Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.

BACKGROUND: Insulin resistance has a role in diabetic kidney complications. The K121Q (lysine to glutamine substitution at amino acid 121, encoded by single-nucleotide polymorphism rs1044498) variant of the ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) has been associated with insulin resistance and related vascular complications in patients with type 2 diabetes (T2D) in many, although not all, studies. This study investigated whether the ENPP1 Q121 variant modulates the risk of decreased glomerular filtration rate (GFR) in patients with T2D. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 2 diabetes units from Italy (in Gargano and Padua) and 1 from the United States (Boston, MA) recruited a total of 1,392 patients with T2D. PREDICTOR: The ENPP1 Q121 variant. MEASUREMENTS: Estimated GFR from serum creatinine, urinary albumin excretion, blood pressure, hemoglobin A(1c), triglycerides, total cholesterol, and high-density lipoprotein cholesterol. OUTCOMES: Decreased GFRs (ie, estimated GFR <60 mL/min/1.73 m(2)). RESULTS: In the Gargano and Boston populations, according to the dominant model of inheritance, Q121 carriers (ie, individual with either KQ or QQ alleles) had an increased risk of decreased GFR: odds ratios (ORs) of 1.69 (95% confidence interval [CI], 1.1 to 2.6) and 1.50 (95% CI, 1.0 to 2.2), respectively. In the Padua set, the association was in the same direction, but did not reach formal statistical significance (OR, 1.77; 95% CI, 0.7 to 4.5). When the 3 studies were pooled, Q121 carriers showed an increased risk of decreased GFR (OR, 1.58; 95% CI, 1.2 to 2.1; P = 0.002). Also, pooled mean differences in absolute GFRs were different across genotype groups, with Q121 carriers showing lower GFRs compared with KK individuals (P = 0.04). LIMITATIONS: P values not approaching a genome-wide level of significance. CONCLUSIONS: Our data suggest that patients with T2D carrying the ENPP1 Q121 variant are at increased risk of decreased GFR.

Increased urinary albumin excretion, insulin resistance, and related cardiovascular risk factors in patients with type 2 diabetes: evidence of a sex-specific association.

OBJECTIVE: While the relevant role of insulin resistance in the pathogenesis of increased urinary albumin excretion (UAE) is well established in type 1 diabetes, its contribution in type 2 diabetes is controversial. Our aim was to investigate whether insulin resistance was associated with increased UAE in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 363 men and 349 women, aged 61 +/- 9 years, with a disease duration of 11 +/- 9 years and HbA(1c) levels of 8.6 +/- 2.0% were included. Insulin resistance was derived from the homeostasis model assessment of insulin resistance (HOMA(IR)), and UAE was derived from the albumin-to-creatinine ratio (ACR) defined as increased if the value was > or =2.5 mg/mmol in men and > or =3.5 mg/mmol in women. ACR was correlated with HOMA(IR) (r = 0.15, P = 0.0001), independently of age, disease duration, blood pressure, HbA(1c), triglycerides, waist circumference, and smoking. RESULTS: When the two sexes were investigated separately, a significant correlation between ACR and HOMA(IR) was reached in men (n = 363; r = 0.21, P = 0.0001) but not women (n = 349; r = 0.08, P = 0.14), suggesting that insulin resistance and sex may interact (P for interaction = 0.04) in determining UAE. When men were subgrouped into quartiles of HOMA(IR), those of the third and fourth quartile (i.e., the most insulin resistant) were at higher risk to have increased ACR than patients of the first quartile (third quartile: odds ratio 2.2 [95% CI 1.2-4.2], P = 0.01) (fourth quartile: 4.1 [2.2-7.9], P = 0.00002). Finally, ACR was significantly higher in men with two or more insulin resistance-related cardiovascular risk factors (i.e., abdominal obesity, dyslipidemia, and arterial hypertension) than in men with fewer than two insulin resistance-related cardiovascular risk factors (0.90 [0.2-115.1] vs. 1.56 [0.1-1367.6], respectively, P = 0.005). CONCLUSIONS: In type 2 diabetic patients, increased UAE is strongly associated with insulin resistance and related cardiovascular risk factors. This association seems to be stronger in men than in women.

Heterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk.

Conflicting results have been reported regarding whether the PPARgamma2 Pro12Ala polymorphism plays a role in the risk of type 2 diabetes (T2D), suggesting genetic heterogeneity. To investigate this issue, a meta-analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted. Ala12 carriers had a 19% T2D risk reduction, but this association was highly heterogeneous (p = 0.005). A great proportion (48%) of heterogeneity was explained by the controls' BMI, with risk reduction being greater when BMI was lower. Risk reduction of Ala12 carriers in Asia (35%) was higher than in Europe (15%, p = 0.02) and tended to be higher than in North America (18%, p = 0.10). Difference between Asians and Europeans was no longer significant (p = 0.15) after adjusting for the controls' BMI. Studies from Europe were still heterogeneous (p = 0.02) with risk reduction in Ala12 carriers being progressively smaller (test for trend in the odds ratios, p = 0.02) from Northern (26% reduction, p < 0.0001) to Central (10%, p = 0.04) and Southern (0%, p = 0.94) Europe. In conclusion, in our meta-analysis, the reduced risk of T2D in Ala12 carriers is not homogeneous. It is greater in Asia than in Europe and, among Europeans, it is higher in Northern Europe, barely significant in Central Europe, and nonexistent in Southern Europe.