| 61. |
- Di Paola, R, et al.
(författare)
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A variation in 3 ' UTR of hPTP1B increases specific gene expression and associates with insulin resistance
- 2002
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 70:3, s. 806-812
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Tidskriftsartikel (refereegranskat)abstract
- Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling and, when overexpressed, plays a role in insulin resistance (Ahmad et al. 1997). We identified, in the 3' untranslated region of the PTP1B gene, a 1484insG variation that, in two different populations, is associated with several features of insulin resistance: among male individuals, higher values of the insulin resistance HOMA(IR) index (P = .006), serum triglycerides (P = .0002), and total/HDL cholesterol ratio (P = .025) and, among female individuals, higher blood pressure (P = .01). Similar data were also obtained in a family-based association study by use of sib pairs discordant for genotype (Gu et al. 2000). Subjects carrying the 1484insG variant showed also PTP1B mRNA overexpression in skeletal muscle (6,166 +/- 1,879 copies/40 ng RNA vs. 2,983 +/- 1,620;). Finally, PTP1B mRNA stability was significantly higher (P < .01) in human embryo kidney 293 cells transfected with 1484insG PTP1B, as compared with those transfected with wild-type PTP1B. Our data indicate that the 1484insG allele causes PTP1B overexpression and plays a role in insulin resistance. Therefore, individuals carrying the 1484insG variant might particularly benefit from PTP1B inhibitors, a promising new tool for treatment of insulin resistance (Kennedy and Ramachandran 2000).
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| 62. |
- Florez, J. C., et al.
(författare)
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Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:6, s. 1209-1217
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. Subjects and methods We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. Results In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p=0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p=0.059). The combined OR was 1.20 (p=0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. Conclusion/interpretation Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
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| 63. |
- Frayling, Timothy M., et al.
(författare)
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A Genome-Wide Scan in Families With Maturity-Onset Diabetes of the Young: Evidence for Further Genetic Heterogeneity.
- 2003
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 52:3, s. 872-881
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Tidskriftsartikel (refereegranskat)abstract
- Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non–insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15–20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of β-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169–175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.
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| 64. |
- Glad, Camilla A M, 1981, et al.
(författare)
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The GH receptor exon 3 deleted/full-length polymorphism is associated with central adiposity in the general population.
- 2015
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X .- 0804-4643. ; 172:2, s. 123-128
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test the hypothesis that the growth hormone (GH) receptor (GHR) d3/fl polymorphism influences anthropometry and body composition in the general population. Design and Setting: The Swedish Obese Subjects (SOS) reference study is a cross-sectional population-based study, randomly selected from a population registry. A sub-group of the population-based Malmö Diet and Cancer Study (MDC-CC) was used as a replication cohort. Methods: The SOS reference study comprises 1135 subjects (46.2% men), with an average age of 49.5 yrs. The MDC-CC includes 5451 successfully genotyped subjects (41.5% men), with an average age of 57.5 yrs. GHR d3/fl genotypes were determined using tagSNP rs6873545. Linear regression analyses were used to test for genotype - phenotype associations. Results: In the SOS reference study, subjects homozygous for the d3-GHR weighed approximately four kilos more (p=0.011), had larger waist-to-hip ratio (WHR, p=0.036), waist circumference (p=0.016) and more fat free mass estimated from total body potassium (TBK, p=0.026) than grouped fl/d3 and fl/fl subjects (d3-recessive genetic model). The association with WHR was replicated in the MDC-CC (p=0.002), but not those with other anthropometric traits. Conclusions: In this population-based study the GHR d3/fl polymorphism was found to be of functional relevance and associated with central adiposity, such that subjects homozygous for the d3-GHR showed an increased abdominal obesity.
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| 65. |
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| 66. |
- Haghighi, Mona, et al.
(författare)
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A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.
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| 67. |
- Isomaa, B., et al.
(författare)
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Cardiovascular morbidity and mortality associated with the metabolic syndrome
- 2001
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Ingår i: Diabetes Care. - 1935-5548. ; 24:4, s. 683-689
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE - To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organisation (WHO). RESEARCH DESIGN AND METHODS - A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. in subjects who had type 2 diabetes in = 1,697) impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798), or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988). the metabolic syndrome was de fined as presence of at least two of the following risk factors: obesity hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years. RESULTS - In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT. 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001) Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80. P = 0.002). CONCLUSIONS - The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from different studies.
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| 68. |
- Isomaa, B, et al.
(författare)
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The metabolic syndrome influences the risk of chronic complications in patients with type II diabetes
- 2001
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 44:9, s. 1148-1154
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We examined features of the metabolic syndrome to see if they modified the risk of chronic diabetic complications in patients with Type II (non-insulin-dependent) diabetes mellitus. METHODS: A total of 85 randomly selected patients with the metabolic syndrome (WHO definition) were compared with 85 Type II diabetic patients matched for age, sex, duration of diabetes, glycaemic control and without the syndrome to assess the microvascular and macrovascular complications. RESULTS: The patients with the metabolic syndrome had a higher prevalence of cardiovascular disease (52 vs 21%, p < 0.001), microalbuminuria or macroalbuminuria (23 vs 7%, p = 0.003) and distal neuropathy (16 vs 6%, p = 0.048) than patients without the syndrome. The patients with the metabolic syndrome had smaller LDL particle size (25.4+/-1.4 vs 26.4+/-1.1 nm; p < 0.001), which correlated with the ratio of serum triglycerides to HDL cholesterol (r = -0.64, p < 0.001). In a multiple logistic regression analysis the metabolic syndrome was associated with coronary heart disease (RR 3.84, p < 0.001) and microalbuminuria (RR 3.99, p = 0.01). Small LDL particle size was independently associated with neuropathy (RR 0.58; p = 0.04), whereas a high HbA1c was related to neuropathy (RR 1.69, p = 0.04), retinopathy (RR 1.53, p = 0.002) and microalbuminuria (RR 1.54, p = 0.01). CONCLUSION/INTERPRETATION: Although chronic hyperglycaemia is the main predictor of microvascular complications in patients with Type II diabetes, this risk is modified by some of the components of the metabolic syndrome.
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| 69. |
- Jujić, Amra, et al.
(författare)
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Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality : a prospective study
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:5, s. 1043-1054
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.Methods: GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.Results: In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.Conclusions/interpretation: In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.
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| 70. |
- Kadi, M., et al.
(författare)
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Demixing of fluorinated and hydrogenated surfactants into distinct aggregates and into distinct regions within aggregates. A combined NMR, fluorescence quenching, and cryo-TEM study
- 2002
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 18:24, s. 9243-9249
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Tidskriftsartikel (refereegranskat)abstract
- The formation of two different kinds of micelles in the cationic surfactant mixture of HFDePC and CTAC as well as the increased mixing with increasing temperature has been investigated. A critical temperature of demixing was appreciated to 42 degreesC. NMR self-diffusion measurements reveal to us a coexistence of larger fluorocarbon-rich and smaller hydrocarbon-rich micelles, which is also observed using cryo-TEM. We also suggest, from F-19 line width data, that the two surfactant species constituting the demixed micelles are I'microphase-separated. The existence of such aggregates has earlier only been speculated upon. From time-resolved fluorescence quenching measurements, we have estimated the fraction of fluorocarbon surfactant in the hydrocarbon-rich micelles to larger than 0.1.
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