Mutation analysis of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus

Ek, Jakob; Andersen, Gitte; Urhammer, Søren A.; Gæde, Peter; Drivsholm, Thomas; Borch‐Johnsen, Knut; Hansen, Thorsten; Pedersen, Oluf

doi:10.1007/s001250100032

Cited by 278 publications

(242 citation statements)

References 13 publications

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“…A primary mitochondrial dysfunction as a cause of IMCL accumulation may constitute a self-perpetuating mechanism inducing a damage to mitochondria via ROS production [27]. It has been suggested that the molecular mechanisms behind the abnormal pattern of lipid oxidation may be linked with a common polymorphism of the PPAR-γ coactivator 1 (a transcriptional regulator of genes responsible for mitochondrial biogenesis and fat oxidation) in a Danish population [28] and in Pima Indians [29]. In addition, in the skeletal muscle of patients with type 2 diabetes, there was a reduction in the expression of genes encoding the PPAR-γ coactivator 1 [30,31].…”

Section: Discussionmentioning

confidence: 99%

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Lattuada¹,

Costantino²,

Caumo³

et al. 2005

Diabetologia

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Aims/hypothesis: Intramyocellular lipid accumulation and insulin resistance are thought to be due to reduced lipid oxidation in a human model of high risk of developing type 2 diabetes. Methods: We studied 32 offspring of type 2 diabetic parents and 32 control individuals by means of DXA, indirect calorimetry, insulin clamp and 1 H MRS of the calf muscles, and differences between and within study groups were analysed before and after segregation by quartiles of fasting lipid oxidation. Results: In comparison with control subjects, the offspring showed impaired insulin sensitivity, which was associated with higher fasting intramyocellular lipid content (Spearman's rho −0.35; p=0.04), but fasting lipid oxidation did not differ between groups (1.21±0.46 vs. 1.25±0.37 mg·kg −1 lean body mass per min; p=0.70). Nevertheless, offspring in the lowest quartile of lipid oxidation had the most severe impairment of insulin sensitivity and a strong association was shown between lipid oxidation and insulin sensitivity within quartiles (Spearman's rho 0.47; p=0.01); this was not observed within the control group (Spearman's rho 0.13; p=0.47). Intramyocellular lipid content was not significantly different within quartiles of lipid oxidation in either of the groups. Conclusions/interpretation: Insulin sensitivity improved across increasing quartiles of fasting lipid oxidation in the offspring group, but remained constant in the control group, supporting the hypothesis that impaired fat oxidation is a primary pathogenic factor of insulin resistance in people with a genetic background for type 2 diabetes. Despite their association with impaired insulin sensitivity, soleus and tibialis anterior intramyocellular lipid content remained constant across increasing quartiles of fasting lipid oxidation within both groups.

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Section: Discussionmentioning

confidence: 99%

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Lattuada¹,

Costantino²,

Caumo³

et al. 2005

Diabetologia

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“…The Gly482Ser variant in the PGC-1α gene has been reported to be associated with type 2 diabetes in Danish [38] and Japanese [39] subjects. In contrast, no association was found in French Caucasians [40] or in Pima Indians [41] and in additon, no interaction was observed between this variant and the Pro12Ala polymorphism of the PPAR-γ2 gene [38].…”

Section: Introductionmentioning

confidence: 99%

“…Genes involved in oxidative metabolism and responsive to PGC-1α, as well as PGC-1α itself, have been showed to be co-ordinately down-regulated in diabetic subjects [35,36] and even in insulin-resistant individuals [37]. The Gly482Ser variant in the PGC-1α gene has been reported to be associated with type 2 diabetes in Danish [38] and Japanese [39] subjects. In contrast, no association was found in French Caucasians [40] or in Pima Indians [41] and in additon, no interaction was observed between this variant and the Pro12Ala polymorphism of the PPAR-γ2 gene [38].…”

Section: Introductionmentioning

confidence: 99%

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

et al. 2004

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Aim/hypothesis. We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor γ2 (PPAR-γ2; Pro12Ala) and in PPAR-γ coactivator 1α (PGC-1α; Gly482Ser) genes on the conversion from impaired glucose tolerance to type 2 diabetes in participants in the STOP-NIDDM trial. This trial aimed to study the effect of acarbose in the prevention of type 2 diabetes. Methods. Genotyping was performed in 770 study subjects whose DNA was available. The Gly482Ser variant in the PGC-1α gene was determined with the polymerase chain reaction amplification, Hpa II enzyme digestion, and gel electrophoresis. The Pro12Ala polymorphism of the PPAR-γ2 gene was determined by the polymerase chain reaction-singlestrand conformation polymorphism analysis. Results. The Pro12Pro genotype of the PPAR-γ2 gene predicted the conversion to diabetes in women in the acarbose group (odds ratio 2.89, 95% CI 1.20 to 6.96; p=0.018). The 482Ser allele of the PGC-1α gene had a significant interaction with the mode of treatment (p=0.012), and in the placebo group the 482Ser allele was associated with a 1.6-fold higher risk for type 2 diabetes compared to the Gly482Gly genotype (95% CI 1.06 to 2.33; p=0.023). Acarbose prevented the development of diabetes independently of the genotype of the PPAR-γ2 gene, but only the carriers of the 482Ser allele of the PGC-1α gene were responsive to acarbose treatment. Conclusion/interpretation. We conclude that the Pro12Pro genotype of the PPAR-γ2 gene and the 482Ser allele of the PGC-1α gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.

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“…Specifically, a common PPARGC1A polymorphism, Gly482Ser, has been studied for association with type 2 diabetes with conflicting results [8][9][10][11][12]. The Gly482Ser variant has also been associated with insulin resistance [9], indices of obesity in women [13], and mean insulin secretory response and lipid oxidation [11].…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

et al. 2006

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Aims/hypothesis: Peroxisome proliferator-activated receptor-γ co-activator-1α (PPARGC1A) is a transcriptional co-activator with a central role in energy expenditure and glucose metabolism. Several studies have suggested that the common PPARGC1A polymorphism Gly482Ser may be associated with risk of type 2 diabetes, with conflicting results. To clarify the role of Gly482Ser in type 2 diabetes and related human metabolic phenotypes we genotyped this polymorphism in a case-control study and performed a meta-analysis of relevant published data. Materials and methods: Gly 482Ser was genotyped in a type 2 diabetes case-control study (N=1,096) using MassArray technology. A literature search revealed publications that examined Gly482-Ser for association with type 2 diabetes and related metabolic phenotypes. Meta-analysis of the current study and relevant published data was undertaken. Results: In the pooled meta-analysis, including data from this study and seven published reports (3,718 cases, 4,818 controls), there was evidence of between-study heterogeneity (p<0.1). In the fixed-effects meta-analysis, the pooled odds ratio for risk of type 2 diabetes per Ser482 allele was 1.07 (95% CI 1.00-1.15, p=0.044). Elimination of one of the studies from the meta-analysis gave a summary odds ratio of 1.11 (95% CI 1.04-1.20, p=0.004), with no between-study heterogeneity (p=0.475). For quantitative metabolic traits in normoglycaemic subjects, we also found significant between-study heterogeneity. However, no significant association was observed between Gly482-Ser and BMI, fasting glucose or fasting insulin. Conclusions/ interpretation: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk.

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Mutation analysis of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus

Cited by 278 publications

References 13 publications

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

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