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)

Insulin promoter factor 1 (IPF-1) is a homeodomain-containing protein that is thought to be a key regulator of pancreatic islet development and insulin gene transcription in beta-cells. This report describes the isolation and characterization of the human IPF-1 gene. The coding region, which showed 83% nucleotide identity with the mouse IPF-1 gene, was encoded by two exons that extended over a 5-kb region of human genome. The deduced human IPF-1 protein contained 283 amino acids, 1 amino acid less than the mouse IPF-1 protein. The homeodomain region of IPF-1 was encoded by the second exon, and it was highly conserved among species. The human IPF-1 gene was mapped to chromosome 13q12(12.1) by fluorescent in situ hybridization (FISH) analysis. A simple sequence repeat polymorphism (ipf1CA2) was identified in the genomic clone. Polymerase chain reaction (PCR) amplification of this repeat region revealed two alleles (heterozygosity = 0.32). This simple sequence repeat polymorphism, and thus the IPF-1 gene, was incorporated into the human linkage map by genotyping reference Human Polymorphism Study Center (CEPH) pedigrees. Multipoint analysis with the CEPH genotype database placed the gene with equal likelihood between two marker intervals: D13S292-cdx3GA1 and cdx3GA1-D13S289 on chromosome 13, consistent with the results of FISH analysis. Two-point linkage analysis inferred that the most likely location for ipf1CA2 was at theta = 0 from cdx3GA1 locus. The exon-intron boundaries of the IPF-1 gene were sequenced, and primers were synthesized to search the homeodomain region for potential variants in patients with NIDDM. By single-strand conformational polymorphism analysis, no variants were found within this region in 61 Japanese patients, which could contribute to the pathogenesis of NIDDM. The isolation of the human IPF-1 gene, along with characterization of its genomic structure and chromosomal mapping, will now permit the assessment of the role of this gene in the pathogenesis of NIDDM in various populations.
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PMID:Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene. 863 54

The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. An anti-IPF1 antiserum used in gel-mobility shift analysis supershifted the DNA protein complex formed with the hUPE3 probe and nuclear extracts from HIT-T15 cells, thus supporting the involvement of IPF1 in GK gene activation in HIT-T15 cells. In contrast to the insulin gene, however, neither the synergistic effect of the Pan1 expression on the IPF1-induced promoter activation nor the glucose responsiveness of the activity was observed for the GK gene promoter. These results revealed some conservative but unique features for the transcriptional regulation of the beta-cell-specific genes in humans. Being implicated in insulin and GK gene regulations as a common transcription factor, IPF1/STF-1/PDX-1 is likely to play an essential role in maintaining normal beta-cell functions.
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PMID:The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells. 886 50

The differential diagnosis of hyperglycemia in childhood and adolescence has to take into consideration early-onset non-insulin-dependent diabetes, defined as maturity onset diabetes of the young (MODY). To date, mutations in genes of five proteins have been shown to cause MODY: glucokinase (MODY2), hepatic nuclear factor-1 alpha (HNF-1 alpha) (MODY3), hepatic nuclear factor-4 alpha (HNF-4 alpha) (MODY1), insulin promoter factor 1 (IPF-1) (MODY4) and hepatic nuclear factor-1 beta (HNF-1 beta) (MODY5), but other MODY genes still await elucidation. Clinical and metabolic heterogeneity of these subtypes of type 2 diabetes need to be defined, as deficiency of each factor has its own phenotype. Pediatric diabetologists should be aware of the increasing importance of MODY as a possible cause of hyperglycemia in children and adolescents. This will allow for the early diagnosis of these metabolic conditions and for the appropriate follow-up and treatment.
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PMID:Maturity-onset diabetes of the young (MODY): a new challenge for pediatric diabetologists. 1041 64

