Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes (NIDDM) characterized by an early age of diagnosis (usually < 25 years) and an autosomal dominant mode of inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1alpha) [MODY3] gene represent the most common cause of MODY in the UK and a common cause of MODY in many other populations. Sixty-three different mutations have been described in a total of 112 families worldwide. This report describes two families, not known to be related, who carry a novel insertion/deletion mutation (I414G415ATCG-->CCA) and a 6bp intronic deletion of the HNF-1alpha gene in cis. We propose that the insertion/deletion mutation has arisen by formation of a hairpin loop due to the presence of a quasi-palindromic sequence, followed by insertion of CC and deletion of TCG resulting in the increased stability of the hairpin loop.
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PMID:Proposed mechanism for a novel insertion/deletion frameshift mutation (I414G415ATCG-->CCA) in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene which causes maturity-onset diabetes of the young (MODY). 1098 May 42

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (<25 years) and pancreatic beta-cell dysfunction. MODY is genetically heterogeneous with five different genes identified to date: hepatocyte nuclear factor-4 alpha (HNF-4 alpha) [MODY1]; glucokinase [MODY2]; hepatocyte nuclear factor-1 alpha (HNF-1 alpha) [MODY3]; insulin promoter factor-1 (IPF-1) [MODY4]; and hepatocyte nuclear factor-1 beta (HNF-1 beta) [MODY5]. Mutations in the HNF-1 alpha gene represent a common cause of MODY in the majority of populations studied. Sixty-five different mutations have been described in a total of 116 families. The most common mutation is a C-insertion (P291fsinsC) in the polyC tract of exon 4, which has been reported in 22 families. The identification of an HNF-1 alpha gene mutation in a patient with type 2 diabetes confirms the diagnosis of MODY and has important implications for clinical management.
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PMID:Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. 1105 94

Type 2 diabetes is a complex disease and genetic as well as environmental factors play a role in its pathogenesis. Six different genes have been identified so far to be responsible for rare forms of autosomal dominant, early onset type 2 diabetes mellitus. All but one are transcription factors which influence expression of the other genes through the regulation of mRNA synthesis. These are hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, insulin promoter factor (IPF)-1 and HNF-1 beta, which are associated with MODY1, 3, 4, 5 respectively. MODY1 is a relatively rare and usually severe form of diabetes. It is associated with progressive hyperglycemia and frequent chronic complications. The HNF-4 alpha gene is localized on chromosome 20q. Similar clinical characteristics apply to the MODY3 form, however the latter is much more frequent among early onset, autosomal dominant type 2 diabetes (20-40%). HNF-1 alpha gene is localized on chromosome 12q. HNF-1 beta (MODY5 locus on chromosome 17q) is a protein which forms heterodimers with HNF-1 alpha. This rare form of diabetes has a clinical picture similar to MODY1 and MODY3. It is sometimes accompanied by symptoms of early kidney damage which are independent from diabetes. The other two transcription factors responsible for the development of autosomal dominant type 2 diabetes are proteins which bind directly to the insulin promoter. MODY4 (IPF-1, chromosome 13q) is a rare form and of a typical middle and late onset type 2 diabetes. BETA 2/Neurod1 has been recently associated with MODY by Dr Krolewski's group from Joslin Diabetes Center, Boston, MA, USA. BETA 2 is responsible for about 2% of autosomal dominant type 2 diabetes. The clinical characteristics depend on the localization of the mutations in the specific functional domains of the protein. Mutations identified in the glucokinase gene are associated with the MODY2 form. Glucokinase is an enzyme involved in the first level of glucose metabolism in b-cells-enzymatic phosphorylation. MODY2 is a modest form of diabetes. It is characterized by mild hyper-glycemia, mainly fasting, and the chronic complications are very rare. Glucokinase gene is localized on chromosome 7p. It is expected that in the nearest future more type 2 susceptibility genes will be identified.
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PMID:[Molecular background and clinical characteristics of autosomal dominant type 2 diabetes mellitus]. 1129 29

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes.
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PMID:[Diabetes mellitus]. 1130 9

Recently, several genes associated with early-onset, autosomal dominant Type 2 diabetes (MODY) have been identified. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene seem to account for a substantial proportion of this type of diabetes in several populations. However, it is still of interest to estimate the frequency of HNF-1alpha mutations in various ethnic groups. The aim of our study was to determine the contribution of the HNF-1alpha gene to the development of MODY in a Polish population. We selected 15 families with MODY for this project. The 10 exons and promoter region of the gene were screened for sequence differences by direct sequencing of probands DNA. We detected 7 previously described polymorphisms that were not associated with diabetes. However, one sequence difference, a deletion of a cytosine in codon 225 in exon 3 (designated S225fdelC), was a new mutation resulting in a frame shift and synthesis of a nonsense peptide from amino acid 225 to 232 followed by the stop codon. Thus, the S225fdelC mutation effectively caused the loss of a part of the DNA binding domain and the entire transactivation domain. This mutation was present in 4 affected members of the family. They developed diabetes at an early age (mean age at diagnosis 23 yr) and were characterized by severely impaired insulin secretion. In addition, one family member who was not a carrier of the S225fdelC mutation was diagnosed with diabetes. Thus, he represents an example of phenocopy. In conclusion, we have identified a new HNF-1alpha variant that represents the first MODY mutation described in a Polish population. MODY3 mutations, including those in the exon 4 "hot spot", do not appear to be a very common cause of MODY in the Polish population.
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PMID:Identification of a new mutation in the hepatocyte nuclear factor-1alpha gene in a Polish family with early-onset type 2 diabetes mellitus. 1180 70

