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  • 1
    Electronic Resource
    Electronic Resource
    Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues (1985)
    Springer
    Diabetologia 28 (1985), S. 343-347 
    Details
    ISSN: 1432-0428
    Keywords: RNA blot hybridization ; rat ; proinsulin mRNA ; brain mRNA ; pancreatic islets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of these studies was to determine whether insulin detected immunochemically in extrapancreatic tissues of the adult rat is synthesized in situ by quantitating mRNA in these tissues. A blot hybridization assay was utilized with cloned 32P-proinsulin cDNA. The lower limit of detection was estimated to be 3pg. Proinsulin mRNA concentration was found to be 1000–1500 μg in isolated pancreatic islets and was easily detected in total pancreatic RNA at 10–15 pg/ μg. Proinsulin mRNA was quantitated in rat insulinoma cells adapted to culture at levels 1∶50 those in normal islets. Samples of RNA (20–50 μg) enriched about 50-fold for mRNA sequences by repeated oligo-deoxythymidylate chromatography were assayed. No insulin mRNA was detected in 50 μg samples of RNA from brain or in 20 μg samples from subsections of brain or other extrapancreatic tissues. RNA samples were undegraded as assessed by ability to stimulate protein synthesis in a cell-free system. Proinsulin mRNA from pancreas was added to brain homogenates and recovered intact. Brain RNA samples with insulin mRNA levels 1:1000 that of pancreas would be predicted to have 50–75 pg proinsulin mRNA/50 μg sample assayed if present. Because none was found, brain must have a concentration 〈1:6,000 that of pancreas. These findings suggest that immunoassayable insulin detected in extrapancreatic tissues of the adult rat is synthesized by the pancreas.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00283141
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  • 2
    Electronic Resource
    Electronic Resource
    Differential expression of rat pancreatic islet Beta-cell glucose transporter (GLUT 2), proinsulin and islet amyloid polypeptide genes after prolonged fasting, insulin-induced hypoglycaemia and dexamethasone treatment (1992)
    Springer
    Diabetologia 35 (1992), S. 1125-1132 
    Details
    ISSN: 1432-0428
    Keywords: Proinsulin ; islet amyloid polypeptide mRNA ; islet glucose transporter (GLUT 2) mRNA ; Western blots ; fasting ; insulin-induced hypoglycaemia ; dexamethasone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The question posed by these studies was whether chronic adaptive changes in glucose-stimulated insulin secretion are accompanied by comparable changes in islet Betacell glucose transporter (GLUT 2) gene expression. Control, fasted (3-day), insulin-injected hypoglycaemic (5-day), and dexamethasone-treated (4-day) rats (n=5 for each condition), were studied. After fasting significant decrements in proinsulin mRNA/μg RNA (−32 %, p〈0.05) and islet amyloid polypeptide mRNA/μg RNA (−44%, p〈0.05) were observed, while there was no change in GLUT 2 mRNA/μg RNA (−13%, p〉0.05). After insulin-induced hypoglycaemia, decrements in proinsulin mRNA/μg RNA (−49%, p〈0.01) and islet amyloid polypeptide mRNA/μg RNA (−44 %, p〈0.01) were also observed, with no change in islet GLUT 2 mRNA/μg RNA (−18 %, p〉0.05). Dexamethasone treatment resulted in a marked stimulatory effect on proinsulin mRNA/μg RNA (+236%, p〈0.001) and islet amyloid polypeptide mRNA/μg RNA (+221 %, p〈0.01), while again there was no change in islet GLUT 2 mRNA/μg RNA (+0.3%, p〉0.05). Quantitative immunoblot analysis with a GLUT 2 specific antibody revealed no change in islet GLUT 2 protein with fasting, but a small decrease (−39±11%) in islet GLUT2/μg protein after insulin-induced hypoglycaemia. These results do not support the hypothesis that chronic changes in glucose-stimulated insulin secretion are accompanied by changes in GLUT 2 expression. In contrast to the lack of correlation with GLUT 2, there was a striking correlation between proinsulin and islet amyloid polypeptide mRNAs for all experimental conditions (r=0.974, p〈0.001). These results suggest common transcriptional or turnover regulatory mechanisms or both for proinsulin and islet amyloid polypeptide gene expression, which differ for GLUT 2 gene expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401365
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  • 3
    Electronic Resource
    Electronic Resource