Neonatal diabetes mellitus (NDM) is defined as hyperglycaemia occurring in the first few weeks of life. It can be either transient (TNDM) or permanent (PNDM), and until recently, little was known about the condition. A cohort of 30 infants with a history of TNDM has been studied, and findings have suggested that NDM does not have the same aetiology as classical type 1 childhood diabetes. Uniparental isodisomy of chromosome 6 and an unbalanced duplication of paternal chromosome 6 have both been described as a genetic basis for TNDM in over 75% of the cases. In addition, cerebellar hypoplasia and Walcott-Rallison syndrome have been associated with PNDM, suggesting an autosomal recessive inheritance pattern; furthermore, a mutation in the gene insulin promoter factor 1 has been identified as a cause of pancreatic agenesis in PNDM. In the long term, TNDM may reduce beta cell functional capacity and present a predisposition to type 2 diabetes mellitus.
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PMID:Neonatal diabetes: new insights into aetiology and implications. 1089 36

Abundant evidence supports a genetic predisposition to both type 2 diabetes and the traits that precede diabetes (insulin resistance and insulin secretion). Unusual causes of diabetes have been identified, including autosomal dominant, single gene forms due to mutations of glucokinase, the hepatocyte nuclear factors, and insulin promoter factor 1. Mitochondrial mutations also may cause type 2 diabetes, but together these causes explain only a small fraction of type 2 diabetes. In contrast, up to 10% of type 2 diabetes, at least in Caucasian populations, may be autoimmune. Animal models of type 2 diabetes support multiple genetic loci. To identify the loci in the remaining 85% of cases, investigators have tested candidate genes in known pathways formutations with some success. However, no candidate identified to date appears to act as a major susceptibility locus. More recently investigators have used linkage approaches to find genes for type 2 diabetes and the prediabetic traits of insulin resistance and insulin secretion. A locus has now been mapped and potential causative variants identified on chromosome 2q, and many other studies are in progress. New genetic tools and the anticipated completion of the human genome project will likely result in the discovery of yet new genes and pathways that may offer new targets for intervention. Whether a better understanding of the pathophysiology can lead to earlier prediction and detection or prevention will depend on the magnitude of risk conferred by individual genes and particular populations.
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PMID:Genetics of type 2 diabetes: an overview for the millennium. 1146 42

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

Psammomys obesus, an animal model of type 2 diabetes, shows rapid and marked depletion of pancreatic insulin content as hyperglycemia develops when fed a high-calorie diet. P. obesus islets do not increase proinsulin gene expression when exposed to high glucose, which may be related to absence of the conserved form of the transcription factor insulin promoter factor 1/pancreatic-duodenal homeobox 1. The present study assesses the importance of regulation of proinsulin gene expression by glucose for insulin production. Islets of diabetes-prone P. obesus and diabetes-resistant Wistar rats, cultured at various glucose concentrations for up to 24 h, were analyzed for proinsulin mRNA by quantitative RT-PCR, proinsulin biosynthesis by leucine incorporation into proinsulin, and insulin content and secretion by RIA. No increase in proinsulin mRNA was observed in P. obesus islets during 24-h exposure to increasing concentrations of glucose. In contrast, rat islets exposed to high glucose responded with a 2- to 3-fold stimulation of proinsulin mRNA. The failure of P. obesus islets to increase proinsulin mRNA was accompanied by a reduced proinsulin biosynthetic response: after 24 h, maximal proinsulin biosynthesis was blunted, associated with depletion of islet insulin content. Inhibition of glucose-stimulated proinsulin gene transcription in rat islets by actinomycin D did not affect the early proinsulin biosynthetic response, which, however, was reduced to the level of P. obesus islets after 24 h in culture. We conclude that stimulation of proinsulin gene transcription by glucose is necessary for maintaining proinsulin biosynthesis and hence conserving pancreatic insulin stores, under conditions of sustained secretory drive, but not for short-term regulation of proinsulin biosynthesis Our findings support the hypothesis that inadequate regulation of proinsulin gene expression by glucose contributes to the failure of P. obesus to cope with the increased demand for insulin associated with caloric excess, leading to depletion of insulin stores and diabetes.
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PMID:Glucose-regulated proinsulin gene expression is required for adequate insulin production during chronic glucose exposure. 1219 32

