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- Grigorescu, F, et al.
(författare)
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HAPLOGENDIS INITIATIVE - SICA
- 2009
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Ingår i: ACTA ENDOCRINOLOGICA-BUCHAREST. - : ACTA Endocrinologica Foundation. - 1841-0987 .- 1843-066X. ; 5:1, s. 143-148
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Tura, A., et al.
(författare)
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An empirical index of insulin sensitivity from short IVGTT: validation against the minimal model and glucose clamp indices in patients with different clinical characteristics
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:1, s. 144-152
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Minimal model analysis for insulin sensitivity has been validated against the glucose clamp and is an accepted method for estimating insulin sensitivity from IVGTT. However minimal model analysis requires a 3 h test and relevant expertise to run the mathematical model. The aim of this study was to suggest a simple predictor of minimal model analysis index using only 1 h IVGTT. Methods We studied participants with different clinical characteristics who underwent 3 h regular (n=336) or insulin-modified (n=160) IVGTT, or 1 h IVGTT and euglycaemic-hyperinsulinaemic clamp (n=247). Measures of insulin sensitivity were insulin sensitivity index estimated by minimal model analysis ( SI) and the mean glucose infusion rate (clamp) (M). A calculated S-I (CSI) predictor, CSI alpha x K-G/(Delta AUC(INS)/T), was suggested, based on the calculation of the rate of glucose disappearance K-G and the suprabasal AUC of insulin concentration Delta AUC(INS) over T=40 min. For all the participants, a was assumed equal to the regression line slope between K-G/(Delta AUC(INS)/T) and S-I in control participants. Results CSI and S-I showed high correlation (R-2=0.68-0.96) and regression line slopes of approximately one in the majority of groups. CSI tended to overestimate S-I in type 2 diabetic participants, but results were more reliable when CSI was computed with insulin-modified rather than regular IVGTT. CSI showed behaviours similar to S-I as regards relationships with BMI, acute insulin response and sex. CSI showed good correlation with M (R-2=0.82). Conclusions/interpretation A short test can achieve a good approximation of minimal model analysis and clamp insulin sensitivity. The importance of a method such as CSI is that it allows analysis of IVGTT datasets with samples limited to 1 h.
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- Boesgaard, T. W., et al.
(författare)
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The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients--the EUGENE2 study
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:5, s. 816-20
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients. METHODS: We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity. RESULTS: Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity. CONCLUSIONS/INTERPRETATION: Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
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- Boesgaard, T. W., et al.
(författare)
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Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study
- 2009
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Ingår i: PLoS One. - 1932-6203. ; 4:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKROUND: A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. METHODOLOGY/RESULTS: Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2(nd) phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. CONCLUSION: The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.
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- Hribal, M. L., et al.
(författare)
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Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B
- 2011
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 54:4, s. 795-802
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.
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