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- Holmkvist, Johan, et al.
(författare)
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Common variants in HNF-1 alpha and risk of type 2 diabetes.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Oct 11, s. 2882-2891
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 (p=0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR=2.3, p=0.002). This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.
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| 3. |
- Johansson, Lovisa, et al.
(författare)
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Variation in the adiponutrin gene influences its expression and associates with obesity.
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:3, s. 826-833
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Tidskriftsartikel (refereegranskat)abstract
- Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess.
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- Nilsson, Emma A, et al.
(författare)
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The hormone-sensitive lipase C-60G promoter polymorphism is associated with increased waist circumference in normal-weight subjects.
- 2006
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 30:9, s. 1442-1448
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from triglyceride stores in adipocytes. The aim of the present study was to investigate the role of the HSL gene promoter variant C-60G, a polymorphism which previously has been associated with reduced promoter activity in vitro, in obesity and type 2 diabetes. DESIGN: We genotyped two materials consisting of obese subjects and non-obese controls, one material with offspring-parents trios, where the offspring was abdominally obese and one material with trios, where the offspring had type 2 diabetes or impaired glucose homeostasis. HSL promoter containing the HSL C-60G G-allele was generated and tested against a construct with the C-allele in HeLa cells and primary rat adipocytes. HSL mRNA levels were quantified in subcutaneous and visceral fat from 33 obese subjects. RESULTS: We found that the common C-allele was associated with increased waist circumference and WHR in lean controls, but there was no difference in genotype frequency between obese and non-obese subjects. There was a significant increased transmission of C-alleles to the abdominally obese offspring but no increased transmission of C-alleles was observed to offspring with impaired glucose homeostasis. The G-allele showed reduced transcription in HeLa cells and primary rat adipocytes. HSL mRNA levels were significantly higher in subcutaneous compared to visceral fat from obese subjects. CONCLUSION: The HSL C-60G polymorphism is associated with increased waist circumference in non-obese subjects.
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