Peroxisome Proliferator-Activated Receptor-γ2 Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

Abstract

The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-␥2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-␥2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-␥2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P ‫؍‬ 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P ‫؍‬ 0.01). The percentage decrease in UAE observed in PPAR-␥ Ala12 allele carriers relative to noncarriers (P ‫؍‬ 0.003) rose from 0.2% (P ‫؍‬ 0.99) to 54% (P ‫؍‬ 0.008) and to 70% (P ‫؍‬ 0.01) when the duration of diabetes increased from <10 years to 10 -19 years and to >20 years, respectively. Similarly, the odds ratios of having albuminuria decreased from 1.22 (P ‫؍‬ 0.54) to 0.61 (P ‫؍‬ 0.23) and to 0.11 (P ‫؍‬ 0.007), respectively. Among patients with type 2 diabetes, PPAR-␥2 Ala12 allele carriers had significantly lower UAE and tended to develop overt proteinuria less frequently. These observations suggest a protective effect of the Ala12 allele in relation to diabetic nephropathy. Diabetes 51: 2653-2657, 2002

Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-γ coactivator-1 gene might be a risk factor for diabetic retinopathy in Slovene population (Caucasians) with type 2 diabetes and the Pro12Ala polymorphism of thePPARγ gene is not

“…This finding suggests the existence of other factors such as differences in the ability of insulin secretion, differences in the frequency of episodes of hypoglycemia or adverse events associated with insulin therapy (hypoglycemia, worsening diabetic retinopathy if HbA 1c decreases rapidly) [28,29]. The Pro12Ala polymorphism of the PPARγ gene has recently been demonstrated to confer protection from type 2 diabetes and diabetic nephropathy [18,19,30,31]. In the present study, the Pro12Ala polymorphism of the PPARγ gene failed to be associated with diabetic retinopathy in patients with type 2 diabetes, which is in agreement with two recent reports [17,30].…”

Association of genetic variants with diabetic nephropathy

“…The Pro12Ala gene variant was associated with lower albumin excretion rates among Ala12 carriers with type 2 diabetic nephropathy. Thus it could be suggested that Pro12Ala polymorphism may be protective against the disease since microalbuminuria is considered to be a risk factor for diabetic nephropathy [64] . This study was confirmed by Pollex et al [65] who showed that the Ala12 allele carriers have 1.5-fold reduction of the albumin/ creatinine ratio and thus reduced occurrence of microalbuminuria.…”

The Dipeptide H‐Trp‐Glu‐OH Shows Highly Antagonistic Activity against PPARγ: Bioassay with Molecular Modeling Simulation

“…[18] It is reported that high-fat diet-induced (HF diet-induced) or aging-induced adipocyte hypertrophy, obesity, and insulin resistance can be effectively avoided in a heterozygous PPARg-deficient mice model, [19,20] whilst a moderate reduction in the transcriptional activity of PPARg through Pro12Ala polymorphism in human PPARg2 also exerted resisting effects against type II diabetes and obesity. [21][22][23] Moreover, PPARg antagonists were able to reduce triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. Furthermore, they could also enhance leptin's effects and increase fatty acid combustion and energy dissipation, thereby ameliorating HP diet-induced obesity and insulin resistance.…”