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 antihyper-tensive 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.

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). 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. 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

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.

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 similar to 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.

High pulse pressure (PP), a proxy of arterial stiffness, has been linked to cardiovascular events (CVE) in diabetic and non-diabetic population [ 1 Schram M.T. Kostense P.J. Van Dijk R.A. Dekker J.M. Nijpels G. Bouter L.M. et al. Diabetes, pulse pressure and cardiovascular mortality: the Hoorn Study. J Hypertens. 2002; 20: 1743-1751 Crossref PubMed Scopus (148) Google Scholar , 2 Benetos A. Safar M. Rudnichi A. Smulyan H. Richard J.L. Ducimetieère P. et al. Pulse pressure a predictor of long-term cardiovascular mortality in a French male population. Hypertension. 1997; 30: 1410-1415 Crossref PubMed Scopus (962) Google Scholar ], and to albuminuria in diabetic subjects [ 3 Palmas W. Moran A. Pickering T. Eimicke J.P. Teresi J. Schwartz J.E. et al. Ambulatory pulse pressure and progression of urinary albumin excretion in older patients with type 2 diabetes mellitus. Hypertension. 2006; 48: 301-308 Crossref PubMed Scopus (43) Google Scholar , 4 Yano Y. Sato Y. Fujimoto S. Konta T. Iseki K. Moriyama T. et al. Association of high pulse pressure with proteinuria in subjects with diabetes, prediabetes, or normal glucose tolerance in a large Japanese general population sample. Diabetes Care. 2012; 35: 1310-1315 Crossref PubMed Scopus (25) Google Scholar ]. The increasing body mass index (BMI) affects arterial compliance and consequently PP [ [5] Kwagyan J. Tabe C.E. Xu S. Maqbool A.R. Gordeuk V.R. Randall O.S. The impact of body mass index on pulse pressure in obesity. J Hypertens. 2005; 23: 619-624 Crossref PubMed Scopus (30) Google Scholar ]. Offspring of albuminuric parents with T2DM showed a higher BMI and albuminuria, than offspring of normoalbuminuric parents [ [6] Forsblom C.M. Kanninen T. Lehtovirta M. Saloranta C. Groop L.C. Heritability of albumin excretion rate in families of patients with type 2 diabetes. Diabetologia. 1999; 42: 1359-1366 Crossref PubMed Scopus (71) Google Scholar ]. Therefore, BMI, PP and albuminuria may be related to each other. Moreover, all of them are heritable traits and could share some genetic background.

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 +/- 7 years), 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. (C) 2017 Elsevier Inc. All rights reserved.

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.

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.

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.

Background The pathogenesis of cardiovascular (CV) mortality, whose rate is increased in type 2 diabetes, is poorly understood. While high serum adiponectin is associated with increased CV mortality in the general population, no data are available in type 2 diabetes. We here investigated whether this counterintuitive association was observable also in diabetic patients and whether it was sex-specific. 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). Circulating adiponectin predicted CV mortality in men from HPFS (HR = 1.44, 1.21-1.72), but not in women from NHS (HR = 1.08, 0.86-1.35), used as replication samples. In a pooled analysis, HRs were 1.47 (1.27-1.70) in 1,075 men and 1.07 (0.86-1.33) in 1,019 women (p for HRs heterogeneity across sexes = 0.018). 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.

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 HbA(1c) and both fibrinogen and HDL-c and between HDL-c and fibrinogen were significant only in CAD-positive patients (beta = 10.655, p = 0.002; beta = -1.056, p = 0.013; b = -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% Cl = 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.