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

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

Type 2 diabetes mellitus (T2DM) is strongly inherited, but the major genes for this disease have been elusive. In contrast, early-onset, autosomal-dominant diabetes results from at least 5 loci, of which hepatocyte nuclear factor 1a (HNF1alpha or TCF1) is the most common cause. Mutations in HNF1alpha also cause later-onset diabetes in some Caucasian populations, but the role of these mutations has not been tested in African American populations. We used a variety of screening methods, including both single-strand conformation polymorphism (SSCP) analysis and dideoxy fingerprint analysis, to search for mutations in 51 African American subjects with onset of diabetes before age 50 years. Potential mutations were confirmed by direct sequencing. We identified 21 different variants, of which 11 were unique to African Americans. Four mutations either altered the amino acid sequence (Gly52Ala and Gly574Ser) or were close to a splice site (intron 1 and intron 10). A 5-nucleotide insertion in intron 1 was present in both diabetic members of a small family, but Gly52Ala, Gly574Ser, and the intron 10 mutation did not segregate with diabetes. Gly574Ser was present in 2 large families and 5% of controls, all of which appeared to share the same common HNF1alpha haplotype. Surprisingly, radioactive SSCP analysis under 2 room-temperature conditions performed as well as methods using fluorescent labeling that were expected to be more sensitive. We conclude that in African American individuals under age 50, variation in the HNF1a gene is common but unlikely to be a significant cause of T2DM.
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PMID:Molecular scanning analysis of hepatocyte nuclear factor 1alpha (TCF1) gene in typical familial type 2 diabetes in African Americans. 1069 Sep 59

During pancreatic development, the paired homeodomain transcription factor PAX4 is required for the differentiation of the insulin-producing beta cells and somatostatin-producing delta cells. To establish the position of PAX4 in the hierarchy of factors controlling islet cell development, we examined the control of the human PAX4 gene promoter. In both cell lines and transgenic animals, a 4.9-kilobase pair region directly upstream of the human PAX4 gene transcriptional start site acts as a potent pancreas-specific promoter. Deletion mapping experiments demonstrate that a 118-base pair region lying approximately 1.9 kilobase pairs upstream of the transcription start site is both necessary and sufficient to direct pancreas-specific expression. Serial deletions through this region reveal the presence of positive elements that bind several pancreatic transcription factors as follows: the POU homeodomain factor HNF1alpha, the orphan nuclear receptor HNF4alpha, the homeodomain factor PDX1, and a heterodimer composed of two basic helix-loop-helix factors. Interestingly, mutations in the genes encoding four of these factors cause a dominantly inherited form of human diabetes called Maturity Onset Diabetes of the Young. In addition, PAX4 itself has at least two high affinity binding sites within the promoter through which it exerts a strong negative autoregulatory effect. Together, these results suggest a model in which PAX4 expression is activated during pancreatic development by a combination of pancreas-specific factors but is then switched off once PAX4 protein reaches sufficient levels.
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PMID:Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. 1096 7

Mutations in the HNF4alpha gene are associated with the subtype 1 of maturity-onset diabetes of the young (MODY1), which is characterized by impaired insulin secretory response to glucose in pancreatic beta-cells. Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor critical for liver development and hepatocyte-specific gene expression. However, the role of HNF4alpha in the regulation of pancreatic beta-cell gene expression and its correlation with metabolism secretion coupling have not been previously investigated. The tetracycline-inducible system was employed to achieve tightly controlled expression of both wild type (WT) and dominant-negative mutant (DN) of HNF4alpha in INS-1 cells. The induction of WT-HNF4alpha resulted in a left shift in glucose-stimulated insulin secretion, whereas DN-HNF4alpha selectively impaired nutrient-stimulated insulin release. Induction of DN-HNF4alpha also caused defective mitochondrial function substantiated by reduced [(14)C]pyruvate oxidation, attenuated substrate-evoked mitochondrial membrane hyperpolarization, and blunted nutrient-generated cellular ATP production. Quantitative evaluation of HNF4alpha-regulated pancreatic beta-cell gene expression revealed altered mRNA levels of insulin, glucose transporter-2, L-pyruvate kinase, aldolase B, 2-oxoglutarate dehydrogenase E1 subunit, and mitochondrial uncoupling protein-2. The patterns of HNF4alpha-regulated gene expression are strikingly similar to that of its downstream transcription factor HNF1alpha. Indeed, HNF4alpha changed the HNF1alpha mRNA levels and HNF1alpha promoter luciferase activity through altered HNF4alpha binding. These results demonstrate the importance of HNF4alpha in beta-cell metabolism-secretion coupling.
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PMID:Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta -cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. 1096 20

