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ABSTRACT: Mutations in the gene encoding glucokinase (GCK) cause a mild hereditary form of diabetes termed maturity-onset diabetes of the young (MODY)2 or GCK-MODY. The disease does not progress over time, and diabetes complications rarely develop. It has therefore been suggested that GCK-MODY represents a metabolically compensated condition, but experimental support for this notion is lacking. Here, we profiled metabolites in serum from patients with MODY1 (HNF4A), MODY2 (GCK), MODY3 (HNF1A), and type 2 diabetes and from healthy individuals to characterize metabolic perturbations caused by specific mutations. Analysis of four GCK-MODY patients revealed a metabolite pattern similar to that of healthy individuals, while other forms of diabetes differed markedly in their metabolite profiles. Furthermore, despite elevated glucose concentrations, carriers of GCK mutations showed lower levels of free fatty acids and triglycerides than healthy control subjects. The metabolite profiling was confirmed by enzymatic assays and replicated in a cohort of 11 GCK-MODY patients. Elevated levels of fatty acids are known to associate with β-cell dysfunction, insulin resistance, and increased incidence of late complications. Our results show that GCK-MODY represents a metabolically normal condition, which may contribute to the lack of late complications and the nonprogressive nature of the disease.
Diabetes 11/2012; · 8.29 Impact Factor
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[show abstract]
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ABSTRACT: Mutations in the gene encoding glucokinase (GCK) cause a mild hereditary form of diabetes termed maturity onset diabetes of the young (MODY) 2 or GCK-MODY. The disease does not progress over time and diabetes complications rarely develop. It has therefore been suggested that GCK-MODY represents a metabolically compensated condition but experimental support for this notion is lacking. Here, we profiled metabolites in serum from patients with MODY 1 (HNF4A), MODY 2 (GCK), MODY 3 (HNF1A), type 2 diabetes, and healthy individuals, to characterize metabolic perturbations caused by specific mutations. Analysis of four GCK-MODY patients revealed a metabolite pattern similar to that of healthy individuals while other forms of diabetes differed markedly in their metabolite profiles. Furthermore, despite elevated glucose concentrations, carriers of GCK mutations showed lower levels of free fatty acids and triglycerides than healthy controls. The metabolite profiling was confirmed by enzymatic assays and replicated in a cohort of 11 GCK-MODY patients. Elevated levels of fatty acids are known to associate with ß-cell dysfunction, insulin resistance and increased incidence of late complications. Our results show that GCK-MODY represents a metabolically normal condition, which may contribute to the lack of late complications and the non-progressive nature of the disease.
Diabetes 08/2012; · 8.29 Impact Factor
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ABSTRACT: Gas chromatography/mass spectrometry-based metabolomics was applied to investigate dynamic changes in the plasma metabolome upon an oral glucose tolerance test (OGTT). The OGTT is a frequently used diagnostic test of glucose homeostasis and diabetes. Diabetes is diagnosed either when glucose levels ≥7.0 mM in the fasting state or ≥11.0 mM at 2 h after oral glucose intake. The accuracy of the OGTT would, however, most likely improve if additional variables could be identified. In the present study, plasma samples were drawn every 15 min for 2 h after an oral glucose load of 75 g preceded by an overnight fast in healthy individuals. Blood plasma levels of more than 200 putative metabolites were measured. Multivariate modelling was used to distinguish metabolic regulation due to the glucose challenge from that of other variability. Two data scaling methods were applied, yielding similar results when evaluated by appropriate diagnostic tools. Fatty acid levels were found to be strongly decreased during the OGTT. Also, the levels of amino acids were shown to decrease. However, technical and uninduced biological variations were found to affect the amino acid levels to a greater extent than the fatty acid levels, making the fatty acids more reliable as indicators of metabolic regulation. Levels of several metabolites correlated with the quadratic glucose profile and two were found having an inverse correlation. Raw data plots of all identified significantly altered metabolites confirmed the excellent performance of the multivariate models. Using this approach, a better understanding of the metabolic response to an OGTT can be achieved, paving the way for inclusion of other variables describing appropriate metabolic control.
Metabolomics 06/2010; 6(1):56-66. · 4.51 Impact Factor
