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| 2. |
- Almqvist, E G, et al.
(författare)
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Hypothalamic-pituitary-adrenal response to different tests in type 1 diabetes mellitus
- 2001
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 61:7, s. 557-565
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether different tests of the adrenocorticotropic hormone (ACTH) reserve are influenced by diabetic state and metabolic control in newly diagnosed type 1 diabetic patients. DESIGN AND METHODS: We evaluated the ACTH reserve in 10 patients with uncomplicated type 1 diabetes during periods of poor and improved metabolic control and in 10 healthy subjects. The ACTH-cortisol secretion was assessed by a diurnal profile, an intravenous corticotropin-releasing hormone (CRH) test and an insulin tolerance test (ITT). RESULTS: The diurnal profiles were similar in all groups. CRH resulted in a diminished ACTH response during poor compared with improved metabolic control (mean+/-SD) (AUC 4950+/-4227 vs. 5847+/-3788 ng/L min, p<0.05). The response in the diabetic patients during improved metabolic control was of the same magnitude as in the control subjects (5934+/-1778 ng/L x min). ITT elicited a similar ACTH and cortisol response in the diabetic patients during poor and improved metabolic control as in the healthy control subjects. CONCLUSIONS: The ITT was uninfluenced by diabetic state and metabolic control and should therefore be considered the method of choice in evaluation of the ACTH reserve in patients with type 1 diabetes.
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| 3. |
- Antonelli, A, et al.
(författare)
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Autoimmunity to CD38 and GAD in Type I and Type II diabetes: CD38 and HLA genotypes and clinical phenotypes
- 2002
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 45:9, s. 1298-1306
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis. Autoantibodies against CD38 have been found in some patients with Type II (non-insulin-dependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i) overlaps with anti-GAD autoimmunity, (ii) identifies an insulin-deficient phenotype, (iii) is under the influence of genetic factors. Methods. We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects). Results. CD38-autoantibodies were found in 8.4% of Type II diabetic patients (p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD38ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti-CD38 positive had DQB1 *02 compared with 38% of anti-CD38 negative (p=0.04). On the OGTT, beta-cell function (as the ratio of insulin-to-glucose areas) was impaired (p=0.02) only in association with anti-GAD positivity (3.2 +/- 3.1 U/mol, mean +/- SD) but not in anti-CD38 positive patients (5.6 +/- 2.9) as compared with patients free of autoimmunity (4.5 +/- 4.6, p=NS). In 44 Type II diabetic patients (22 negative and 22 positive for anti-CD38), no mutations were detected in any of the 8 exons, 5' end of intron 1 or the 5' and 3' untranslated regions of the CD38 gene. The previously described missense mutation (Arg140Trp) in exon 3 was not found in this cohort. There was no association between the PvUII polymorphism and clinical phenotype. Conclusion. Anti-CD38 autoimmunity identifies a clinical phenotype similar to non-autoimmune Type II diabetes, with relative preserved beta-cell function and weak genetic influence.
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| 4. |
- Bengtsson-Ellmark, S. H, 1900, et al.
(författare)
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Association between a polymorphism in the carboxyl ester lipase gene and serum cholesterol profile
- 2004
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Ingår i: European journal of human genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 12:8, s. 627-632
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Tidskriftsartikel (refereegranskat)abstract
- Carboxyl ester lipase (CEL) is involved in the hydrolysis and absorption of dietary lipids, but it is largely unknown to what extent CEL could be involved in determining the serum lipid levels. The C-terminal part of CEL consists of a unique structure with proline-rich O-glycosylated repeats of 11 amino-acid residues each. The common variant of the human CEL gene contains 16 proline-rich repeats, but there is a high degree of polymorphism in the repeated region. While the biological function of the polymorphic repeat region is unknown, it has been suggested that it may be important for protein stability and/or secretion of the enzyme. Given that the polymorphism in the repeated region may affect the functionality of the protein, this study aimed to investigate whether the number of repeated units is correlated to serum lipid phenotype. Comparison of CEL repeat genotype and serum lipid phenotype revealed an association between the number of repeats and serum cholesterol profile. Individuals carrying at least one allele with fewer than the common 16 repeats had significantly lower total and low-density lipoprotein (LDL) cholesterol levels compared to individuals carrying two common alleles. This gives support to the notion that CEL may be involved in determining the plasma lipid composition.
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| 5. |
- Bengtsson, Kristina, et al.
(författare)
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Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes
- 2001
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Ingår i: Hypertension. - 1524-4563. ; 37:5, s. 1303-1308
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether polymorphisms in the beta(2)-adrenergic receptor gene (5'LC-Arg19Cys, Arg16Gly, Gln27Glu) are associated with hypertension in patients with or without type 2 diabetes and with the blood pressure levels in normotensive sib pairs. The association study included 291 hypertensive patients without type 2 diabetes, 124 hypertensive patients with type 2 diabetes, and 265 healthy control subjects from SWEDEN: In addition, normotensive sib pairs that were discordant for the Arg16Gly (72 pairs) and Gln27Glu (40 pairs) polymorphisms were identified in type 2 diabetes families from FINLAND: Genotyping was performed using polymerase chain reaction-restriction fragment-length polymorphism analysis. Homozygous carriers of the Arg16 allele had a significantly increased odds ratio (OR) for hypertension in patients with type 2 diabetes (OR 2.14; 95% confidence interval [CI], 1.05 to 4.33), particularly among lean (body mass index<27 kg/m(2)) patients (OR 3.47; 95% CI, 1.06 to 11.33). The Gln27 allele showed a weaker association to hypertension (OR 1.55; 95% CI, 1.00 to 2.41) and was found to be in linkage disequilibrium with the Cys19 allele of the 5'LC-Arg19Cys polymorphism. In the paired-sibling analysis, siblings with at least 1 copy of the Arg16 allele had higher systolic blood pressure (P=0.049), and nondiabetic siblings had a higher body mass index (P=0.026) than siblings homozygous for the Gly16 allele. These results indicate that the Arg16 allele of the beta(2)-adrenergic receptor gene confers an increased risk for hypertension in subjects with type 2 diabetes and is associated with higher blood pressure levels and higher body mass index in sib pairs who are discordant for the polymorphism.
