Hepatic steatosis with significant fibrosis is associated with an increased 10-year estimated risk of cardiovascular disease in adults with type 1 diabetes mellitus.

BACKGROUND: We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event. RESULTS: Using the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54-36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator. CONCLUSIONS: The 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis.

Circulating adiponectin and cardiovascular mortality in patients with type 2 diabetes mellitus: evidence of sexual dimorphism.

BACKGROUND: The pathogenesis of cardiovascular (CV) mortality, whose rate is increased in type 2 diabetes, is poorly understood. METHODS: Three prospective cohorts were analyzed: 1) Gargano Heart Study (GHS; 359 patients, 58 events/1,934 person-years; py); 2) Health Professional Follow-up Study (HPFS; 833 men, 146 events/10,024 py); 3) Nurses' Health Study (NHS; 902 women, 144 events/15,074 py). RESULTS: In GHS serum adiponectin predicted CV mortality in men (hazard ratio, HR, and 95% CI per standard deviation, SD, increment = 1.54, 1.19-2.01), but not women (HR = 0.98, 0.48-2.01). CONCLUSIONS: This is the first report showing that high circulating adiponectin predicts increased CV mortality in men, but not in women with type 2 diabetes. Further studies are necessary to unravel the mechanisms through which adiponectin influences CV mortality in a sex-specific manner.

Kidney dysfunction and related cardiovascular risk factors among patients with type 2 diabetes.

BACKGROUND: Kidney dysfunction is a strong predictor of end-stage renal disease and cardiovascular (CV) events. The main goal was to study the clinical correlates of diabetic kidney disease in a large cohort of patients with type 2 diabetes mellitus (T2DM) attending 236 Diabetes Clinics in Italy. METHODS: Clinical data of 120 903 patients were extracted from electronic medical records by means of an ad hoc-developed software. Estimated glomerular filtration rate (GFR) and increased urinary albumin excretion were considered. Factors associated with the presence of albuminuria only, GFR < 60 mL/min/1.73 m(2) only or both conditions were evaluated through multivariate analysis. RESULTS: Mean age of the patients was 66.6 ± 11.0 years, 58.1% were male and mean duration of diabetes was 11.1 ± 9.4 years. The frequency of albuminuria, low GFR and both albuminuria and low GFR was 36.0, 23.5 and 12.2%, respectively. Glycaemic control was related to albuminuria more than to low GFR, while systolic and pulse pressure showed a trend towards higher values in patients with normal kidney function compared with those with both albuminuria and low GFR. Multivariate logistic analysis showed that age and duration of disease influenced both features of kidney dysfunction. Male gender was associated with an increased risk of albuminuria. Higher systolic blood pressure levels were associated with albuminuria, with a 4% increased risk of simultaneously having albuminuria and low GFR for each 5 mmHg increase. CONCLUSIONS: In this large cohort of patients with T2DM, reduced GFR and increased albuminuria showed, at least in part, different clinical correlates. A worse CV risk profile is associated with albuminuria more than with isolated low GFR.

MASLD, hepatic steatosis and fibrosis are associated with the prevalence of chronic kidney disease and retinopathy in adults with type 1 diabetes mellitus.

AIM: We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM). METHODS: We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants. RESULTS: Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05-2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13-1.46) than those without steatosis. CONCLUSION: This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM.

Sex Differences in Cardiovascular Disease and Cardiovascular Risk Estimation in Patients With Type 1 Diabetes.

CONTEXT: Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk than the general population. OBJECTIVE: This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults. METHODS: We conducted a multicenter, cross-sectional study involving 2041 patients with T1D (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we used the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events. RESULTS: CVD prevalence (n = 116) was higher in men than in women aged ≥55 years (19.2 vs 12.8%, P = .036), but comparable between the 2 sexes in those aged <55 years (P = .91). In patients without pre-existing CVD (n = 1925), mean 10-year estimated CVD risk was 15.4 ± 0.4% without any significant sex difference. However, stratifying this patient group by age, the 10-year estimated CVD risk was significantly higher in men than in women until age 55 years (P < .001), but this risk equalized after this age. Carotid artery plaque burden was significantly associated with age ≥55 years and with a medium and high 10-year estimated CVD risk, without any significant sex difference. Diabetic retinopathy and sensory-motor neuropathy were also associated with higher 10-year CVD risk and female sex. CONCLUSION: Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged <55 years than in women of similar age, but these sex differences disappeared at age ≥55 years, suggesting that female sex was no longer protective.

