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 ≥2.5 mg/mmol in men and ≥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.

Conflicting results have been reported regarding whether the PPARγ2 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 To investigate this issue, a meta‐analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted.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.

OBJECTIVE: Coronary artery disease (CAD), a major cause of mortality in patients with type 2 diabetes (T2D), is often diagnosed late because of silent myocardial ischaemia (SMI). Exercise electrocardiogram testing (ECG) stress is the most utilized screening test for SMI. Its applicability and accuracy, which have never been reported in asymptomatic high-risk T2D patients, have been investigated in this study. DESIGN: A cross-sectional study with coronary angiography as the gold standard for detecting CAD was used. METHODS: Two hundred and six consecutive T2D patients, without symptoms and resting ECG signs of ischaemia but with peripheral vascular disease (PVD) and/or > or = two atherogenic factors, were studied. Ischaemia at ECG stress was indicated by horizontal or downsloping ST segment depression > or =1 mm at 0.08 s after the J point. CAD was defined by stenosis > or =70%. RESULTS: Only 141/206 (68%) patients had a diagnostic test: 27 (19%) tested positive and 114 (81%) tested negative. Coronary angiography in 71 patients (the 27 who tested positive and 44 randomly selected patients who tested negative) indicated a CAD prevalence of 29% and the ECG stress accuracy was 79%. 'False negative' patients (18%) had a higher prevalence (P<0.01) of long duration of diabetes and PVD. CONCLUSIONS: This is the first study which provides insights into the applicability and accuracy of ECG stress in screening SMI in high-risk patients with T2D. Due to the high prevalence of CAD, alternative screening tests in patients unable to perform the test and in those with a high chance of being 'false negative' should be looked for and validated.

Objective— Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk. Methods and Results— We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP ( P =8.0×10 ⁻⁴ ). In the families, the Q121 variant accounted for 0.08 of PP heritability ( P =9.4×10 ⁻⁴ ). This association was formally replicated in a second sample of 475 individuals ( P =2.6×10 ⁻² ) but not in 2 smaller samples of 289 and 236 individuals ( P =0.49 and 0.21, respectively). In the individual patients’ data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant ( P =1.2×10 ⁻³ ). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation ( P =0.03), Ser ⁴⁷³ -Akt phosphorylation ( P =0.03), and NO synthase activity ( P =0.003). Conclusions— Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers.