The PPARγ Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects

Chistiakov, Dimitry A.; Потапов, В. А.; Khodirev, Dmitry S.; Шамхалова, Минара Шамхаловна; Shestakova, Marina Vladimirovna; Носиков, В. В.

doi:10.1177/1479164109347689

Cited by 30 publications

(27 citation statements)

References 35 publications

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“…However, the decrease in insulin and insulin signaling in the presence of a 23% decrease in plasma adiponectin would argue against that alternative and suggests that the elephant seal develops insulin resistance over the course of its fast (25). This is reinforced further by the decrease of PPAR␥ whose expression has been associated with insulin sensitivity in humans (6,25). The decreases in PPAR␥ and plasma adiponectin also demonstrate that the adipocytes were mature (15), and so differentiation does not likely contribute to the observed increase in Glut4.…”

Section: Discussionmentioning

confidence: 92%

Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

Viscarra

Vázquez‐Medina

Crocker

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Viscarra JA, Vázquez-Medina JP, Crocker DE, Ortiz RM. Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups. Am J Physiol Regul Integr Comp Physiol 300: R150 -R154, 2011. First published October 27, 2010 doi:10.1152/ajpregu.00478.2010.-Postprandial cellular glucose uptake is dependent on an insulin-signaling cascade in muscle and adipose tissue, resulting in the translocation of the insulindependent glucose transporter 4 (Glut4) into the plasma membrane. Additionally, extended food deprivation is characterized by suppressed insulin signaling and decreased Glut4 expression. Northern elephant seals are adapted to prolonged fasts characterized by high levels of plasma glucose. To address the hypothesis that the fastinginduced decrease in insulin is associated with reduced insulin signaling in prolonged fasted seals, we compared the adipose protein levels of the cellular insulin-signaling pathway, Glut4 and plasma glucose, insulin, cortisol, and adiponectin concentrations between Early (n ϭ 9; 2-3 wks postweaning) and Late (n ϭ 8; 6 -8 wks postweaning) fasted seals. Plasma adiponectin (230 Ϯ 13 vs. 177 Ϯ 11 ng/ml), insulin (2.7 Ϯ 0.4 vs. 1.0 Ϯ 0.1 U/ml), and glucose (9.8 Ϯ 0.5 vs. 8.0 Ϯ 0.3 mM) decreased, while cortisol (124 Ϯ 6 vs. 257 Ϯ 30 nM) doubled with fasting. Glut4 increased (31%) with fasting despite the significant decreases in the cellular content of phosphatidylinositol 3-kinase as well as phosphorylated insulin receptor, insulin receptor substrate-1, and Akt2. Increased Glut4 may have contributed to the decrease in plasma glucose, but the decrease in insulin and insulin signaling suggests that Glut4 is not insulin-dependent in adipose tissue during prolonged fasting in elephant seals. The reduction of plasma glucose independent of insulin may make these animals an ideal model for the study of insulin resistance. elephant seal; glucocorticoids; glucose transporter; hyperglycemia; insulin resistance REGARDLESS OF AGE OR gender, the northern elephant seal (Mirounga angustirostris) endures a 2-3 mo fast twice a year as a natural component of its life history (21, 24). Unlike hibernators, which can experience similar bouts of food deprivation but conserve energy by lowering their metabolic rate and core body temperature (26), fasting seals remain normothermic and metabolically active during their prolonged fasts (8,35). Fasting seals remain physically active as well, with males using their time on land to form and defend harems, with females giving birth to and nursing newborn pups, and with postweaning pups developing the diving ability they will need when they go out to sea, all the while completely abstaining from food or water.Fasting elephant seals rely primarily on the oxidation of their extensive fat stores to meet ϳ90 -95% of their energy requirements and maintain high levels of plasma glucose (5, 21) during their fast. Such reliance on lipid oxidation results in elevated circulating free fatty acids levels (4, 32

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Section: Discussionmentioning

confidence: 92%

Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

Viscarra

Vázquez‐Medina

Crocker

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…[25] An association was also reported between increased risk of T2DM and Pro allele of PPAR-γ2 gene in a Russian population. [26]…”

Section: Discussionmentioning

confidence: 99%

Association between PRO12ALA polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in Iranian patients

