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Maturity-onset Diabetes (maturity-onset + diabetes)
Selected AbstractsMaturity-Onset Diabetes of the Young with Necrobiosis Lipoidica and Granuloma AnnularePEDIATRIC DERMATOLOGY, Issue 3 2006Federico Marchetti M.D. After initial evaluation, high fasting blood glucose levels and high hemoglobin A1c were found. The family history for non-insulin-dependent diabetes was suggestive of maturity-onset diabetes of the young. Coexistence of necrobiosis lipoidica and granuloma annulare, together with a family history of non-insulin-dependent diabetes, the age of onset, and the absence of ketosis, are specific features making possible, a clinical diagnosis. Genetic confirmation may not be so easily accessible or necessary. [source] Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1, gene mutations: evidence for pharmacogenetics in diabetesDIABETIC MEDICINE, Issue 7 2000E. R. Pearson SUMMARY Introduction Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1, gene are the commonest cause of MODY. Individual patients with HNF-1, mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1, mutations that show marked hypersensitivity to sulphonylureas. Case reports In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. Conclusions HNF-1, MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1, MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control. Keywords, genetics, HNF-1,, MODY, pharmacogenetics, sulphonylurea sensitivity [source] Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young,,HUMAN MUTATION, Issue 4 2003Vilma Mantovani Abstract Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of disorders characterized by early onset non-insulin-dependent diabetes mellitus, autosomal dominant inheritance, and primary defect in the function of the beta cells of the pancreas. Mutations in the glucokinase (GCK) gene account for 8%,56% of MODY, with the highest prevalences being found in the southern Europe. While screening for GCK mutations in 28 MODY families of Italian origin, we identified 17 different mutations (corresponding to 61% prevalence), including eight previously undescribed ones. The novel sequence variants included five missense mutations (p.Lys161Asn c.483G>C in exon 4, p.Phe171Leu c.511T>C in exon 5 and p.Thr228Ala c.682A>G, p.Thr228Arg c.683C>G, p.Gly258Cys c.772G>T in exon 7), one nonsense mutation (p.Ser383Ter c.1148C>A in exon 9), the splice site variant c.1253+1G>T in intron 9, and the deletion of 12 nucleotides in exon 10 (p.Ser433underscore;Ile436del c.1298_1309del12). Our study indicates that mutations in the GCK/MODY2 gene are a very common cause of MODY in the Italian population and broadens our knowledge of the naturally occurring GCK mutation repertoire. © 2003 Wiley-Liss, Inc. [source] Genetics of type 2 diabetes mellitus: status and perspectivesDIABETES OBESITY & METABOLISM, Issue 2 2005Lars Hansen Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1,6 according to the mutated genes that by being expressed in the pancreatic ,-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected ,candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-, and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects. [source] Incorrect and incomplete coding and classification of diabetes: a systematic reviewDIABETIC MEDICINE, Issue 5 2010M. A. Stone Diabet. Med. 27, 491,497 (2010) Abstract Aims, To conduct a systematic review to identify types and implications of incorrect or incomplete coding or classification within diabetes or between diabetes and other conditions; also to determine the availability of evidence regarding frequency of occurrence. Methods, Medical Subject Headings (MeSH) and free-text terms were used to search relevant electronic databases for papers published to the end of August 2008. Two researchers independently reviewed titles and abstracts and, subsequently, the full text of potential papers. Reference lists of selected papers were also reviewed and authors consulted. Three reviewers independently extracted data. Results, Seventeen eligible studies were identified, including five concerned with distinguishing between Type 1 and Type 2 diabetes. Evidence was also identified regarding: the distinction between diabetes and no-diabetes, failure to specify type of diabetes, and diagnostic errors or difficulties involving maturity-onset diabetes of the young, latent autoimmune diabetes in adults, pancreatic diabetes, persistence of foetal haemoglobin and acquired immune deficiency syndrome (AIDS). The sample was too heterogeneous to derive accurate information about frequency, but our findings suggested that misclassification occurs most commonly in young people. Implications relating to treatment options and risk management were highlighted, in addition to psychological and