Association between different modalities of insulin administration and metabolic dysfunction-associated fatty liver disease in adults with type 1 diabetes mellitus.

AIM: We examined whether different insulin administration modalities, i.e., multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII by insulin pumps), are differently associated with the risk of having metabolic dysfunction-associated fatty liver disease (MAFLD), with or without coexisting significant liver fibrosis (assessed by validated non-invasive biomarkers), in adults with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,417 adult individuals with established T1DM treated with MDI or CSII. We calculated hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting MAFLD (defined by HSI >36), with or without coexisting significant fibrosis (defined by FIB-4 index ≥ 1.3 or <1.3, respectively). RESULTS: Compared to the MDI group (n = 1,161), insulin-pump users (n = 256; 18.1%) were more likely to be younger (mean age: 40 vs. 48 years, P < 0.001), had better glycemic control (mean hemoglobin A1c: 7.7%  vs. 7.9%, P = 0.025) and a markedly lower prevalence of MAFLD with coexisting significant fibrosis (2.7%  vs. 8.1%, P = 0.010), but a comparable prevalence of MAFLD without fibrosis. In multinomial logistic regression analysis, CSII therapy was associated with a ∼70%-lower risk of MAFLD with significant fibrosis (unadjusted odds ratio 0.32, 95% confidence interval 0.14-0.70; P = 0.004), but this association was no longer significant after adjustment for age, hemoglobin A1c and other potential confounders. CONCLUSION: The lower prevalence of MAFLD with coexisting significant fibrosis we observed in adults with T1DM using CSII therapy, compared to those using MDI therapy, is primarily mediated by inter-group differences in age.

ENPP1 Q121 variant, increased pulse pressure and reduced insulin signaling, and nitric oxide synthase activity in endothelial cells.

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 x 10(-4)). In the families, the Q121 variant accounted for 0.08 of PP heritability (P=9.4 x 10(-4)). This association was formally replicated in a second sample of 475 individuals (P=2.6 x 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 x 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.

Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes.

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-kappaB (NF-kappaB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4-3.8, P = 0.001) and 2.0 (1.3-2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C < or =7.0% and 1.2 for those with A1C >7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30-45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

Common haplotypes at the adiponectin receptor 1 (ADIPOR1) locus are associated with increased risk of coronary artery disease in type 2 diabetes.

Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common polymorphisms in the adiponectin receptor 1 (ADIPOR1) gene mediating these effects influence the risk of coronary artery disease (CAD) in type 2 diabetes. Linkage disequilibrium analysis of 28 single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR1 locus revealed two haplotype blocks that could be tagged by six SNPs. These six markers were typed in two populations of CAD-positive and -negative subjects with type 2 diabetes, one from Boston (n = 411) and the other from Italy (n = 533). In the Boston population, the three tags of the more 3' block were all significantly associated with CAD (P = 0.001-0.01). A similar trend, although not significant, was found in Italian subjects. Haplotype analysis of the combined populations revealed different haplotype distributions in case and control subjects (P = 0.0002), with one common haplotype being associated in homozygotes with a greater than threefold increase in cardiovascular risk (odds ratio 3.6 [95% CI 1.8-7.2]). Some of the genotypes associated with increased cardiovascular risk were associated with 30-40% lower ADIPOR1 mRNA levels in blood mononuclear cells (n = 60) and adipose tissue biopsies (n = 28) (P = 0.001-0.014). Our findings point to genetic variability at the ADIPOR1 locus as a strong determinant of CAD susceptibility in type 2 diabetes.

Silent coronary heart disease in patients with type 2 diabetes: application of a screening approach in a follow-up study.

