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)

Glucokinase, the major enzyme that phosphorylates glucose upon entry into liver and islet beta-cells, has been considered a prime candidate for inherited defects predisposing to NIDDM. Now that the human gene has been isolated, this question has been addressed directly. Polymorphic markers flanking the gene were identified. These markers (microsatellites) are composed of variable numbers of dinucleotide repeats that vary in size, resulting in different alleles. Variably sized alleles can be typed rapidly from genomic DNA of individuals by the PCR. Studies of inheritance of glucokinase genes have revealed significant linkage in families with early-onset NIDDM, or MODY, and mutations have been identified within the coding region of the gene in some families. These studies are extremely encouraging, as they indicate that genes can be identified even in this heterogeneous genetic disorder. This study considers the phenotypes that result from glucokinase defects and the relationship of MODY to NIDDM, and it estimates the role of glucokinase defects in NIDDM in general.
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PMID:Glucokinase and NIDDM. A candidate gene that paid off. 139 13

Glucokinase is thought to play a glucose-sensor role in the pancreas, and abnormalities in its structure, function, and regulation can induce diabetes. We isolated the human glucokinase gene, and determined its genomic structure including exon-intron boundaries. Structure of the glucokinase gene in human was very similar to that in rat. Then, by screening Japanese diabetic patients using polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) and direct-sequencing strategies, we identified a missense mutation substituting arginine (AGG) for glycine (GGG) at position 261 in exon 7 of the glucokinase gene in a patient with early-onset non-insulin-dependent diabetes (NIDDM).
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PMID:Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus. 146 39

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) which is characterized by an early age at onset and an autosomal dominant mode of inheritance. Except for these features, the clinical characteristics of patients with MODY are similar to those with the more common late-onset form(s) of NIDDM. Previously we observed tight linkage between DNA polymorphisms in the glucokinase gene on the short arm of chromosome 7 and NIDDM in a cohort of sixteen French families having MODY. Glucokinase is an enzyme that catalyses the formation of glucose-6-phosphate from glucose and may be involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Because the glucokinase gene was a candidate for the site of the genetic lesion in these families, we scanned this gene for mutations. Here we report the identification of a nonsense mutation in the gene encoding glucokinase and its linkage with early-onset diabetes in one family. To our knowledge, this result is the first evidence implicating a mutation in a gene involved in glucose metabolism in the pathogenesis of NIDDM.
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PMID:Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. 157 17

Glucokinase is a key enzyme of glucose metabolism that phosphorylates glucose to glucose-6-phosphate (G-6-P). This is the first step of glucose metabolism after the uptake of glucose by glucose transporter 2 (GLUT 2). Glucokinase is one of the hexo-kinases and is expressed only in pancreatic beta cells and hepatocytes. Recently it was reported that glucokinase gene is associated with some families with MODY (maturity-onset diabetes of the young). As MODY is a subtype of diabetes which is inherited autosomal dominantly, the correlation of diabetes with glucokinase gene was vigorously studied in many laboratories. The first mutation in exon 7 of the glucokinase gene was reported in 1992. Since the first report of the glucokinase gene mutation in exon 7, a number of mutations and a deletion were reported to be associated with MODY or late-onset NIDDM. But investigations by many groups revealed that glucokinase gene abnormalities are responsible for less than one per cent of NIDDM which is relatively small compared with diabetes with mitochondrial gene alterations.
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PMID:[Glucokinase gene abnormalities in maturity-onset diabetes of the young (MODY) and late-onset NIDDM]. 798 82

Glucokinase has been proposed to play an important role as a glucose sensor in pancreatic beta-cells. Mutations in the glucokinase gene have been shown to be the major cause of maturity-onset diabetes of the young (MODY) in Caucasian subjects. In population-association study with microsatellite DNA polymorphisms in Japanese subjects with NIDDM, a negative association was evident between NIDDM and the glucokinase gene locus, although contradictionary results were present. Using PCR-SSCP analysis, no glucokinase mutation, which induces changes in amino acid residues, was identified in Japanese subjects with classical late-onset NIDDM. These results suggest that mutations in this gene are not the major cause of common form NIDDM in Japanese.
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PMID:[Mutations of glucokinase gene in Japanese subjects with NIDDM]. 798 1

