| 51. |
- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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| 52. |
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| 53. |
- Thanabalasingham, G., et al.
(författare)
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A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes
- 2011
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54:11, s. 2801-2810
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Tidskriftsartikel (refereegranskat)abstract
- An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values > 10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 x 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 x 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) a parts per thousand yenaEuro parts per thousand 0.91, p a parts per thousand currency signaEuro parts per thousand 1 x 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.
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| 54. |
- Tripathy, Devjit, et al.
(författare)
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Familiality of metabolic abnormalities is dependent upon age at onset and phenotype of the type 2 diabetic proband.
- 2003
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Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 285:6, s. 1297-1303
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Tidskriftsartikel (refereegranskat)abstract
- To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first degree relatives, we studied 2100 first degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH-). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion (30min incremental insulin /glucose, I/G 30), and insulin sensitivity (HOMA insulin resistance). A subset participated in a euglycemic clamp (n=75) and an intravenous glucose tolerance test (n=300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first degree relatives of diabetic probands with high and low waist to hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant as seen from higher HOMA-IR index (P=0.007) and lower rate of insulin-stimulated glucose uptake (P=0.001) and had more features of the metabolic syndrome (P=0.02, P=0.0002) compared with FH- subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs FH- subjects (P=0.04). Relatives of diabetic probands with a high WHR had reduced insulin mediated glucose uptake compared with relatives of probands with a low WHR (P = 0.04). Relatives of diabetic patients with age at onset < 44 years had higher HOMA IR (P < 0.005) and lower DI (P < 0.005) than relatives of patients with age at onset >65 yrs (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the non-diabetic firstdegree relative
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| 55. |
- Tuomi, T, et al.
(författare)
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Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturity-onset diabetes of the young type 3
- 2006
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 29:2, s. 189-194
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE - To study the effect of the short-acting insulin secretagogue nateglinide in patients with maturity-onset diabetes of the young type 3 (MODY3), which is characterized by a defective insulin response to glucose and hypersensitivity to sulfonylureas. RESEARCH DESIGN AND METHODS - We compared the acute effect of nateglinide, glibenclamide, and placebo on prandial plasma glucose and serum insulin, C-peptide, and glucagon excursions in 15 patients with MODY3. After an overnight fast, they received on three randomized occasions placebo, 1.25 mg glibenclamide, or 30 mg nateglinide before a standard 450-kcal test meal and light bicycle exercise for 30 min Starting 140 min after the ingestion of the first test drug. RESULTS - insulin peaked earlier after nateglinide than after glibenclamide or placebo (median [interquartile range] time 70 [50] vs. 110 [20] vs. 110 [30] min, P = 0.0002 and P = 0.0025, respectively). Consequently, compared with glibenclamide and placebo, the peak plasma glucose (P = 0.031 and P < 0.0001) and incremental glucose areas under curve during the first 140 min of the test (P = 0.041 and P < 0.0001) remained lower after nateglinide. The improved prandial glucose control with nateglinide was achieved with a lower peak insulin concentration than after glibenclamide (47.0 [26.0] vs. 80.4 [71.7] mU/l; P = 0.023). Exercise did not induce hypoglycemia after nateglinide or placebo, but after glibenclamide six patients experienced symptomatic hypoglycemia and three had to interrupt the test. CONCLUSIONS - A low dose of nateglinide prevents the acute postprandial rise in glucose more efficiently than glibenclamide and with less stimulation of peak insulin concentrations and less hypoglycemic symptoms.
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| 56. |
- Vassy, Jason L., et al.
(författare)
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Association between parental history of diabetes and type 2 diabetes genetic risk scores in the PPP-Botnia and Framingham Offspring Studies
- 2011
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 93:2, s. 76-79
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Parental history of diabetes and specific gene variants are risk factors for type 2 diabetes, but the extent to which these factors are associated is unknown. Methods: We examined the association between parental history of diabetes and a type 2 diabetes genetic risk score (GRS) in two cohort studies from Finland (population-based PPP-Botnia study) and the US (family-based Framingham Offspring Study). Results: Mean (95% CI) GRS increased from 16.8 (16.8-16.9) to 16.9 (16.8-17.1) to 17.1 (16.8-17.4) among PPP-Botnia participants with 0, 1, and 2 parents with diabetes, respectively (p(trend) = 0.03). The trend was similar among Framingham Offspring but was not statistically significant (p = 0.07). The meta-analyzed p value for trend from the two studies was 0.005. Conclusions: The very modest associations reported above suggest that the increased risk of diabetes in offspring of parents with diabetes is largely the result of shared environmental/lifestyle factors and/or hitherto unknown genetic factors. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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