    Linkage analysis of the glucokinase locus in familial Type 2 (non-insulin-dependent) diabetic pedigrees (1993)
    Springer
    Diabetologia 36 (1993), S. 141-145 
    Details
    ISSN: 1432-0428
    Keywords: Familial Type 2 (non-insulin-dependent) diabetes mellitus linkage analysis ; glucokinase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glucokinase is among the few genes which may play a key role in both insulin secretion and insulin action. Glucokinase is present in pancreatic beta cells where it may have a key role in the glucose sensing mechanism, and it is present in hepatocytes, where it may participate in glucose flux. Glucokinase defects have recently been implicated in maturity-onset diabetes of the young. To examine the hypothesis that glucokinase plays a key role in the predisposition to common familial Type 2 (non-insulin-dependent) diabetes mellitus, we typed 399 members of 18 Utah pedigrees with multiple Type 2 diabetic individuals for two markers in the 5′ and 3′ flanking regions of the glucokinase gene. Linkage analysis was performed under both dominant and recessive models. We also repeated these analyses with individuals with impaired glucose tolerance who were considered affected if their stimulated (2-h) glucose exceeded age-specific normal levels for 95 % of the population. Under several dominant models, linkage was significantly excluded, and under recessive models log of the odds (LOD) score was less than −1. We were also unable to demonstrate statistical support for the hypothesis that a small subgroup of pedigrees had glucokinase defects, but the most suggestive pedigree (individual pedigree LOD 1.8–1.9) ranked among the youngest and leanest in our cohort. We can exclude a major role for glucokinase in familial Type 2 diabetes, but our data cannot exclude a role for this locus in a minority of pedigrees. Further testing of the hypothesis that glucokinase defects contribute to diabetes in a small proportion of Type 2 diabetic pedigrees must await thorough sequence analysis of the glucokinase gene, including regulatory regions, particularly from pedigrees with positive LOD scores.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400695
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  • 4
    Electronic Resource
    Electronic Resource
    Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning (1994)
    Springer
    Diabetologia 37 (1994), S. 104-110 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes mellitus ; glucokinase ; gestational diabetes ; American Blacks ; single-strand conformation polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mutations of the glucokinase gene result in early-onset familial Type 2 (non-insulin-dependent) diabetes mellitus, and several members of the mutant glucokinase kindreds were originally diagnosed as having gestational diabetes. This study examined the glucokinase gene in 270 American Black women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed Type 2 diabetes after pregnancy (overt diabetes), and 99 normal control subjects who were recruited during the peripartum period. Two simple sequence repeat polymorphisms flanking either end of the glucokinase gene were evaluated. No association was found between glucokinase alleles and gestational diabetes only or overt diabetes, after adjustment for multiple comparisons. To detect single base changes, all 11 exons and proximal islet and liver promoter regions were examined by polymerase chain reaction plus single-stranded conformational polymorphism analysis in 45 gestational diabetes only patients who had not yet developed Type 2 diabetes. Nine coding region variants were identified: Ala11 (GCC) to Thr11 (ACC) in islet exon 1, and 8 variants either in untranslated regions or in the third base of a codon. Four variant sites were found in introns, but none in splicing consensus sequences. Analysis of the promoter regions revealed two common variants, G→A at islet −30 (24%), and G→A at liver −258 (42%). The frequencies of the promoter variants, determined by allele specific polymerase chain reaction analysis, did not differ among the three groups. Thus, no significant coding sequence glucokinase mutations were found in 90 alleles from 45 patients with gestational diabetes. Further studies will be required to rule out a minor role of the newly-described promoter region variants as susceptibility factors in this disorder.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00428785