Glucokinase plays an important role in the regulation of insulin secretion and is therefore an attractive candidate gene for both insulin dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. A single G-A nucleotide polymorphism at the -30 position of the beta-cell specific promoter region of the glucokinase gene was previously associated with reduced beta-cell function. In the present study we analysed 268 consecutive newly diagnosed Swedish patients classified with either IDDM (n = 205), NIDDM (n = 31) or unclassifiable (n = 32) diabetes between the ages of 15 and 35 years along with a group of 158 age- and sex-matched control subjects. The beta-cell promoter region was amplified by the polymerase chain reaction and the G-A variant identified by single strand conformational polymorphism. There was no significant difference in allele frequencies of G and A between any of the subject groups and likewise, no significant difference in the frequencies of the G/G, G/A, or A/A genotypes. Eight subjects were homozygous for the less common A allele, five had IDDM and three were control subjects. Our results suggest that the -30 beta-cell glucokinase promoter variant is not associated with IDDM.
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PMID:The beta cell glucokinase promoter variant is an unlikely risk factor for diabetes mellitus. Diabetes Incidence Study in Sweden (DISS). 926 92

Glucokinase plays an important role in regulating insulin secretion in response to changes in blood glucose levels. As a result, one form of maturity onset diabetes of the young (MODY) results from haploinsufficiency of glucokinase. In both liver and pancreatic islet, glucokinase is allosterically regulated by an inhibitory protein (glucokinase regulatory protein, GCKR). GCKR has therefore become an important gene for functional analysis in type 2 diabetes. To allow genetic assessment of any such role, we have determined the structure of the human GCKR gene. Characterization of P1 and YAC clones containing GCKR shows it to consist of 19 exons spanning 27 kb. RT-PCR, RACE, and RNase protection experiments defined a transcriptional start site for GCKR 66 bp upstream of the initiation codon, but provided no evidence for islet cell specific alternative splicing in the rat. By SSCP screening, a common polymorphic sequence variant has been defined within exon 15 of human GCKR, at nt 1400 of the cDNA. This alters amino acid residue 446 from proline, conserved in rat and Xenopus, to leucine.
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PMID:Organization of the human glucokinase regulator gene GCKR. 957 Sep 59

Glucokinase (GK, EC 2.7.1.2), a member of the enzyme family of hexokinases, has been shown to be linked to maturity-onset diabetes of the young type II (MODY-2). Although nucleotide and amino acid sequence information are available for the human varieties, they are not known for the variety from Bacillus stearothermophilus, which is often used in protein binding studies. Here, a combination of electrospray Fourier transform mass spectrometry (FTMS) and infrared multiphoton dissociation (IRMPD) is used to obtain accurate molecular weight and preliminary amino acid sequence information for the protein. Electrospray FTMS provides evidence of a solution phase dimer. In addition, dithiothreitol reduction shows no shift in high-resolution isotopic distributions, indicating a probable absence of disulfide bonds in the protein. The partial sequence information obtained from IRMPD could be the basis for creating a DNA probe for the protein.
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PMID:High-resolution electrospray ionization Fourier transform mass spectrometry with infrared multiphoton dissociation of glucokinase from Bacillus Stearothermophilus. 979 87

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

Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose levels within a narrow range. Mutations in the glucokinase gene cause a rare form of diabetes called maturity-onset diabetes of the young (MODY). An early onset (less than 25 years), autosomal dominant inheritance and low insulin secretion stimulated by glucose characterize MODY patients. Specific insulin and proinsulin were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared to non-diabetic unrelated individuals (control group 1) matched for age and body mass index (BMI). In one kindred, some of these subjects were also obese (BMI > 26 kg/m2), and other family members also presented with obesity and/or late-onset NIDDM. The MODY patients were also compared to a group of five of their first-degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was different in members of the two MODY kindreds. Fasting proinsulin and the proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects from control group 1, but were significantly lower than in MODY members of kindred SA (P < 0.02 and P < 0.01, for proinsulin and proinsulin/insulin ratio, respectively). Moreover, MODY members of family SA had higher levels of proinsulin and proinsulin/insulin ratio, although not significantly different, when compared to their first-degree relatives and to subjects from control group 2. In conclusion, we observed variable degrees of proinsulin levels and proinsulin/insulin ratio in MODY members of two different kindreds. The higher values of these parameters found in MODY and non-MODY members of kindered SA is probably related to the obesity and late-onset NIDDM background present in this family.
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PMID:Specific insulin and proinsulin secretion in glucokinase-deficient individuals. 1034 5


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