Maturity onset diabetes of the young (MODY syndrome) is characterized by a non-ketotic type II diabetes mellitus (DM) that is inherited by an autosomal dominant mode and appears in young people, <25 yrs old, with a prominent family history of DM in successive generations from one side of the parents. Usually, it presents as asymptomatic mild hyperglycemia, which can be undetected for prolonged periods. Therefore, diagnosis can be made rather late in adulthood and diabetic complications could be present at diagnosis. It is estimated that it could account for 1-5% of cases in the US and other industrialized countries and can result from mutations on any of six different genes that are expressed in the beta-cells of the pancreas. These genes encode the glycolytic enzyme glucokinase (MODY 2) and the other five encode the transcription factors hepatocyte nuclear factor (HNF) 4alpha (MODY 1), HNF-1alpha (MODY 3), HNF-1beta (MODY 5), insulin promoter factor 1 (IPF-1) (MODY 4) and neurogenic differentiation factor-1 (NeuroD1) (MODY 6).
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PMID:An underdiagnosed type of diabetes: the MODY syndromes. Pathophysiology, clinical presentation and renal disease progression. 1559 29

Pre-B cell leukemia transcription factor 1 (PBX1) encodes a homeodomain containing protein that is essential for pancreatic development and interacts with insulin promoter factor 1 to regulate insulin secretion. PBX1 maps to chromosome 1q22, a region with replicated linkage to type 2 diabetes (T2DM). We screened for sequence variation in nine exons, intronic regions flanking the exons, the 3' untranslated region (3' UTR), as well as 1-kb upstream of exon 1 in 16 Caucasians and 16 African American individuals with T2DM. We evaluated 18 variants including the nonsynonymous substitution G21S in exon 1, one 4 bp insertion/deletion, and one 7 bp insertion/deletion. We typed 10 variants on the basis of frequency and linkage disequilibrium patterns unrelated Caucasian subjects with T2DM and controls, and nine common variants in 129 Caucasian individuals for whom we had detailed assessments of insulin action and insulin secretion. We typed four common variants in African Americans individuals and additional SNPs in pooled DNA samples from both populations. No coding variant was associated with diabetes and no association was found among African American subjects. However, three variants in Caucasians (78287, 91227, and 252050 bp) were associated with T2DM (p<0.05), as were four marker haplotypes that included intron 2 variants. Additionally, three variants including G21S (61 bp) and the diabetes associated SNP at 78287 were significant determinants of insulin sensitivity (S(I)) in interaction with body mass index (p<0.02). Sequence variants in different locations of the PBX1 gene may have modest pleiotropic effects on T2DM susceptibility in Caucasians.
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PMID:Evaluation of sequence variants in the pre-B cell leukemia transcription factor 1 gene: a positional and functional candidate for type 2 diabetes and impaired insulin secretion. 1614 May 54

We have identified Kruppel-like factor 7 (KLF7) as a new candidate for conferring susceptibility to type 2 diabetes. To ascertain the possible involvement of KLF7 in the pathogenesis of type 2 diabetes, we examined the functional roles of KLF7 in various types of cells. In human adipocytes overexpressing KLF7, the expression of adiponectin and leptin was decreased compared with that in control cells, whereas expression of IL-6 was increased. In the insulin-secreting cell line (HIT-T15 cells), the expression and glucose-induced secretion of insulin were significantly suppressed in KLF7-overexpressed cells compared with control cells, accompanied by the reduction in the expression of glucose transporter 2, sulfonylurea receptor 1, Kir6.2, and pancreatic-duodenal homeobox factor 1. We also found that the overexpression of KLF7 resulted in the decrease of hexokinase 2 expression in smooth muscle cells, and of glucose transporter 2 expression in the HepG2 cells. These results suggest that KLF7 may contribute to the pathogenesis of type 2 diabetes through an impairment of insulin biosynthesis and secretion in pancreatic beta-cells and a reduction of insulin sensitivity in peripheral tissues. Therefore, we suggest that KLF7 plays an important role in the pathogenesis of type 2 diabetes, and may be a useful target for new drugs to aid in the prevention and treatment of this disease.
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PMID:Overexpression of Kruppel-like factor 7 regulates adipocytokine gene expressions in human adipocytes and inhibits glucose-induced insulin secretion in pancreatic beta-cell line. 1633 72


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