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a nuclear receptor involved in glucose homeostasis and is required for normal beta-cell function. Mutations in the HNF4alpha gene are associated with maturity-onset diabetes of the young type 1. E276Q and R154X mutations were previously shown to impair intrinsic transcriptional activity (without exogenously supplied co-activators) of HNF4alpha. Given that transcriptional partners of HNF4alpha modulate its intrinsic transcriptional activity and play crucial roles in HNF4alpha function, we investigated the effects of these mutations on potentiation of HNF4alpha activity by p300, a key co-activator for HNF4alpha. We show here that loss of HNF4alpha function by both mutations is increased through impaired physical interaction and functional cooperation between HNF4alpha and p300. Impairment of p300-mediated potentiation of HNF4alpha transcriptional activity is of particular importance for the E276Q mutant since its intrinsic transcriptional activity is moderately affected. Together with previous results obtained with chicken ovalbumin upstream promoter-transcription factor II, our results highlight that impairment of recruitment of transcriptional partners represents an important mechanism leading to abnormal HNF4alpha function resulting from the MODY1 E276Q mutation. The impaired potentiations of HNF4alpha activity were observed on the promoter of HNF1alpha, a transcription factor involved in a transcriptional network and required for beta-cell function. Given its involvement in a regulatory signaling cascade, loss of HNF4alpha function may cause reduced beta-cell function secondary to defective HNF1alpha expression. Our results also shed light on a better structure-function relationship of HNF4alpha and on p300 sequences involved in the interaction with HNF4alpha.
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PMID:Maturity-onset diabetes of the young Type 1 (MODY1)-associated mutations R154X and E276Q in hepatocyte nuclear factor 4alpha (HNF4alpha) gene impair recruitment of p300, a key transcriptional co-activator. 1143 18

The bifunctional protein DCoH (Dimerizing Cofactor for HNF1) acts as an enzyme in intermediary metabolism and as a binding partner of the HNF1 family of transcriptional activators. HNF1 proteins direct the expression of a variety of genes in the liver, kidney, pancreas, and gut and are critical to the regulation of glucose homeostasis. Mutations of the HNF1alpha gene underlie maturity onset diabetes of the young (MODY3) in humans. DCoH acts as a cofactor for HNF1 that stabilizes the dimeric HNF1 complex. DCoH also catalyzes the recycling of tetrahydrobiopterin, a cofactor of aromatic amino acid hydroxylases. To examine the roles of DCoH, a targeted deletion allele of the murine DCoH gene was created. Mice lacking DCoH are viable and fertile but display hyperphenylalaninemia and a predisposition to cataract formation. Surprisingly, HNF1 function in DCoH null mice is only slightly impaired, and mice are mildly glucose-intolerant in contrast to HNF1alpha null mice, which are diabetic. DCoH function as it pertains to HNF1 activity appears to be partially complemented by a newly identified homolog, DCoH2.
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PMID:Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene. 1201 Oct 81