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| 6. |
- Bengtsson, Kristina, et al.
(författare)
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Polymorphism in the beta(1)-adrenergic receptor gene and hypertension
- 2001
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Ingår i: Circulation. - 1524-4539. ; 104:2, s. 187-190
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Arg389 variant of the beta(1)-adrenergic receptor gene mediates a higher isoproterenol-stimulated adenylate cyclase activity than the Gly389 variant in vitro. We investigated whether the Arg389Gly or the Ser49Gly polymorphism is associated with hypertension in Scandinavians. Methods and Results-- A total of 292 unrelated, nondiabetic, hypertensive patients and 265 unrelated healthy control subjects were included in a case-control association study. From 118 families, 102 nondiabetic sibling pairs without antihypertensive medication who were discordant for the Arg389Gly polymorphism were selected for a sibling study. Allele and genotype frequencies of the Arg389Gly and Ser49Gly polymorphisms were compared between hypertensive patients and normotensive control subjects. Blood pressure and heart rate were compared between carriers of the different genotypes. In the case-control study, the age- and body mass index-adjusted odds ratio for hypertension in subjects homozygous for the Arg389 allele was 1.9 (95% confidence interval, 1.3 to 2.7; P=0.0005) when compared with carriers of 1 or 2 copies of the Gly389 allele. The genotype-discordant sibling pair analysis revealed that siblings homozygous for the Arg389 allele had significantly higher diastolic blood pressures (79.4+/-9.9 versus 76.0+/-10.1 mm Hg; P=0.003) and higher heart rates (68.3+/-11.0 versus 65.1+/-9.4 bpm; P=0.02) than siblings carrying 1 or 2 copies of the Gly389 allele. The Ser49Gly polymorphism was not associated with hypertension. CONCLUSION: Our data suggest that individuals homozygous for the Arg389 allele of the beta(1)-adrenergic receptor gene are at increased risk to develop hypertension.
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| 8. |
- Carlsson, M, et al.
(författare)
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Common variants in the beta2-(Gln27Glu) and beta3-(Trp64Arg)--adrenoceptor genes are associated with elevated serum NEFA concentrations and type II diabetes
- 2001
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 44:5, s. 629-636
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Higher NEFA concentrations predict Type II (non-insulin-dependent) diabetes mellitus but it is not known whether higher NEFA concentrations are genetically determined or reflect coexisting obesity. To address this question we studied whether common variants in two genes encoding for key regulators of lipolysis, the beta2- and beta3- adrenoceptors (B2AR and B3AR) are associated with NEFA concentrations and Type II diabetes. METHODS: A total of 1054 Swedish subjects with varying degrees of glucose tolerance were genotyped for the Gln27Glu variant in the B2AR and for the Trp64Arg variant in the B3AR genes using PCR-RFLP. RESULTS: The B2AR Gln27 allele was more frequent in 219 Type II diabetic patients than in 237 non-diabetic subjects (59.8 % vs 52.3 %; OR = 1.72, p = 0.02) while there was no significant difference in the frequency of the B3AR Arg64 allele. Subjects homozygous for the protective alleles (Glu27 and Trp64) had, however, a lower prevalence of diabetes than subjects with other genotype combinations (OR = 0.58, p = 0.03). Among sibling pairs discordant for the B2AR Gln27Glu polymorphism, siblings with an excess of the Gln27 allele had higher fasting insulin (n = 217; p = 0.02) and NEFA concentrations (107 sex-matched pairs; p = 0.01) than siblings with an excess of the Glu27 allele. Among sibling pairs discordant for the B3AR Trp64Arg variant, siblings with the Arg64 allele had higher 2 h glucose (n = 48; p = 0.01) and NEFA concentrations (16 pairs matched for sex; p < 0.04) than siblings with the Trp64Trp64 genotype. CONCLUSIONS/INTERPRETATION: Common variants in the beta2- and beta3- adrenoceptor genes are associated with increased fasting insulin and NEFA concentrations and could increase susceptibility to Type II diabetes.
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| 9. |
- Carlsson, Martin, et al.
(författare)
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The T 54 allele of the intestinal fatty acid-binding protein 2 is associated with a parental history of stroke
- 2000
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - 1945-7197. ; 85:8, s. 2801-2804
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Tidskriftsartikel (refereegranskat)abstract
- To test the hypothesis that the A/T polymorphism of the fatty acid-binding protein 2 gene (FABP2) is associated with impaired lipid metabolism and cardiovascular disease, we compared clinical characteristics and a parental history of cardiovascular disease between 213 sibling pairs discordant for the polymorphism. Siblings with an excess of the T54 allele had higher triglyceride (P = 0.002) and cholesterol (P = 0.019) concentrations than siblings with the A54 allele. Parents of offspring with the T54T and T54A genotypes reported an increased prevalence of stroke compared to parents of offspring with the A54A genotype (P = 0.007). In summary, we have confirmed the association of the FABP2 T54 allele with increased concentrations of cholesterol and triglycerides in genotype-discordant sibling pairs. We also present novel evidence that genetic variation in the FABP2 gene may increase susceptibility to stroke.
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| 10. |
- Cervin, Camilla, et al.
(författare)
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Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.
- 2002
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 45:12, s. 1703-1708
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene. METHODS: Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. RESULTS: Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.
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