Motavallian¹,

Andalib²,

Vaseghi³

et al. 2013

Indian J Hum Genet

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BACKGROUND:Peroxisome proliferator-activated receptor (PPARs) have been identified as ligand-activated transcription factors that belong to the nuclear receptor superfamily. It has been shown that an association exists between Proline 12 alanine (Pro12Ala) polymorphism of PPAR-GAMMA2 (PPAR-γ2) gene and increased risk of type 2 diabetes mellitus (T2DM) in different populations. Therefore, the present study was designed to investigate the association between Pro12Ala polymorphism of PPAR-γ2 gene and T2DM in an Iranian population.MATERIALS AND METHODS:Two hundred unrelated people, including 100 healthy controls and 100 diabetic patients were recruited diagnosed based on American Diabetes Association criteria. Blood samples were used for isolation of genomic deoxyribonucleic acid (DNA). Having extracted the genomic DNA from human blood leukocytes by means of High Pure polymerase chain reaction (PCR) Template preparation kit, we carried out polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on each blood sample. Then, Genomic DNA was digested by BstU-I restriction enzyme. Thereafter, restriction products were analyzed by means of Polyacrylamide gel electrophoresis and stained by Ethidium Bromide.RESULTS:We found that the frequency of Ala allele in healthy subjects was significantly higher than in diabetic subjects (P = 0003). Moreover, the genotype frequency of Ala/Ala in healthy subjects was significantly higher than in diabetic subjects (P < 0.001). However, the genotype frequency of Ala/Pro in diabetic subjects was significantly higher than in healthy subjects (P < 0.001).CONCLUSION:The present study suggests that polymorphism of PPAR-γ2 gene is associated with T2DM. Furthermore, Ala allele is significantly found in non-diabetic individual’s Iranian population.

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“…Indeed, most of the studies about nucleotide variations in PPARG have mainly focused on the association between a DNA variant and a specific phenotype (such as predictors of diabetes, obesity, and BMI) [57, 85–89] or related biochemical markers (plasma levels of hormones, peptides, or metabolites) demonstrated—or just supposed—to be transcriptionally regulated by PPAR γ itself [78, 90–102]. …”

Section: Pparg Target Genes: Polymorphisms Haplotypes and Gene Ementioning

confidence: 99%

“…The most widely studied SNP in PPARG gene [57, 72, 73, 83], Pro12Ala, occurs in PPAR γ 2 isoform and has been very often associated to clinical consequences and several alterations of physiological metabolic status [57, 72, 73, 85–87, 89, 103]. About the direct effect of this polymorphism on PPAR γ activity, some functional studies have revealed that Pro12Ala confers to PPAR γ 2 a decreased binding affinity to PPRE and a reduced transactivation ability, both in a luciferase reporter gene assay and in TZD-induced adipogenesis [73, 75].…”

Section: Pparg Target Genes: Polymorphisms Haplotypes and Gene Ementioning

confidence: 99%

PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues

et al. 2010

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Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most extensively studied ligand-inducible transcription factors (TFs), able to modulate its transcriptional activity through conformational changes. It is of particular interest because of its pleiotropic functions: it plays a crucial role in the expression of key genes involved in adipogenesis, lipid and glucid metabolism, atherosclerosis, inflammation, and cancer. Its protein isoforms, the wide number of PPARγ target genes, ligands, and coregulators contribute to determine the complexity of its function. In addition, the presence of genetic variants is likely to affect expression levels of target genes although the impact of PPARG gene variations on the expression of target genes is not fully understood. The introduction of massively parallel sequencing platforms—in the Next Generation Sequencing (NGS) era—has revolutionized the way of investigating the genetic causes of inherited diseases. In this context, DNA-Seq for identifying—within both coding and regulatory regions of PPARG gene—novel nucleotide variations and haplotypes associated to human diseases, ChIP-Seq for defining a PPARγ binding map, and RNA-Seq for unraveling the wide and intricate gene pathways regulated by PPARG, represent incredible steps toward the understanding of PPARγ in health and disease.

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The PPARγ Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects

Cited by 30 publications

References 35 publications

Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

Association between PRO12ALA polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in Iranian patients

PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues

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