Metabolite Profiling Reveals Normal Metabolic Control in Carriers of Mutations in the Glucokinase Gene (MODY2)
نویسندگان
چکیده
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.
منابع مشابه
Clinical follow-up of two Brazilian subjects with glucokinase-MODY (MODY2) with description of a novel mutation.
Mutations in the glucokinase gene (GCK) account for many cases of monogenic diabetes featuring maturity-onset diabetes of the young type 2 (MODY2). The clinical pattern of this form of hyperglycemia is rather stable, with a slight elevation in blood glucose, which is usually not progressive. Patients rarely require pharmacological interventions and microvascular complications related to diabete...
متن کاملScreening of mutations in the GCK gene in Jordanian maturity-onset diabetes of the young type 2 (MODY2) patients.
Maturity-onset diabetes of the young type 2 (MODY2) is a genetic form of diabetes mellitus caused by mutations in the glucokinase gene (GCK). We assessed the frequency of GCK gene mutations in Jordanian suspected MODY2 patients. We screened exons 7, 8 and 9, which are specific for pancreatic glucokinase, for mutations at positions 682A>G, p.T228A; 895G>C, p.G299R, and 1148C>A, p.S383X, respecti...
متن کامل[Novel glucokinase mutation in a boy with maturity-onset diabetes of the young].
INTRODUCTION Maturity-onset diabetes of the young (MODY) is a heterogenous group of disorders characterized by an early onset of insulin-independent diabetes mellitus, an autosomal dominant mode of inheritance and a primary defect in beta-cell. There are six subtypes of MODY. MODY2 and MODY3 are the most frequent. CASE OUTLINE We present a nine-year-old boy with intermittent hyperglycaemia. A...
متن کاملIndentification of single base mutations in the GCK gene of patients with diagnosis of MODY2
Background Diabetes mellitus (DM) refers to a group of common metabolic disorders, with multiple causes, that share a common phenotype: hyperglycemia (Kota, 2012). The concept of multiple etiologies is recent and a third group of DM is proposed today, a monogenic form with autosomal dominant inheritance: MODY. There are 13 subtypes described for MODY, which in MODY2 is one of the most common, a...
متن کاملLong-Term Follow-Up of Oral Glucose Tolerance Test–Derived Glucose Tolerance and Insulin Secretion and Insulin Sensitivity Indexes in Subjects With Glucokinase Mutations (MODY2)
OBJECTIVE We investigated the natural history of glucokinase (GCK)-related maturity-onset diabetes of the young type 2 (MODY2), notably the factors associated with deterioration of hyperglycemia over time. RESEARCH DESIGN AND METHODS We report an 11-year follow-up of glucose tolerance and indexes of insulin secretion and insulin sensitivity derived from oral glucose tolerance tests in 33 MODY...
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