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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause of maturity-onset diabetes of the young type 3 (MODY3), which is characterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) diabetes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large population-based sample of unrelated Danish Caucasian Type I diabetic patients with an affected first degree relative, 39 patients (6.7%) who did not carry any high-risk HLA-haplotypes, i.e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing of the coding region and the minimal promoter of the HNF-1alpha gene. Four of the 39 Type I diabetic patients (10%) were identified as carrying mutations in the HNF-1alpha gene. One patient carried a missense mutation (Glu48Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exon 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with diabetes, and were not identified in 84 unrelated, healthy subjects. Furthermore, family history in three of the four families showed diabetes in four consecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10% of Danish diabetic patients without a high-risk HLA-haplotype, originally classified as having Type I diabetes could have diabetes caused by mutations in the HNF-1alpha gene. Clinical awareness of family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients.
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PMID:Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes. 986 22

Glucokinase (GK) gene mutations cause diabetes mellitus in both humans and mouse models, but the pathophysiological basis is only partially defined. We have used cre-loxP technology in combination with gene targeting to perform global, beta cell-, and hepatocyte-specific gene knock-outs of this enzyme in mice. Gene targeting was used to create a triple-loxed gk allele, which was converted by partial or total Cre-mediated recombination to a conditional allele lacking neomycin resistance, or to a null allele, respectively. beta cell- and hepatocyte-specific expression of Cre was achieved using transgenes that contain either insulin or albumin promoter/enhancer sequences. By intercrossing the transgenic mice that express Cre in a cell-specific manner with mice containing a conditional gk allele, we obtained animals with either a beta cell or hepatocyte-specific knock-out of GK. Animals either globally deficient in GK, or lacking GK just in beta cells, die within a few days of birth from severe diabetes. Mice that are heterozygous null for GK, either globally or just in the beta cell, survive but are moderately hyperglycemic. Mice that lack GK only in the liver are only mildly hyperglycemic but display pronounced defects in both glycogen synthesis and glucose turnover rates during a hyperglycemic clamp. Interestingly, hepatic GK knock-out mice also have impaired insulin secretion in response to glucose. These studies indicate that deficiencies in both beta cell and hepatic GK contribute to the hyperglycemia of MODY-2.
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PMID:Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. 986 45

The various types of diabetes mellitus are now more precisely classified according to their etiopathogenies. Therefore, type 1 (autoimmune or not), type 2, gestational diabetes, as well as MODY (Maturity Onset-Diabetes of the Young) and secondary diabetes are considered as separate entities. Any type of diabetes brings its set of complications. Biological chemistry is directed to define the etiopathogenic characteristics of the various types of diabetes and to assess the severity of metabolic and functional disturbances. Diagnostic criteria in term of glycemia have also been reviewed to asses diabetes and glucose intolerance.
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PMID:[Sugar diabetes. Update elements]. 992 23

Non-insulin dependent diabetes mellitus (NIDDM) is a heterogeneous disorder and both genetic and nongenetic factors are associated with the development of diabetes. Until now five genes (HNF-4 alpha, glucokinase, HNF-1 alpha, IPF-1 and HNF-1 beta), whose mutation can result in MODY, insulin and insulin receptor genes, and mitochondria DNA have been reported to be responsible for diabetes. Furthermore the mutations in some genes which work for insulin secretion or action also have been reported. This review discusses our current knowledge of these NIDDM susceptibility genes.
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PMID:[NIDDM susceptibility genes]. 1019 31

Seven mutations in the hepatocyte nuclear factor (HNF)-4alpha gene have been shown to correlate with type 1 maturity-onset diabetes of the young (MODY 1), a monogenic form of type 2 diabetes. Up to now, only the functional properties of two MODY 1 HNF-4alpha mutants, Q268X and V393I, have been investigated to address how the mutations in the HNF-4alpha gene, found by genetic studies, can give rise to impaired activities of mutated HNF-4alpha proteins and can cause this disease. The E276Q mutation results in a nonconservative substitution occurring in the HNF-4alpha E domain, which is involved in dimerization and transactivation activities as well as in protein-protein interactions with other transcription factors or coactivators. Using the mutated human HNF-4alpha2, we have found that, in the absence of chicken ovalbumin upstream promoter transcription factor II (COUP TFII), the E276Q substitution does not significantly affect the dimerization and transactivating activities of HNF-4alpha, at least on the promoters studied herein. On the other hand, in the presence of COUP TFII, the substitution impairs the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impaired synergy between COUP TFII and HNF-4 on the HNF-1 promoter results from an alteration of their interaction. HNF-1 expression plays a crucial role in transactivation of insulin promoter and of numerous genes coding for enzymes involved in glucose homeostasis. Therefore, its downregulation resulting from the E276Q mutation in HNF-4alpha gene most probably impairs the function of pancreatic beta-cells.
Diabetes 1999 May
PMID:Functional study of the E276Q mutant hepatocyte nuclear factor-4alpha found in type 1 maturity-onset diabetes of the young: impaired synergy with chicken ovalbumin upstream promoter transcription factor II on the hepatocyte nuclear factor-1 promoter. 1033 24

