1 Α) genes accounting for up to 85% of MODY in Europe.…”

Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young

“…In France, GCK mutations are the most common cause of MODY, with more than 60% of studied population carrying mutations in this gene [12,18,21]. GCK defects are also the first cause of MODY among Italian and Spanish patients [29,34]. However, studies in the United Kingdom [35] and Germany [5] found GCK mutations in only 11% and 8% of the series, respectively.…”