financial implications and the potential impact on the validity of quality of care evaluations and research. Conclusions, This review draws attention to the occurrence and implications of incorrect or incomplete coding or classification of diabetes, particularly in young people. A pragmatic and clinically relevant approach to classification is needed to assist those involved in making decisions about types of diabetes. [source] Genetics of Type 2 diabetesDIABETIC MEDICINE, Issue 5 2005I. Barroso Abstract Type 2 diabetes (T2D) has become a health-care problem worldwide, with the rise in disease prevalence being all the more worrying as it not only affects the developed world but also developing nations with fewer resources to cope with yet another major disease burden. Furthermore, the problem is no longer restricted to the ageing population, as young adults and children are also being diagnosed with T2D. In recent years, there has been a surge in the number of genetic studies of T2D in attempts to identify some of the underlying risk factors. In this review, I highlight the main genes known to cause uncommon monogenic forms of diabetes (e.g. maturity-onset diabetes of the young,MODY,and insulin resistance syndromes), as well as describe some of the main approaches used to identify genes involved in the more common forms of T2D that result from the interaction between environmental risk factors and predisposing genotypes. Linkage and candidate gene studies have been highly successful in the identification of genes that cause the monogenic variants of diabetes and, although progress in the more common forms of T2D has been slow, a number of genes have now been reproducibly associated with T2D risk in multiple studies. These are discussed, as well as the main implications that the diabetes gene discoveries will have in diabetes treatment and prevention. [source] Type 2 diabetes mellitus in UK children , an emerging problemDIABETIC MEDICINE, Issue 12 2000S. Ehtisham SUMMARY Aims Type 2 diabetes mellitus has never previously been described in UK children, although an increasing incidence in childhood is recognized in international studies. The prevalence of obesity in UK children is increasing and is a recognized risk factor for the development of diabetes. The aim of this study was to identify and characterize children with Type 2 diabetes in the West Midlands and Leicester. Methods Children were identified by contacting paediatricians responsible for diabetes in five hospitals. Details were collected on demographics, mode of presentation, investigations and treatment on a standard proforma. Results Eight girls were identified with Type 2 diabetes, aged 9,16 years and who were of Pakistani, Indian or Arabic origin. They were all overweight (percentage weight for height 141,209%) and had a family history of diabetes in at least two generations. They presented insidiously with hyperglycaemia and glycosuria without ketosis and five were asymptomatic. Islet cell antibodies measured in seven patients were negative. Four had acanthosis nigricans which is a cutaneous marker of insulin resistance and the other four had high plasma levels of insulin and/or C peptide. These patients are distinct from those with maturity-onset diabetes of the young (MODY). All were initially managed with dietary measures, seven have been treated with oral anti-diabetic agents of whom two have subsequently required insulin. Conclusions These are the first UK case reports of Type 2 diabetes in children. Paediatricians need to be aware of the risk of Type 2 diabetes developing in childhood in high-risk ethnic groups, particularly in association with obesity and a positive family history. [source] Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young,,HUMAN MUTATION, Issue 4 2003Vilma Mantovani Abstract Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of disorders characterized by early onset non-insulin-dependent diabetes mellitus, autosomal dominant inheritance, and primary defect in the function of the beta cells of the pancreas. Mutations in the glucokinase (GCK) gene account for 8%,56% of MODY, with the highest prevalences being found in the southern Europe. While screening for GCK mutations in 28 MODY families of Italian origin, we identified 17 different mutations (corresponding to 61% prevalence), including eight previously undescribed ones. The novel sequence variants included five missense mutations (p.Lys161Asn c.483G>C in exon 4, p.Phe171Leu c.511T>C in exon 5 and p.Thr228Ala c.682A>G, p.Thr228Arg c.683C>G, p.Gly258Cys c.772G>T in exon 7), one nonsense mutation (p.Ser383Ter c.1148C>A in exon 9), the splice site variant c.1253+1G>T in intron 9, and the deletion of 12 nucleotides in exon 10 (p.Ser433underscore;Ile436del c.1298_1309del12). Our study indicates that mutations