Glucokinase (GK) is expressed in the pancreatic beta-cells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wild-type (WT) GK and several mutant forms associated with maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analysis of the purified expressed proteins. The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80Ala, Thr168Pro, Arg36Trp, Thr209Met, Cys213Arg, and Val226Met. These missense mutations were shown to have variable effects on GK kinetic activity. The Gly80Ala and Thr168Pro mutations resulted in a large decrease in Vmax and a complete loss of the cooperative behavior associated with glucose binding. In addition, the Gly80Ala mutation resulted in a sixfold increase in the half-saturating substrate concentration (S0.5) for ATP, and Thr168Pro resulted in eight- and sixfold increases in the S0.5 values for ATP and glucose, respectively. The Thr209Met and Val226Met mutations exhibited three- and fivefold increases, respectively, in the S0.5 for ATP, whereas the Cys213Arg mutation resulted in a fivefold increase in the S0.5 for glucose. These mutations also led to a small yet significant reduction in Vmax. Of all the mutations studied, only the Cys213Arg mutation had reduced enzymatic activity and decreased thermal stability. Two mutants, Ala53Ser and Val367Met, showed kinetic and thermal stability properties similar to those of WT. These mutants had increased sensitivities to the known negative effectors of GK activity, palmitoyl-CoA, and GK regulatory protein. Taken together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alterations but also to the regulation of GK activity.
Diabetes 1999 Aug
PMID:Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype. 1042 85

Mutations in the glucokinase (GK) gene cause type-2 maturity-onset diabetes of the young type 2 (MODY-2) and GK-linked hyperinsulinaemia (GK-HI). Recombinant adenoviruses expressing the human wild-type islet GK or one of four mutant forms of GK, (the MODY-2 mutants E70K, E300K and V203A and the GK-HI mutant V455M) were transduced into glucose-responsive insulin-secreting beta-HC9 cells and tested functionally in order to initiate the first analysis in vivo of recombinant wild-type and mutant human islet GK. Kinetic analysis of wild-type human GK showed that the glucose S(0. 5) and Hill coefficient were similar to previously published data in vitro (S(0.5) is the glucose level at the half-maximal rate). E70K had half the glucose affinity of wild-type, but similar enzyme activity. V203A demonstrated decreased catalytic activity and an 8-fold increase in glucose S(0.5) when compared with wild-type human islet GK. E300K had a glucose S(0.5) similar to wild-type but a 10-fold reduction in enzyme activity. E300K mRNA levels were comparable with wild-type GK mRNA levels, but Western-blot analyses demonstrated markedly reduced levels of immunologically detectable protein, consistent with an instability mutation. V455M was just as active as wild-type GK, but with a markedly reduced S(0.5). The effects of the different GK mutants on glucose-stimulated insulin release support the kinetic and expression data. These experiments show the utility of a combined genetic, biochemical and cell-biological approach to the quantification of functional and structural changes of human GK that result from MODY-2 and GK-HI mutations.
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PMID:Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI). 1045 21

Fifty-nine patients were diagnosed with diabetes in the ten years from 1987 to 1996 in the Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand. All patients were less than fifteen years old. Fifty-five patients (93.3%) were type 1 diabetes, three (5%) were type 2 diabetes and MODY, and one (1.7%) was diabetes secondary to beta thalassemia major. Patients with type 2 diabetes, MODY, and secondary diabetes were excluded from this study, and fifty-five patients with type 1 diabetes were analysed. The aims of this study were to determine some of the general characteristics of Thai childhood type 1 diabetes and to see whether a seasonal variation is present. The results showed a female to male ratio of 1.39:1. The peak age at diagnosis was from 9 to 12 years. Seventy-seven per cent had diabetic ketoacidosis at the time of diagnosis. The majority of patients (93.9%) had a BMI of less than 20 kg/m2. A family history of diabetes was reported in 38 per cent but only 2 per cent were type 1 diabetes. We found a high prevalence of patients in the summer and winter seasons (35-48% and 37-50% respectively) and a lower prevalence in the rainy season (14.8-15%). These results are different from a previously reported study in 1984-1985 which found no differences in summer, winter, and rainy seasons. Further research study into Thai childhood type 1 diabetes is needed, especially the influence of seasonal factors, the incidence of the disease, and the significance of family history.
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PMID:Type 1 diabetes in Thai children aged 0-14 years. 1051 93

Mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic beta-cell dysfunction. We have examined the effects of five diabetes-associated mutations (L12H, G191D, R263C, P379fsdelCT, and L584S585fsinsTC) on HNF-1alpha function including DNA binding ability, intracellular localization, and transactivation activity. L12H, P379fsdelCT, and L584S585fsinsTC mutations were found in patients with a clinical diagnosis of MODY, while G191D and R263C mutations were identified in patients diagnosed with type 2 diabetes. These mutations had diverse effects on the functional properties of HNF-1alpha. Comparison of the functional data with clinical information suggested that transactivation activity of mutant HNF-1alpha in beta cells like MIN6 may be the primary determinants of the phenotypic differences observed among diabetic patients with HNF-1alpha mutations.
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PMID:Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor. 1058 Nov 89

The hepatocyte nuclear factor (HNF)4alpha, a member of the nuclear receptor superfamily, regulates genes that play a critical role in embryogenesis and metabolism. Recent studies have shown that mutations in the human HNF4alpha gene cause a rare form of type 2 diabetes, maturity onset diabetes of the young (MODY1). To investigate the properties of these naturally occurring HNF4alpha mutations we analysed five MODY1 mutations (R154X, R127W, V255M, Q268X and E276Q) and one other mutation (D69A), which we found in HepG2 hepatoma cells. Activation of reporter genes in transfection assays and DNA binding studies showed that the MODY1-associated mutations result in a variable reduction in function, whereas the D69A mutation showed an increased activity on some promoters. None of the MODY mutants acted in a dominant negative manner, thus excluding inactivation of the wild-type factor as a critical event in MODY development. A MODY3-associated mutation in the HNF1alpha gene, a well-known target gene of HNF4alpha, results in a dramatic loss of the HNF4 binding site in the promoter, indicating that mutations in the HNF4alpha gene might cause MODY through impaired HNF1alpha gene function. Based on these data we propose a two-hit model for MODY development.
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PMID:Naturally occurring mutations in the human HNF4alpha gene impair the function of the transcription factor to a varying degree. 1060 40


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