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  • 5
    Electronic Resource
    Electronic Resource
    Cloning of human pancreatic islet large conductance Ca2 + -activated K + channel (hSlo) cDNAs: evidence for high levels of expression in pancreatic islets and identification of a flanking genetic marker (1996)
    Springer
    Diabetologia 39 (1996), S. 891-898 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Calcium-activated potassium channels ; islets of Langerhans ; diabetes mellitus ; radiation hybrids ; physical map ; chromosome 10
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin secretion from pancreatic beta cells is dependent on membrane potential changes that result from the concerted regulation of multiple ion channels. Among the distinct K + channels known to be expressed in beta cells, large conductance Ca2 + -activated K + channels have been suggested to play an important role in stimulus-secretion coupling. In the course of a strategy to identify transcripts that are enriched in human pancreatic islet cells, we isolated a partial cDNA encoding a human large conductance Ca2 + -activated K + channel mRNA (hSlo). Northern analysis of mRNA showed that among a panel of human tissues hSlo is expressed at its highest levels in pancreatic islets. Screening of human insulinoma and islet cDNA libraries with the partial cDNA resulted in the isolation of 19 hSlo cDNAs. These comprised three splice variants: one shared the common underlying structure of previously reported Slo cDNAs, another variant encoded a novel 60-amino acid insertion in the putative Ca2 + -sensing domain of hSlo, while the third group of clones had an alternate exon encoding eight amino acids in the predicted COOH-terminal end. Analysis of somatic-cell hybrids containing different portions of chromosome 10 indicated that hSlo maps to chromosome 10q22.2–q23.1. Furthermore, high resolution localization was obtained by analysis of genome-wide radiation hybrids and the CEPH “B” mega-YAC library, both of which identified for the first time a highly polymorphic genetic marker (D10S195) linked to hSlo. These studies provide tools with which to explore the physiological role of Ca2 + -activated K + channel proteins in pancreatic islets, and also to investigate the contribution of this locus to the inherited susceptibility to non-insulin-dependent diabetes mellitus. [Diabetologia (1996) 39: 891–898]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00403907
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  • 6
    Electronic Resource
    Electronic Resource
    A human pancreatic islet inwardly rectifying potassium channel: cDNA cloning, determination of the genomic structure and genetic variations in Japanese NIDDM patients (1996)
    Springer
    Diabetologia 39 (1996), S. 447-452 
    Details
    ISSN: 1432-0428
    Keywords: Potassium channel ; inward rectifier ; non-insulin-dependent diabetes mellitus ; genetics ; single strand conformation polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ligand gated potassium channels, such as the ATP-regulated potassium channel, play crucial roles in coupling of stimuli to insulin secretion in pancreatic beta cells. Mutations in the genes might lead to the insulin secretory defects observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). We isolated a cDNA encoding a putative subunit of a ligand gated potassium channel from a human islet cDNA library. The channel, which we designated hiGIRK2, appeared to be an alternative spliced variant and a human homologue of recently reported mbGIRK2, KATP-2/BIR1. Transcripts were detected in human brain and pancreas, but not in other tissues including cardiac muscle. The sizes of transcripts in the pancreas differed from those in the brain, suggesting tissue-specific alternative splicing and possible isoforms. We then isolated human genomic clones, determined the complete genomic structure and localized the gene to chromosome 21 (21q22). The gene was comprised of four exons and the protein was encoded by three exons. The entire coding region of the hiGIRK2 gene was scanned by polymerase chain reaction-single strand conformation polymorphism analysis in 80 Japanese NIDDM patients. We found five nucleotide substitutions; three were silent mutations of the third base of codons, one in the first intron, 9 bases upstream of exon 2, and one in the 3′-untranslated region. We conclude that mutations in the gene encoding MGIRK2, a (subunit of) ligand gated potassium channel, is not a major determinant of the susceptibility to NIDDM in Japanese.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400676
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  • 7
    Electronic Resource
    Electronic Resource
    Level of skeletal muscle glucose transporter protein correlates with insulin-stimulated whole body glucose disposal in man (1991)
    Springer
    Diabetologia 34 (1991), S. 763-765 
    Details
    ISSN: 1432-0428
    Keywords: Glucose transport ; insulin ; muscle ; euglycaemic clamp ; GLUT4
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The content of GLUT4 glucose transporter mRNA and protein were measured in samples of the vastus lateralis muscle of normal volunteers subjected to a 4-h hyperinsulinaemic, euglycaemic clamp. Plasma glucose concentration was clamped at 5.3±0.1 mmol/l, and serum insulin concentration was maintained at 740±5 pmol/l. Whole body glucose uptake averaged 38.3±2.2 μmol · kg−1 · min−1, 62% of this being due to disposal via non-oxidative pathways. A significant correlation existed between basal levels of GLUT4 protein and the rate of whole body glucose disposal (r=0.77, p〈0.02) and non-oxidative glucose disposal (r=0.80, p〈0.02). There was no correlation between GLUT4 protein content and oxidative glucose disposal (r=0.08, NS). These observations are consistent with an important role for skeletal muscle GLUT4 protein in whole body glucose disposal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401526
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  • 8
    Electronic Resource
    Electronic Resource
    A genetic marker at the glucokinase gene locus for Type 2 (non-insulin-dependent) diabetes mellitus in Mauritian Creoles (1992)
    Springer
    Diabetologia 35 (1992), S. 632-638 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes mellitus ; glucokinase ; population association study ; polymorphism ; dinucleotide (CA)n repeat ; obesity ; genetic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The prevalence of Type 2 (non-insulin-dependent) diabetes mellitus is high in Mauritius, a multiethnic island nation in the southwestern Indian Ocean. Evaluation of candidate genes in the different ethnic groups represents a means of assessing the genetic component. As glucokinase is known to be a key regulator of glucose homeostasis in liver and pancreatic Beta-cells, the human gene was isolated and a dinucleotide repeat (CA)n marker was identified at this locus. A polymerase chain reaction assay was developed, and alleles differing in size were observed in individuals, according to the number of repeats in the amplified fragment. Eighty-five Creoles and 63 Indians of known glucose tolerance status were typed by amplification of genomic DNA for this dinucleotide (CA)n repeat marker. Four different alleles were observed including Z, the most common allele, and Z+2, Z+4, and Z+10, which differed from Z by 2, 4, and 10 nucleotides respectively. In Mauritian Creoles, the frequency of the Z+2 allele was greater in Type 2 diabetic subjects than in control subjects (23.8 % vs 8.9 %, p=0.008), and the frequency of the Z allele was lower in Type 2 diabetic subjects (60% vs 75.6%, p=0.03). Analysis with univariate logistic regression models indicated that the Z+2 allele had the highest odds ratio, 3.08 (95% confidence interval 1.14–8.35, p=0.0416), among the other risk factors (age, sex, body mass index, and waist/hip ratio). The multivariate odds ratio for Type 2 diabetes was 2.88 (95% confidence interval 0.98–8.50, p=0.0551). In contrast, in the Mauritian Indian population, no differences were noted between the frequency of any glucokinase allele in the Type 2 diabetic and control groups. These data suggest that the Z+2 allele is an important risk factor for Type 2 diabetes in Mauritian Creoles, but not in Mauritian Indians, and also imply that the glucokinase gene may play a role in the pathogenesis of Type 2 diabetes in Mauritian Creoles. Further studies are needed to define the nature of this defect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400254
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  • 9
    Electronic Resource
    Electronic Resource
    Two microsatellite repeat polymorphisms flanking opposite ends of the human glucokinase gene: use in haplotype analysis of Welsh Caucasians with Type 2 (non-insulin-dependent) diabetes mellitus (1993)
    Springer
    Diabetologia 36 (1993), S. 409-413 
    Details
    ISSN: 1432-0428
    Keywords: Glucokinase gene ; microsatellite ; polymorphism ; linkage disequilibrium ; haplotypes ; Type 2 (non-insulin-dependent) diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of this study was to evaluate the role of potential glucokinase defects contributing to susceptibility to Type 2 (non-insulin-dependent) diabetes mellitus in Welsh Caucasians. For this analysis, two microsatellite repeat polymorphisms flanking opposite ends of the gene were employed. For a recently described microsatellite (GCK2), located 6 kilobases upstream of islet exon 1, six different sized alleles were observed, with heterozygosity of 0.50 and polymorphism information content 0.44. Combined heterozygosity with another microsatellite repeat (GCK1) was 0.72. Significant linkage disequilibrium was noted between GCK2 and GCK1, suggesting that haplotypes may be a better predictor of Type 2 diabetes than analysis with either microsatellite alone. Using these two markers, the association with Type 2 diabetes was examined. The frequencies of alleles and genotypes at GCK1 did not differ between the patients with Type 2 diabetes (n=157) and control subjects (n=73). Similarly no differences were observed in GCK2 alleles or genotypes. The frequencies of haplotypes, derived from the two markers, also did not differ between the two groups. To investigate the possibility of minor metabolic effects of glucokinase defects, we also studied the association between the GCK alleles or haplotypes and the response profiles to meal tolerance tests. No association was observed between plasma glucose or insulin responses to meal tolerance tests with GCK haplotypes or alleles. These results suggest that glucokinase mutations in Welsh Caucasians are not major determinants of susceptibility to the common type of Type 2 diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402276
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  • 10
    Electronic Resource
    Electronic Resource
    Variability of the pancreatic islet beta cell/liver (GLUT 2) glucose transporter gene in NIDDM patients (1994)
    Springer
    Diabetologia 37 (1994), S. 420-427 
    Details
    ISSN: 1432-0428
    Keywords: NIDDM ; glucose transporter ; allele ; genotype
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of these experiments was to test the hypothesis that impaired glucose-stimulated insulin secretion in NIDDM is due to mutations in the islet beta cell/liver glucose transporter (GLUT 2) gene. Using oligonucleotide primers flanking each of the 11 exons, the structural portion of the gene was studied by PCR-SSCP analysis. DNA from African-American females (n=48), who had gestational diabetes but developed overt NIDDM after delivery, was studied. Each SSCP variant was sequenced directly from genomic DNA. Two amino acid substitutions from the previously reported sequence were found, one in exon 3 and the other in exon 4 B. Four additional silent mutations in the coding region, and six intron mutations outside the splice junction consensus sequences, were also identified. The mutation GTC x ATC in exon 4B substituted Val197 to Ile197. This amino acid substitution was found in only one NIDDM patient in a single allele, and was not found in 52 control subjects. This residue exists in the fifth membrane spanning domain, and Val at this position is conserved in mouse and rat GLUT 2, and human GLUT 1 to GLUT 4. The other codon change in exon 3, ACT x ATT, substituted Thr110 to Ile110 in the second membrane spanning domain. To determine the frequency of this non-conservative amino acid substitution, a PCR-LCR assay was developed. This assay was simple and highly specific for detection of this single nucleotide substitution. The allelic frequency of the ATT (Ile110) in NIDDM patients (39.6%, n=48) and that in controls (47.1%, n=52) did not differ (p=0.32, Fisher's exact test). In conclusion, we identified two variant GLUT 2 glucose transporters in a subset of NIDDM patients. The rare variant in exon 4 B may contribute to the diabetic susceptibility and awaits further investigation. However, structural abnormalities of the GLUT 2 transporter associated with NIDDM appeared to be rare and were not likely to be a major determinant of genetic susceptibility to this type of diabetes in the population studied.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408481
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