AIMS: The cost-effectiveness of screening for silent coronary heart disease (CHD) in type 2 diabetes (DM2) is still debated. METHODS: We applied a diagnostic algorithm for silent CHD detection, in a cohort of 102 asymptomatic DM2 subjects (57±7years), attending 5 Italian outpatient clinics, to verify its predictive value. The risk of silent CHD was calculated considering classical risk factors, and presence of microangiopathy/macroangiopathy. Patients were divided in 3 groups, i.e. group 1: normal ECG and low silent CHD risk; group 2: abnormal ECG, irrespective of silent CHD risk; group 3: high silent CHD risk, irrespective of ECG. To group 2 and 3, a functional test was recommended and performed in 78% of patients. RESULTS: Silent CHD prevalence was similar in group 2 and 3 (25 vs. 17% respectively; p=0.495). However, evaluating the entire cohort, a significant higher prevalence of silent CHD was observed in subjects with abnormal vs. normal ECG (23 vs. 4%; P=0.004), but not in subjects with high vs. low pre-test silent CHD risk (14 vs. 9%; p=0.472). CONCLUSIONS: An abnormal ECG was a strong, independent predictor of silent CHD (OR 8.9; CI 1.27-62.5; p=0.028) in DM2. Therefore, a functional stress testing should be considered in DM2 patients with ECG abnormalities.

The functional Q84R polymorphism of mammalian Tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from Italy.

Insulin resistance plays a major role in dyslipidemia, cardiovascular disease, and type 2 diabetes. TRB3, a mammalian tribbles homolog, whose chromosomal region 20p13-p12 has been linked to human type 2 diabetes, impairs insulin signaling through the inhibition of Akt phosphorylation and is overexpressed in murine models of insulin resistance. We here report that the prevalent TRB3 missense Q84R polymorphism is significantly (P < 0.05) associated with several insulin resistance-related abnormalities in two independent cohorts (n = 178 and n = 605) of nondiabetic individuals and with the presence of a cluster of insulin resistance-related cardiovascular risk factors in 716 type 2 diabetic patients (OR 3.1 [95% CI 1.2-8.2], P = 0.02). In 100 additional type 2 diabetic patients who suffered from myocardial ischemia, age at myocardial ischemia was progressively and significantly (P = 0.03) reduced from Q84Q to Q84R to R84R individuals. To test the functional role of TRB3 variants, either Q84 or R84 TRB3 full-length cDNAs were transfected in human HepG2 hepatoma cell lines. As compared with control HepG2 cells, insulin-induced Ser473-Akt phosphorylation was reduced by 22% in Q84- (P < 0.05 vs. control cells) and by 45% in R84-transfected cells (P < 0.05 vs. Q84 transfected and P < 0.01 vs. control cells). These data provide the first evidence that TRB3 gene plays a role in human insulin resistance and related clinical outcomes.

The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction.

Insulin resistance (IR) is pathogenic for type 2 diabetes and coronary artery disease (CAD). The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR. Our aim was to investigate the role of the 121Q variant on the risk of type 2 diabetes and CAD. Nondiabetic control subjects (n = 638), type 2 diabetic patients without CAD (n = 535), and type 2 diabetic patients with CAD (n = 434) from Italy and the U.S. were studied. The proportion of 121Q carriers progressively increased in the three groups (27.4, 28.8, and 33.2%, respectively; adjusted P value = 0.027). Among diabetic patients (n = 969), 121Q carriers had an increased risk of developing type 2 diabetes before the age of 65 years (adjusted odds ratio [OR] 2.26, 95% CI 1.26-4.03; P = 0.006) and having a myocardial infarction (MI) (n = 156) by 50 years of age (3.17, 1.46-6.88, P = 0.007). The 121Q variant was also associated with an increased risk for CAD (1.47, 1.01-2.18; P = 0.049) in diabetic patients who did not smoke (n = 546). In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI.

The PPARγ2 P12A polymorphism is not associated with all-cause mortality in patients with type 2 diabetes mellitus.

The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator-activated receptor-γ2 (PPARγ2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARγ2 P12A, according to a dominant model (PA + AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARγ2 P12A and all-cause mortality was observed (HR 1.02, 95 % CI 0.79-1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95 % CI 0.83-1.43). In a meta-analysis of ours and all studies previously published (n = 3241 individuals; 666 events), no association was observed between PPARγ2 P12A and all-cause mortality (HR 1.07, 95 % CI 0.85-1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARγ2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus.

Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients.

OBJECTIVE: Subclinical hypercortisolism (SH) may play a role in several metabolic disorders, including diabetes. No data are available on the relative prevalence of SH in type 2 diabetes (T2D). In order to compare the prevalence of SH in T2D and matched non-diabetic control individuals, we performed a case-controlled, multicenter, 12-month study, enrolling 294 consecutive T2D inpatients (1.7% dropped out the study) with no evidence of clinical hypercortisolism and 189 consecutive age- and body mass index-matched non-diabetic inpatients (none of whom dropped out). DESIGN AND METHODS: Ascertained SH (ASH) was diagnosed in individuals (i) with plasma cortisol after 1 mg overnight dexamethasone suppression >1.8 microg/dl (50 nmol/l), (ii) with more than one of the following: (a) urinary free cortisol >60.0 microg/24 h (165.6 nmol/24 h), (b) plasma ACTH <10.0 pg/ml (2.2 pmol/l) or (c) plasma cortisol >7.5 microg/dl (207 nmol/l) at 24:00 h or >1.4 microg/dl (38.6 nmol/l) after dexamethasone-CRH (serum cortisol after corticotrophin-releasing hormone stimulus during dexamethasone administration) test, and (iii) in whom the source of glucocorticoid excess was suggested by imaging and by additional biochemical tests (for ACTH-dependent ASH). RESULTS: Prevalence of ASH was higher in diabetic individuals than in controls (9.4 versus 2.1%; adjusted odds ratio, 4.8; 95% confidence interval, 1.6-14.1; P = 0.004). In our population the proportion of T2D which is statistically attributable to ASH was approx. 7%. Among diabetic patients, the presence of severe diabetes (as defined by the coexistence of hypertension, dyslipidaemia and insulin treatment) was significantly associated with SH (adjusted odds ratio, 3.8; 95% confidence interval, 1.4-10.2; P = 0.017). CONCLUSIONS: In hospitalized patients, SH is associated with T2D.

The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients.

OBJECTIVE: Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n = 189) and/or (n = 45) with coronary stenosis T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects.

Serum resistin, cardiovascular disease and all-cause mortality in patients with type 2 diabetes.

BACKGROUND: High serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes. METHODS: We tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels. RESULTS: In a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10-1.64) and 1.99 (1.55-2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10-1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06-1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343). CONCLUSIONS: This is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry.

Joint effect of insulin signaling genes on all-cause mortality.

OBJECTIVE: We have previously reported the combined effect of SNPs perturbing insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. METHODS: We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. RESULTS: In the first sample, individuals carrying 1 or ≥ 2 risk alleles had 33% (p = 0.06) and 51% (p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥ 2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08-1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13-1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. CONCLUSION: Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.

Role of relationship between HbA1c, fibrinogen and HDL-cholesterol on cardiovascular disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To assess the impact of relationship between glycated hemoglobin (HbA(1c)), fibrinogen and HDL-cholesterol (HDL-c) on cardiovascular disease in type 2 diabetes. METHODS: We investigated i) the relationship of HbA1c, fibrinogen and HDL-c in 375 coronary artery disease (CAD)-negative and 320 CAD-positive diabetic patients and ii) the association between clustering of these three factors and incident major cardiovascular events in 317/320 CAD-positive patients. RESULTS: i) The relationships between HbA1c and both fibrinogen and HDL-c and between HDL-c and fibrinogen were significant only in CAD-positive patients (ß = 10.655, p = 0.002; ß = -1.056, p = 0.013; ß = -1.751, p = 0.000008, respectively); ii) patients with worse-than-median levels of the three factors showed higher risk for major cardiovascular events than others (HR: 2.22, 95%CI = 1.23-4.02, p = 0.008). Both findings were independent of LDL-c, blood pressure or ongoing therapies. CONCLUSION: Our findings suggest interwoven actions of poor glycemic control, low grade inflammation and low HDL-c on atherosclerotic processes in type 2 diabetes.

Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance.

OBJECTIVE: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. DESIGN AND SETTING: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). RESULTS: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). CONCLUSIONS: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.