Mutations in the HNF4alpha gene have been correlated with maturity-onset diabetes of the young, which is characterized mainly by pancreatic beta-cell dysfunction and is also associated with mild liver abnormalities. HNF4alpha D126Y and D126H mutations were found in a patient with early-onset type 2 diabetes, and the R324H mutation was found in a common type 2 diabetic nephropathic patient. We investigated whether these mutations, which have not yet been functionally characterized, impair HNF4alpha function in three cell models: HEK 293 embryonal kidney cells, HepG2 hepatoma cells, and betaTC3 pancreatic beta-cells. The R324H mutation had no effect on HNF4alpha function with either the HNF1alpha and L-type pyruvate kinase (LPK) promoters, but the D126Y and D126H mutations impaired HNF4alpha transcriptional activities in all tested cell lines. These impairments by D126Y and D126H mutations, which are located in the T box, are not due to a loss of dimerization but to a loss of DNA binding. Interestingly, the strongest functional consequences of these mutations were observed on the HNF1alpha promoter in betaTC3 cells. Given the key role of the transcription factor HNF1alpha in pancreatic beta-cell function, it can be inferred that impairment of HNF4alpha function by these mutations affects metabolic pathways in pancreatic beta-cells and contributes to development of diabetes. Moreover, the HNF4alpha-mediated activation of the apolipoprotein CIII promoter in HepG2 cells was significantly impaired by D126Y and D126H mutations. These results support clinical findings that liver function can also be impaired in diabetic patients having HNF4alpha mutations.
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PMID:Mutations in hepatocyte nuclear factor 4alpha (HNF4alpha) gene associated with diabetes result in greater loss of HNF4alpha function in pancreatic beta-cells than in nonpancreatic beta-cells and in reduced activation of the apolipoprotein CIII promoter in hepatic cells. 1211 Sep 48

Hepatocyte nuclear factor (HNF)1alpha is a homeo-domain-containing transcription factor participating in the regulation of gene expression in liver, kidney, gut and pancreas of vertebrates. In humans mutations in the HNF1 gene are responsible for one form of maturity onset diabetes of the young (MODY3). To define the molecular mechanism underlying MODY3 we investigated the functional properties of seven MODY3-associated mutations representing the spectrum of different kinds of mutations affecting all functional domains of the protein. The mutations introduced into an expression vector encoding human HNF1alpha include in-frame deletion (AN127), nonsense (Q7X, R171X), frameshift (P291fsinsC) and missense (R229Q, P447L, T6201) mutations. Gel retardation and reporter gene assays showed that the functional properties of these mutants differ dramatically, but none of these mutants act in a dominant negative manner. Moreover, the mRNA stability of the mutants AN127, R171X, P291fsinsC and T547E548fsdelTG is impaired compared to the wild-type sequence in transfected cells. This decreased RNA stability is independent of the presence of an intron in the expression vector and thus differs from mechanisms known to be involved in nonsense-mediated decay (NMD). Our results suggest that haploinsufficiency of HNF1alpha is responsible for the pathogenesis of MODY3.
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PMID:Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. 1253 May 34

We previously demonstrated that Irs2-/- mice develop diabetes due to beta-cell growth failure and insulin resistance; however, glucose-induced insulin secretion was increased in islets isolated from Irs2-/- mice. Pdx-1, a transcription factor important for maintenance of the beta-cell function, was recently reported to be severely reduced in Irs2-/- murine beta-cells. We report herein that Pdx-1 expression, including the amount of Pdx-1 localized in the nucleus, is not down-regulated in our Irs2-/- murine beta-cells with a C57BL/6 background. We have also demonstrated the expression of upstream genes of Pdx-1, such as HNF3beta and HNF1alpha, as well as its downstream genes, including insulin, Glut2, and Nkx6.1, to be well preserved. We have further demonstrated Pdx-1 expression to also be preserved in beta-cells of 30-week-old diabetic Irs2-/- mice. In addition, surprisingly, even in Irs2-/- mice on a high fat diet with markedly elevated blood glucose, exceeding 400 mg/dl, Pdx-1 expression was not reduced. Furthermore, we found Pdx-1 to be markedly decreased in certain severely diabetic Irs2-/- mice with a mixed C57BL/6J x 129Sv background. We conclude that 1) Pdx-1 expression in Irs2-/- mice is regulated in a strain-dependent manner, 2) Irs2-/- mice develop diabetes associated with beta-cell growth failure even when Pdx1 expression is preserved, and 3) Pdx-1 expression is preserved in severely hyperglycemic Irs2-/- mice with a C57BL/6 background on a high fat diet.
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PMID:Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner. 1286 53

The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1alpha gene (MODY3) and the A3243G in mtDNA. Beta-cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1alpha were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator-activated receptor (PPAR)gamma was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1alpha mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in beta-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1alpha mutations.
Diabetes 2004 Jul
PMID:Cosegregation of MIDD and MODY in a pedigree: functional and clinical consequences. 1522 Feb 16


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