Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling and, when overexpressed, plays a role in insulin resistance (Ahmad et al. 1997). We identified, in the 3' untranslated region of the PTP1B gene, a 1484insG variation that, in two different populations, is associated with several features of insulin resistance: among male individuals, higher values of the insulin resistance HOMA(IR) index (P=.006), serum triglycerides (P=.0002), and total/HDL cholesterol ratio (P=.025) and, among female individuals, higher blood pressure (P=.01). Similar data were also obtained in a family-based association study by use of sib pairs discordant for genotype (Gu et al. 2000). Subjects carrying the 1484insG variant showed also PTP1B mRNA overexpression in skeletal muscle (6,166 plus minus 1,879 copies/40 ng RNA vs. 2,983 plus minus 1,620; P<.01). Finally, PTP1B mRNA stability was significantly higher (P<.01) in human embryo kidney 293 cells transfected with 1484insG PTP1B, as compared with those transfected with wild-type PTP1B. Our data indicate that the 1484insG allele causes PTP1B overexpression and plays a role in insulin resistance. Therefore, individuals carrying the 1484insG variant might particularly benefit from PTP1B inhibitors, a promising new tool for treatment of insulin resistance (Kennedy and Ramachandran 2000).

Conflicting results have been reported regarding whether the PPAR␥2 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 To investigate this issue, a meta-analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted.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 ϭ 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 ϭ 0.02) and tended to be higher than in North America (18%, p ϭ 0.10). Difference between Asians and Europeans was no longer significant (p ϭ 0.15) after adjusting for the controls' BMI. Studies from Europe were still heterogeneous (p ϭ 0.02) with risk reduction in Ala12 carriers being progressively smaller (test for trend in the odds ratios, p ϭ 0.02) from Northern (26% reduction, p Ͻ 0.0001) to Central (10%, p ϭ 0.04) and Southern (0%, p ϭ 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. Key words: peroxisome proliferator-activated receptor, genetic susceptibility, candidate genes, type 2 diabetesThe peroxisome proliferator-activated receptor ␥2 (PPAR␥2) 1 is a key modulator of adipogenesis and insulin signaling (1). A single nucleotide polymorphism (SNP) in the PPAR␥2 gene, giving a Pro12Ala substitution, has been described (2). Although most studies have shown a statistically significant type 2 diabetes (T2D) risk reduction given by the Ala12 variant (3-11), some others have not (10 -36), thus suggesting variability in the contribution of this variant to the risk of T2D. To investigate this issue, a comprehensive meta-analysis of 41 published studies (3-36) and two unpublished Italian studies was conducted for a total of 42,910 individuals, which, to the best of our knowledge, is the largest one so far conducted (6,37,38). An additional aim of this study was to investigate the effect of covariates on genetic heterogeneity by meta-regression analysis.

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 Ϯ 9 years, with a disease duration of 11 Ϯ 9 years and HbA 1c levels of 8.6 Ϯ 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 Ն2.5 mg/mmol in men and Ն3.5 mg/mmol in women. ACR was correlated with HOMA IR (r ϭ 0.15, P ϭ 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 ϭ 363; r ϭ 0.21, P ϭ 0.0001) but not women (n ϭ 349; r ϭ 0.08, P ϭ 0.14), suggesting that insulin resistance and sex may interact (P for interaction ϭ 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 ϭ 0.01) (fourth quartile: 4.1 [2.2-7.9], P ϭ 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 ϭ 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. Diabetes Care 28:910 -915, 2005I ncreased urinary albumin excretion (UAE) is a strong predictor for development of overt diabetic nephropathy and cardiovascular mortality and morbidity in patients with type 1 and type 2 diabetes (1).Several evidences suggest that insulin resistance precedes and probably contributes to the development of increased UAE in type 1 diabetic patients (2) as well as in nondiabetic subjects (3). At variance, the relationship between insulin resistance and increased UAE in type 2 diabetic patients is less clear. In detail, both negative (4 -6) and positive (7-10) results have been reported on the association between the two conditions in these patients. Worth noting, all previous studies have been carried out in small samples, ranging from 20 (4) to 155 (6) patients. Examining the relationship between insulin resistance and increased UAE may help to clarify some of the mechanisms of increased cardiovascular morbidity and mor...

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 $ two atherogenic factors, were studied. Ischaemia at ECG stress was indicated by horizontal or downsloping ST segment depression $ 1 mm at 0.08 s after the J point. CAD was defined by stenosis $ 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 ðP , 0:01Þ 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.

Background-Insulin resistance plays a role in diabetic kidney complications. The ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) (rs1044498) K121Q polymorphism has been associated with insulin resistance and related vascular complications among patients with type 2 diabetes (T2D), in many although not all studies. This study investigated whether the ENPP1 Q121 variant modulates the risk of reduced GFR in T2D.

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 (Pϭ8.0ϫ10 Ϫ4). In the families, the Q121 variant accounted for 0.08 of PP heritability (Pϭ9.4ϫ10 Ϫ4). This association was formally replicated in a second sample of 475 individuals (Pϭ2.6ϫ10 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.

Cardiac valvular Ehlers‐Danlos syndrome (EDS) is a rare EDS subtype, caused by specific recessive variants in the gene encoding pro‐α2‐chain of type I collagen (COL1A2). Cardiac valvular EDS is mainly characterized by generalized/peripheral joint hypermobility, moderate–severe cardiac valvular disease, skin hyperextensibility and other minor soft tissues features. Only five molecularly confirmed patients have been reported to date. Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2. Clinical data and literature review allowed to better define the clinical spectrum of cardiac valvular EDS which now emerges as a more recognizable EDS variant with progressive heart valve disease firstly affecting the mitral valve. Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis and hypoplasia of the interphalangeal creases. The absence of bone fragility in our patients indicates that cardiac valvular EDS is also separated from patients with autosomal recessive osteogenesis imperfecta and variants in COL1A2, as well as from individuals with autosomal dominant osteogenesis imperfecta and severe cardiac valvular disease.

BackgroundSome patients diagnosed as having type 2 diabetes mellitus (T2DM) are, instead, affected by multigenerational diabetes whose clinical characteristics are mostly undefined.Objective1. To identify among patients who had been previously defined as affected by T2DM those, in fact, affected by multigenerational diabetes; 2. After excluding patients carrying the most common MODY genes and mitochondrial mutations, we compared clinical features of remaining patients with those of patients with T2DM.MethodsAmong 2,583 consecutive adult patients who had been defined as affected by T2DM, we looked for those with diabetes in ≥3 consecutive generations. All probands were screened for mutations in six MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B and NeuroD1) and for the A3243G mitochondrial mutation. After excluding patients with mutations in one of such genes, we compared clinical features of the remaining 67 patients (2.6% of the whole initial sample) affected by multigenerational “familial diabetes of the adulthood” (FDA) and of their diabetic relatives (n = 63) to those with T2DM (n = 1,028) by generalized hierarchical linear models followed by pairwise comparisons.ResultsAge, age at diagnosis, proportion of hypertension (all p<0.001), and waist circumference (p<0.05) were lower in FDA than T2DM. Nonetheless, the two groups had similar age-adjusted incidence rate of all-cause mortality.ConclusionsBeside younger age at diagnosis, FDA patients show lower waist circumference and reduced proportion of hypertension as compared to those with T2DM; despite such reduced potential cardiovascular risk factors, FDA patients did not show a reduced mortality risk than patients with T2DM.