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  • 1
    ISSN: 1432-0428
    Keywords: Maturity onset diabetes of the young (MODY) ; insulin receptor ; linkage analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cloning of the insulin receptor cDNA has permitted the definition of restriction fragment length polymorphisms at that locus. These polymorphisms were used to study the role of the insulin receptor in four pedigrees with maturity onset diabetes of the young through linkage analyses. When each pedigree was individually analysed, no linkage was demonstrated in the two larger pedigrees, implying that an insulin receptor defect was not responsible for the predisposition to diabetes in these pedigrees. One of these pedigrees was known to be hypoinsulinaemic, while insulin levels were unavailable in the second pedigree. In the two smaller pedigrees, however, a single haplotype cosegregated with diabetes. One of these pedigrees is known to be hyperinsulinaemic. The small size of the pedigrees which demonstrated cosegregation precluded statistical proof of linkage. Nonetheless, the presence of an uncommon insertional polymorphism which cosegregated with diabetes in both pedigrees was improbable and suggested that this insertion could be responsible for diabetes in these families. This study thus may be additional evidence for heterogeneity in maturity onset diabetes of the young. For the two larger pedigrees, the insulin gene and HLA region have already been eliminated as genetic markers. This study provides data which eliminate a third candidate gene in these two pedigrees.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: C57BL/KsJ db/db mice ; genetic analysis ; proinsulin mRNA ; polygenic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Expression of obesity-induced diabetes associated with the diabetes or db mutation in mice varies in inbred strains. This study utilized a genetic analysis to evaluate the number of genes responsible for the difference in diabetes responses between mice of the susceptible C57BL/KsJ (BL/Ks) and resistant 129/J inbred strains. BL/Ks (db/+) males and 129/J (+/+) females were bred to generate F1 hybrids, and the F1 females (db/+ and +/+, distinguished by progeny testing) were backcrossed to BL/Ks (db/+) males. A total of 252 backcrossed males were obtained, of which 31 were db/db and obese. While the plasma glucose of all the fed back-crossed mice was greater than 22 mmol/l, the expression of diabetes varied considerably, as measured by fasting plasma glucose, fed plasma insulin, and pancreatic insulin and proinsulin mRNA content. That proinsulin mRNA content was a good indicator of diabetes severity and islet dysfunction was seen in the inverse correlation between proinsulin mRNA content and fasting plasma glucose (r=0.69, p〈0.001), and a direct correlation between proinsulin mRNA and plasma insulin (r=0.86, p〈0.001), and pancreatic insulin content (r=0.61, p〈0.01). If a single gene were responsible for severe islet dysfunction, one-half of the backcrossed mice would develop low proinsulin mRNA levels like the BL/Ks parent, and one-half would be resistant to islet destruction. Statistical evaluation (SKUMIX) of the distribution of these parameters in backcrossed mice rejected with a high degree of probability a bimodal distribution. Thus, it was concluded that while a dominant gene (or genes) is responsible for diabetic (〉22 mmol/l) unfasted plasma glucose in all backcrossed mice, allelic differences at two or more genetic loci are responsible for the differences between the two strains in diabetes severity measured by fasting plasma glucose, pancreatic insulin, and proinsulin mRNA content.
    Type of Medium: Electronic Resource
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  • 3
    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
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  • 4
    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.
