Thrombopoietin Contributes to Enhanced Platelet Activation in Patients with Type 1 Diabetes Mellitus.

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet-leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet-monocyte and platelet-granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet-leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet-leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk.

Opportunistic screening for type 2 diabetes in community pharmacies. Results from a region-wide experience in Italy.

BACKGROUND AND AIMS: Given the paucity of symptoms in the early stages of type 2 diabetes, its diagnosis is often made when complications have already arisen. Although systematic population-based screening is not recommended, there is room to experience new strategies for improving early diagnosis of the disease in high risk subjects. We report the results of an opportunistic screening for diabetes, implemented in the setting of community pharmacies. METHODS AND RESULTS: To identify people at high risk to develop diabetes, pharmacists were trained to administer FINDRISC questionnaire to overweight, diabetes-free customers aged 45 or more. Each interviewee was followed for 365 days, searching in the administrative database whether he/she had a glycaemic or HbA1c test, or a diabetologists consultation, and to detect any new diagnosis of diabetes defined by either a prescription of any anti-hyperglycaemic drug, or the enrolment in the register of patients, or a hospital discharge with a diagnosis of diabetes. Out of 5977 interviewees, 53% were at risk of developing diabetes. An elevated FINDRISC score was associated with higher age, lower education, and living alone. Excluding the number of cases expected, based on the incidence rate of diabetes in the population, 51 new cases were identified, one every 117 interviews. FINDRISC score, being a male and living alone were significantly associated with the diagnosis. CONCLUSIONS: The implementation of a community pharmacy-based screening programme can contribute to reduce the burden of the disease, particularly focusing on people at higher risk, such as the elderly and the socially vulnerable.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients.

AIMS/HYPOTHESIS: Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. METHODS: Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14(+) cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14(-) cell were co-cultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed. RESULTS: MSC- and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-ß, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3(+) regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. CONCLUSIONS/INTERPRETATION: In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.

Polypharmacy in elderly patients with type 2 diabetes receiving oral antidiabetic treatment.

AIM: Polypharmacy in older diabetics can have detrimental effects linked to poor adherence and the risk of drug interaction or more serious/frequent side effects. The aim of this study was to identify the characteristics associated with polypharmacy in a cohort of elderly diabetic patients being treated with oral hypoglycemic agents. METHODS: The study population consisted of 1342 diabetic patients consecutively enrolled in 57 diabetes centers in Italy participating in the METABOLIC Study. Patients meeting the following inclusion criteria were enrolled: diagnosis of type 2 diabetes mellitus, age ≥65 years, and receiving oral antidiabetic treatment. Data concerning diabetes duration and complications, the medications the patients were taking, and the number of hypoglycemic events were registered. Multidimensional impairment was assessed using the Multidimensional Prognostic Index. RESULTS: The mean age of the participants was 73.3 ± 5.5 years. Polypharmacy, defined as being prescribed contemporaneously at least five drugs, was found in 57.1 % of the study population. According to a multivariable logistic model, the female gender was significantly associated with polypharmacy, as were living in Northern Italian regions, diabetes duration longer than 4 years, and having a body mass index ≥30 kg/m(2). Comorbidities, diabetes complications, a better cognitive performance on the Short Portable Mental Status Questionnaire, and being malnourished/at risk of malnourishment according to the mini nutritional assessment were associated with polypharmacy. CONCLUSIONS: Polypharmacy, a condition that may lead to many potential detrimental outcomes in older diabetic subjects, was significantly associated with some risk factors that may be useful to identify subjects at risk.

THE STORM (acute coronary Syndrome in paTients end Of life and Risk assesMent) study.

INTRODUCTION: Elderly patients with coexisting frailty and multiple comorbidities frequently present to the emergency department (ED). Because non-cardiovascular comorbidities and declining health status may affect their life expectancy, management of these patients should start in the ED. This study evaluated the role of Gold Standards Framework (GSF) criteria for identifying patients with acute coronary syndromes (ACS) approaching end of life. METHODS: All consecutive patients admitted to the ED and hospitalised with a diagnosis of ACS between May 2012 and July 2012 were included. According to GSF criteria, patients were labelled as positive GSF status when they met at least one general criterion and two heart disease criteria; furthermore, traditional cardiovascular risk scores (the Global Registry for Acute Coronary Events (GRACE) score and the Age, Creatinine and Ejection Fraction (ACEF) score) were calculated and WHOQOL-BREF was assessed. Mortality and repeat hospitalisation due to cardiovascular and non-cardiovascular causes were evaluated at 3-month and 12-month follow-up. RESULTS: From a total of 156 patients with ACS enrolled, 22 (14%) had a positive GSF. A positive GSF was associated with higher rate of non-cardiovascular events (22.7% vs 6.7%; p=0.03) at 3 months and higher rates of both cardiovascular and non-cardiovascular events (36% vs 16.4%; p=0.04 and 27.3% vs 6.7%; p=0.009, respectively) at 12 months. In multivariate analysis, an in-hospital GRACE score was a predictor of cardiovascular events, while a positive GSF independently predicted non-cardiovascular events. CONCLUSIONS: The GSF score independently predicts non-cardiovascular events in patients presenting with ACS and may be used along with traditional cardiovascular risk scores in choosing wisely the most appropriate treatment. The present results need to be externally validated on larger samples.

What is the impact of sleeve gastrectomy and gastric bypass on metabolic control of diabetes? A clinic-based cohort of Mediterranean diabetic patients.

