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- Adiels, Martin, 1976, et al.
(författare)
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Acute suppression of VLDL(1) secretion rate by insulin is associated with hepatic fat content and insulin resistance
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 50:11, s. 2356-2365
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS: A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS: The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.
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| 3. |
- Adiels, Martin, 1976, et al.
(författare)
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Overproduction of large VLDL particles is driven by increased liver fat content in man
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:4, s. 755-65
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. METHODS: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. RESULTS: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. CONCLUSIONS/INTERPRETATION: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.
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- Sammalisto, S, et al.
(författare)
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A male-specific quantitative trait locus on 1p21 controlling human stature
- 2005
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 42:12, s. 932-939
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. Objective: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. Methods: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. Results: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. Conclusions: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.
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| 5. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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