The PPARγ2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects

Koch, Matthias; Rett, K.; Maerker, Elke; Volk, A.; Haist, Kelsey C.; Deninger, Michael J.; Renn, W.; Häring, Hans‐Ulrich

doi:10.1007/s001250051225

Cited by 117 publications

(88 citation statements)

References 12 publications

(11 reference statements)

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“…In a previous study using the glucose clamp method, no significant relationship was observed between PPARγ 2 substitution and insulin sensitivity in nondiabetic Caucasian subjects who had a history of type 2 diabetes in a first-degree relative (18). However, the Ala allele was associated with significantly higher insulin sensitivity only in severely obese subjects with BMI more than 30 kg/m 2 , showing that the influence of PPARγ 2 substitution on insulin sensitivity was limited to obesity-associated insulin resistance.…”

Section: Discussionmentioning

confidence: 80%

PPARγ2 Pro12Ala Polymorphism and Insulin Resistance in Japanese Hypertensive Patients

et al. 2002

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We investigated the relationship between peroxisome proliferator-activated receptor (PPAR ) Pro12Alasubstitution and insulin resistance in subjects with normal insulin secretory capacity, since it has been reported that PPAR may affect not only insulin resistance but also insulin secretion. We examined 81 Japanese male patients with untreated essential hypertension using the glucose clamp technique. We found 77 subjects with Pro/Pro and 4 subjects with Pro/Ala genotype, and the glucose disposal rate was not signifi-

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Section: Discussionmentioning

confidence: 80%

PPARγ2 Pro12Ala Polymorphism and Insulin Resistance in Japanese Hypertensive Patients

et al. 2002

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“…11 Greater insulin sensitivity was observed in normo glucose-tolerant Swedish 70-year-old men carrying the Ala allele; 24 in subgroups of obese subjects, the increase in insulin sensitivity was also more pronounced. 25 Stumvoll and co-workers demonstrated that the Ala allele of PPAR-g2 becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism such as the G972R variant of IRS-1. 26 The picture, however, is still unclear as reported in a Swedish middle-aged man in whom a significantly higher body mass with predominance of abdominal distribution of adipose tissue was observed along with a marked impairment in estimated insulin sensitivity in homozygotes Ala carriers.…”

Section: Discussionmentioning

confidence: 99%

The common PPAR-γ2 Pro12Ala variant is associated with greater insulin sensitivity

et al. 2004

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Several genetic variants of peroxisome proliferator-activated receptor-c2 (PPAR-c2) have been identified, among which Pro12Ala, a missense mutation in exon 2, is highly prevalent in Caucasian populations. Up to now, conflicting results with regard to the association between this mutation and complex traits, such as obesity, insulin sensitivity and Type 2 diabetes, have been reported. We investigated the influence of the Pro12Ala polymorphism of PPAR-c2 on insulin sensitivity in a large Italian population sample, n ¼ 1215, in whom extensive clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated; in the obese/ overweight subjects an oral glucose tolerance test (OGTT) was also performed and the Matsuda insulin sensitivity index (ISI) calculated. The insulin secretion index (homeostasis model assessment of percent b-cell function, HOMA-b%) was utilized to evaluate b-cell function. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared to Pro/Pro (P ¼ 0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P ¼ 0.013 after correction for multiple comparisons) in all cohort. Moreover, no significant interaction effect was observed between body mass index and X12Ala polymorphism and between gender and X12Ala polymorphism in modulating insulin sensitivity. Our observations substantially extend previous findings and demonstrated that X12Ala variant is significantly associated with greater insulin sensitivity.

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“…Specific primers from the PPAR␥2 sequence (Genbank accession no. AB005520) yielding a 267-bp fragment were designed as reported earlier (25). PCR amplification was performed using the LightCycler/DNA Master SYBR Green I kit (Roche Diagnostics) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Troglitazone Downregulates Δ-6 Desaturase Gene Expression in Human Skeletal Muscle Cell Cultures

et al. 2002

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ring ⌬-6 Desaturase, one of the rate-limiting enzymes, catalyzes the conversion of linoleic acid (C18:2 6) into ␥-linolenic acid (C18:3 6), arachidonic acid (C20:4 6), and further metabolites. Recently, it has been shown that human ⌬-6 desaturase is expressed not only in liver but in a variety of human tissues, including muscle. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty acid composition of muscle lipids. We examined the effects of troglitazone on the regulation of ⌬-6 desaturase gene expression in human muscle cell cultures obtained from muscle biopsies (n ‫؍‬ 15). ⌬-6 Desaturase mRNA and peroxisome proliferator-activated receptor ␥2 (PPAR␥2) mRNA were quantified by two-step RT-PCR, and the activity of the ⌬-6 desaturase enzyme was estimated by gas chromatographic analysis of the 6-C18:3/C18:2 fatty acids ratio. In cells treated with 11.5 mol troglitazone for 4 days, PPAR␥2 mRNA levels were significantly increased (301.0 ؎ 51.5%, P < 0.05) and ⌬-6 desaturase mRNA levels were significantly decreased (41.7 ؎ 5.9%, P < 0.0005) compared with the untreated controls. In accordance with the decrease of ⌬-6 desaturase mRNA, there was a significant decrease in the 6-C18:3/C18:2 ratio down to 47.4 ؎ 7.5% in cholesterol esters, 54.2 ؎ 7.4% in phospholipids, 56.7 ؎ 6.5% in nonesterified fatty acids, and 67.7 ؎ 5.9% in triglycerides. The troglitazone-induced decrease in ⌬-6 desaturase mRNA is associated with a change in the unsaturated fatty acid composition of the muscle cells. These results add new aspects to the known thiazolidinedione effects on lipid metabolism.

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The PPARγ2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects

Cited by 117 publications

References 12 publications

PPARγ2 Pro12Ala Polymorphism and Insulin Resistance in Japanese Hypertensive Patients

PPARγ2 Pro12Ala Polymorphism and Insulin Resistance in Japanese Hypertensive Patients

The common PPAR-γ2 Pro12Ala variant is associated with greater insulin sensitivity

Troglitazone Downregulates Δ-6 Desaturase Gene Expression in Human Skeletal Muscle Cell Cultures

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