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  • 5
    ISSN: 1432-0428
    Keywords: Nicotinamide ; streptozotocin ; albumin permeation ; glomerular filtration rate ; blood flow ; urinary protein excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats injected i. p. with a single dose of nicotinamide (250 mg/kg) 15 min prior to i.v. injection of streptozotocin (65 mg/kg) develop a very mild form of diabetes characterized by slight elevations of plasma glucose, increased levels of HbA1, and reduced insulin secretion in response to an i.v. glucose tolerance test. These rats gain weight normally and they are not hyperphagic, glycosuric, or polyuric. The effects of this very mild form of diabetes vs overt streptozotocin diabetes of three months duration on regional vascular 131I-albumin clearance, blood flow (assessed by 15 μm 85Sr-microspheres), and renal filtration function were examined in male Sprague-Dawley rats. Plasma glucose levels of rats with mild diabetes were 7.4±0.9 (mean±SD) (mmol/l) vs 6.5±0.6 for control rats and 31.3±6.0 for overtly diabetic rats. HbA1 levels were increased 1.4 fold in mildly diabetic and 2.3 fold in overtly diabetic rats. Vascular clearance of 131I-albumin was markedly increased in ocular tissues (anterior uvea, retina, and choroid), sciatic nerve, aorta, new (subcutaneous) granulation tissue, and kidney of both diabetic groups, although increases in overtly diabetic rats exceeded those in the mildly diabetic group (2.2–4.6 times control animals vs 1.6–3.3 times, respectively). Likewise, both overt and very mild diabetes markedly increased glomerular filtration rate (∼1.8 times and 1.2 times control animals, respectively), urinary excretion of endogenous albumin (∼9 times and 4 times) and IgG (∼15 times and 4 times), as well as regional blood flow in the anterior uvea, choroid, and sciatic nerve. Increases in tissue sorbitol levels were much larger in overtly diabetic rats (generally 10–20 times control animals) than in mildly diabetic rats (1.5–3 times controls). myo-Inositol levels were significantly decreased only in lens and sciatic nerve of overtly diabetic rats. These observations indicate that even very mild diabetes is associated with vascular functional changes which develop more slowly than in overtly diabetic rats, but are disproportionately large (in view of the minimal increases in glycaemia and tissue polyol levels) compared to those in overtly diabetic rats.
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  • 6
    ISSN: 1432-0428
    Keywords: Streptozotocin ; diabetes-susceptibility ; genetic analysis ; inbred mouse strains ; H-2 locus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To assess genetic factors determining sensitivity to streptozotocin-induced diabetes in inbred strains of mice, a genetic analysis of streptozotocin-sensitive C57BL/6J and streptozotocin-resistant C3H/HeJ mice was performed. One week after a single dose of streptozotocin (200 mg/kg body weight), differences in plasma glucose concentration were marked between male mice of the C57BL/6J and C3H/HeJ strains (p〈0.001). To determine the number of genes responsible for the difference, F1 male progeny of a cross between parental strains were produced, and found to be streptozotocin resistant like C3H/HeJ parents. F1 mice were, therefore, backcrossed with streptozotocin-sensitive C57BL/6J mice (Backcross: F1♂ ♂ X C57BL/6J ♀ ♀). The plasma glucoses of backcrossed male mice (n=41) following streptozotocin treatment appeared to segregate into two populations, half like the C57BL/6J parent, and half like the F1 parent. Statistical analysis of the data revealed that the data fit a model with two distributions better than one with a single distribution, suggesting a single major gene responsible for the difference in streptozotocin susceptibility. This hypothesis was also supported by the observation that streptozotocin sensitivity in 12 recombinant inbred strains of C57BL/6J and C3H/HeJ mice appeared to segregate into two classes. Resistance to streptozotocin induced diabetes in F1 mice suggested that the expression of this gene is recessive, although X-chromosome linked inheritance could not be excluded. Efforts to map the streptozotocin-sensitivity gene revealed lack of right linkage to several loci including the H-2 locus. If inherited differences in the ability to resist a B-cell toxin play a role in genetic susceptibility to diabetes in man, then mapping the streptozotocin-susceptibility gene in mice may provide a means to evaluate the role of a putative homologous locus in the aetiology of diabetes in man.
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  • 7
    Publication Date: 2018-04-02
    Description: Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7 , SIPA1L2 , and CEP72 are significantly associated with fasting LDL cholesterol response to FFB ( P = 1.24E-07), triglyceride postprandial area under the increase (AUI) ( P = 2.31E-06), and triglyceride postprandial AUI response to FFB ( P = 1.88E-06), respectively. We sought to replicate the association for SIPA1L2 in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study, and thus the gene-based result was not replicated. For functional validation, we found that gene transcript level of SIPA1L2 is associated with triglyceride postprandial AUI ( P 〈 0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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