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of type 2 diabetes characterised by an early onset, an autosomal dominant inheritance, and a primary defect in insulin secretion. MODY comprises 2-5% of cases of type 2 diabetes. So far, six MODY genes have been identified (MODY1-6): hepatocyte nuclear factor (HNF-4 alpha), glucokinase, HNF-1 alpha, HNF-1 beta, insulin promoter factor 1(IPF-1), and neurogenic differentiation factor 1 (NEUROD1). MODY2 and MODY3 are the most common forms of MODY. Mutations in glucokinase/MODY2 result in a mild form of diabetes. In contrast, MODY3 and some of the other MODY forms are characterised by major insulin secretory defects and severe hyperglycaemia associated with microvascular complications. About 25% of known MODY is caused by mutations in yet unknown genes and present results suggest that other monogenic forms of type 2 diabetes might exist. The diagnosis of MODY has implications for the clinical management of the patient's diabetes. The identification of MODY genes also opens new perspectives in the understanding of the molecular basis of diabetes and may probably contribute to the definition of novel targets for drug development and gene therapy.
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PMID:[Maturity-onset diabetes of the young--MODY. Molecular-genetic, pathophysiological and clinical characteristics]. 1198 98

Maturity onset diabetes of the young, subtype 1 (MODY1), is associated with defective glucose-dependent insulin secretion from pancreatic beta cells. MODY1 is caused by mutation in the transcription factor hepatocyte nuclear factor 4 alpha (HNF4 alpha). To understand better the MODY1 phenotype, we tested whether HNF4 alpha was able to modulate directly the insulin gene promoter. Transfection of cultured 293T cells with an HNF4 alpha expression vector led to 10-fold activation of a cotransfected reporter plasmid containing the rat insulin I gene promoter. Computer analysis revealed a potential HNF4 alpha-binding site between nucleotides -57 and -69 of the promoter; mutation of this sequence led to reduced ability of HNF4 alpha to activate the promoter. The ability of HNF4 alpha to bind this sequence was confirmed using gel shift analysis. In transfected INS-1 beta cells, mutation of either the HNF1 alpha site or the HNF4 alpha site in the insulin gene promoter led to 50-75% reduction in reporter gene activity; expression of dominant negative HNF4 alpha led to significant reduction in the activity of wild type and both mutated promoters. Thus, in addition to the previously described indirect action of HNF4 alpha on insulin gene expression mediated through elevated HNF1 alpha levels, HNF4 alpha also activates the insulin gene directly, through a previously unrecognized cis element.
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PMID:Activation of the insulin gene promoter through a direct effect of hepatocyte nuclear factor 4 alpha. 1199 85

The genetic causes of type 2 diabetes are not well understood. The disease has been linked to chromosome 20q12-q13.1 a region which harbors the transcription factor HNF4alpha. Mutations in the coding region of HNF4alpha cause maturity onset diabetes of the young, an autosomal dominant form of diabetes, but do not account for the linkage to this region. An enhancer element has recently been characterized 6 kb 5' of the HNF4alpha P1 promoter containing binding sites for the transcription factors HNF1, HNF4, HNF3, and C/EBP, which are overlapped by glucocorticoid consensus sites. We hypothesized that variation in the enhancer element disrupts HNF4alpha expression in the liver and increases susceptibility to type 2 diabetes. We screened for variants of the enhancer element in 39 white UK young onset diabetic subjects, giving >95% power to identify variants with minor allele frequencies of >5%. No variants of the enhancer element were found in this population. We conclude that variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes.
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PMID:The role of the HNF4alpha enhancer in type 2 diabetes. 1208 13

Maturity onset diabetes of the young (MODY) is a genetically heterogeneous form of type 2 diabetes that is characterized by autosomal dominant inheritance, onset in early adulthood and a primary defect in insulin secretion. Mutations in at least six genes have been shown to underlie MODY, including mutations in GCK (encoding glucokinase, also called MODY2) and mutations in HNF1A (encoding hepatocyte nuclear factor-1alpha, also called MODY3). We sequenced genomic DNA from probands of seven Canadian MODY families. In four probands, we detected four novel GCK mutations, namely IVS2-7G>A, G72R, T206R and S263P. In three other probands, we detected three HNF1A mutations, of which two were novel, namely 1051delCA and Q250X, and one had been previously reported, namely R131Q. The novel mutations expand the spectrum of MODY mutations. In addition, knowledge of the specific defect can be used to pre-symptomatically identify family members at risk for developing MODY.
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PMID:GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). 1244 80

Diabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha gene mutations (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic mechanism(s), we have investigated glibenclamide-induced insulin secretion, glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type and Hnf-1alpha-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1alpha(-/-) mice have a robust glibenclamide-induced insulin secretory response. We demonstrate that the half-life (t(1/2)) of glibenclamide in the blood is increased in Hnf-1alpha(-/-) mice compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or= 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-) mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver extracts from [(3)H]glibenclamide-injected animals by reverse-phase chromatography. We found that the ratio of the concentrations of glibenclamide and its metabolites was moderately increased in livers of Hnf-1alpha(-/-) mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf-1alpha(-/-) mice are caused by a defect in hepatic uptake of glibenclamide. This suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to impaired hepatic clearance and elevated plasma concentrations of the drug.
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PMID:Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha-deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3). 1247 73


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