in the GCK/MODY2 gene are a very common cause of MODY in the Italian population and broadens our knowledge of the naturally occurring GCK mutation repertoire. © 2003 Wiley-Liss, Inc. [source] Analysis of a non-functional HNF-1, (TCF1) mutation in Japanese subjects with familial type 1 diabetesHUMAN MUTATION, Issue 4 2001Issei Yoshiuchi Abstract Mutations in the transcription factor hepatocyte nuclear factor-1, (HNF-1,; gene symbol TCF1) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic ,-cell dysfunction. Recent genetic studies, however, also found mutations in patients diagnosed with idiopathic (non-autoimmune based) type 1 diabetes. We identified a novel frameshift mutation (142delG) in the TCF1 gene in a family with a strong family history of type 1 diabetes and examined the functional properties of the mutant HNF 1,. The expression of the mutant protein was not detected in COS-7 cells by Western blot analysis after transfection of the mutant cDNA. This is the first case of an unstable mutant HNF-1, protein. Reporter gene analysis indicated that the mutant HNF-1, had no transactivation activity in HeLa and MIN6 cells. Haploinsufficiency for HNF-1, may lead to severe forms of diabetes like type 1 diabetes. Hum Mutat 18:345,351, 2001. © 2001 Wiley-Liss, Inc. [source] Maturity-Onset Diabetes of the Young with Necrobiosis Lipoidica and Granuloma AnnularePEDIATRIC DERMATOLOGY, Issue 3 2006Federico Marchetti M.D. After initial evaluation, high fasting blood glucose levels and high hemoglobin A1c were found. The family history for non-insulin-dependent diabetes was suggestive of maturity-onset diabetes of the young. Coexistence of necrobiosis lipoidica and granuloma annulare, together with a family history of non-insulin-dependent diabetes, the age of onset, and the absence of ketosis, are specific features making possible, a clinical diagnosis. Genetic confirmation may not be so easily accessible or necessary. [source] Neonatal hyperinsulinaemic hypoglycaemia and monogenic diabetes due to a heterozygous mutation of the HNF4A geneAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 3 2009Jennifer J. CONN Recent research has demonstrated that mutations of the hepatocyte nuclear factor 4-alpha (HNF4A) gene are associated with neonatal hyperinsulinaemic hypoglycaemia. Mutations of this gene also cause one of the subtypes of monogenic diabetes, a form of diabetes formerly known as maturity-onset diabetes of the young. This article describes a family discovered to have a novel frame-shift mutation of the HNF4A gene in the setting of early-onset maternal diabetes and severe neonatal hyperinsulinaemic hypoglycaemia. The implications of a diagnosis of HNF4A gene mutation for obstetric and paediatric practice are discussed. [source] Mutations in GCK and HNF-1, explain the majority of cases with clinical diagnosis of MODY in SpainCLINICAL ENDOCRINOLOGY, Issue 4 2007Itziar Estalella Summary Objective, The aim of this study was to group patients with MODY (maturity-onset diabetes of the young) according to the genetic alterations underlying the disease and to investigate their clinical characteristics. Patients and methods, Molecular analysis of GCK (MODY2), HNF-1, (MODY3), HNF-4, (MODY1) and HNF-1, (MODY5) genes was performed by DNA sequencing in 95 unrelated index probands (47M/48F; mean age 9·9 ± 5·2 years) with clinical diagnosis of MODY. After classification into MODY subtypes according to the genetic alterations, clinical characteristics were compared between the groups. Results, Seventy-six families were shown to carry mutations in GCK (34 of them previously unreported), eight families presented HNF-1, mutations, and a large genomic rearrangement in HNF-1, was found in a family. No alteration was found in HNF-4,. Thus, relative frequencies in the group studied were 80% MODY2, 8·5% MODY3 and 1% MODY5. Comparison of clinical parameters according to genetic status showed significant differences between MODY2 and MODY3 patients in age at diagnosis (9·4 ± 5·4 years vs. 12·7 ± 4·6 years), diagnosis (impaired glucose tolerance vs. diabetes), diagnostic test used (OGTT vs. fasting glucose), treatment (diet and exercise vs. insulin/oral antidiabetic agents) and birth weight (2·96 ± 0·44 kg vs. 3·40 ± 0·67 kg). Conclusion, Almost 90% of the MODY cases in the group studied are explained by mutations in the major genes GCK (MODY2) and HNF-1,(MODY3), although differences in the relative prevalence of each form could be partly due to patient referral bias (paediatric vs. adult). In general, patients with MODY2 were diagnosed at an earlier age in life than MODY3 patients and had a milder form of diabetes. Moreover, the majority of patients with MODY2 mutations were treated with diet whereas half of MODY3 patients received pharmacological treatment. [source] | ||||||||||