BACKGROUND: Effectiveness of sleeve gastrectomy and gastric bypass on glycemic, blood pressure, and lipids control in obese type 2 diabetic patients is poorly known. OBJECTIVE: To assess the effectiveness of bariatric surgery on obese patients with type 2 diabetes. SETTING: University hospital, Italy. METHODS: Diabetes remission and metabolic changes over postoperative follow-up were assessed in 135 obese patients with type 2 diabetes who underwent bariatric surgery in 2007-2011 (gastric bypass, n = 100; sleeve gastrectomy, n = 35). Repeated-measures analysis of variance and logistic regression were used. RESULTS: Diabetes remission was observed in 22% and 21.5% of the patients, respectively, 1 and 2 years after surgery. Compared with the remaining patients, patients in diabetes remission were significantly younger, had lower diabetes duration, hemoglobin A1c (HbA1c), fasting plasma glucose, and frequency of insulin treatment. Trends of HbA1c, body mass index (BMI), blood pressure, and plasma triglycerides revealed a significant decrease over time and the trend of HDL-cholesterol revealed a significant increase over time in both treatment groups (P<.001). Patients reaching target levels for at least 3 out of 5 indicators of intermediate outcomes of care (composite indicator of good diabetes control) were 25.5% at the baseline and 66.1% at final follow-up visit (P<.001). In logistic regression, age (OR = .89, 95% CI .84-.95), HbA1c (OR = .67, 95% CI .49-0.91) and diabetes duration (OR = .87, 95% CI .77-1.00) were independent predictors of diabetes remission. CONCLUSIONS: Bariatric surgery is an effective approach to optimize glucose, lipids, and blood pressure control in obese type 2 diabetic patients. Bariatric surgery should be offered earlier over the natural course of diabetes to increase the likelihood of diabetes remission in obese patients.

Levels of N-terminal pro brain natriuretic peptide are enhanced in people with the uncomplicated metabolic syndrome: a case-cohort analysis of the population-based Casale Monferrato study.

BACKGROUND: Both metabolic syndrome (MetS) and N-amino terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) confer increased risk of cardiovascular diseases (CVD). We assessed if NT-proBNP levels were greater in people with uncomplicated MetS, who had neither CVD/chronic kidney disease (CKD) nor diabetes, as compared with subjects who met none of the defining criteria of the MetS. METHODS: A case-cohort study from the non-diabetic population-based Casale Monferrato study was performed, after exclusion of all subjects with established CVD, CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2)], and CRP values ≥3 mg/L. Cases (n = 161) with MetS were compared with all subjects within the cohort (n = 124) who were completely free of any component of the MetS. Serum NT-proBNP was centrally measured by immunoenzymatic assay. RESULTS: NT-proBNP levels were significantly higher in cases than in control subjects [35.4 (15.5-98.2) vs 24.4 (11.7-49.6) pg/mL, p = 0.014]. In logistic regression analysis, compared with NT-proBNP values in the lower quartiles (≤49.64 pg/mL), higher values conferred odds ratio 4.17 (1.30-13.44) of having the MetS, independently of age, sex, microalbuminuria, CRP, eGFR, and central obesity. This association was evident even after the exclusion of hypertensive subjects. Further adjustment for log-HOMA and diastolic blood pressure did not modify the strength of the association, while central obesity was a negative confounder. CONCLUSIONS: Compared with people without any component of the MetS, those with uncomplicated MetS, who had neither CVD/CKD nor diabetes, had increased NT-proBNP values, even if they were normotensive and although absolute values were still in the low range. The insulin resistance state did not mediate this association, while central obesity was a negative confounder.

NT-proBNP linking low-moderately impaired renal function and cardiovascular mortality in diabetic patients: the population-based Casale Monferrato Study.

BACKGROUND: Few data are available to assess whether a low-moderate reduction in estimated glomerular filtration rates (eGFR) has a role per se on cardiovascular (CV) mortality or other biomarkers such as NT-proBNP allow to explain such association. METHODS AND FINDINGS: In a prospective study including 1,645 type 2 diabetic subjects of the population-based Casale Monferrato Study, who had no clinical evidence of heart failure and eGFR >45 ml/min/1.73 m2, we examined 6 years CV mortality. Multivariate Cox proportional hazards modeling were used to estimate the effect of NT-proBNP on the association between eGFR and mortality, independently of baseline CV risk factors, albumin excretion rate (AER) and C-reactive protein (CRP). During follow-up, 327 people died (149 of CV diseases) out of 8334.5 person-years. Compared to eGFR≥90 ml/min/1.73 m2, values of 60-89 and 45-59 ml/min/1.73 m2 conferred a fully adjusted hazard ratios (HRs) of CV mortality of 1.74 (1.08-2.82) and 1.95 (1.03-3.68), respectively. After further adjustment for NT-proBNP, however, HRs were no longer significant (HRs 1.42, 0.83-2.42 and 1.22, 0.59-2.51). In this model, HR for logNT-proBNP was 1.84 (1.52-2.22). Adding NT-proBNP to the model improved the C-statistic of CV mortality from 0.79 (0.76-0.83) to 0.84 (0.81-0.87), yielded an IDI of 0.03 (p = 0.02), and a NRI of 0.44 (p = 0.016). CONCLUSIONS: In diabetic people a modest reduction in renal function increased 6-year CV mortality independently of albuminuria. This association, however, was mainly explained by the effect of NT-proBNP, that remained the strongest prognostic marker for a worse CV outcome, even after adjustment for other CV risk factors and pre-existing CVD.

Impact of snacking pattern on overweight and obesity risk in a cohort of 11- to 13-year-old adolescents.

OBJECTIVES: The association between snacking habits and overweight in adolescents is unclear. We evaluated the relation between snacking patterns and overweight/obesity in a cohort of 11- to 13-year-old Italian adolescents. METHODS: The dietary habits of 400 randomly selected adolescents were evaluated; those with body mass index ≥ 85 th percentile were considered as overweight/obese. Participants were classified based on the percentage of caloric intake from snacks (<15%, 15%-20%, >20%), snacking frequency (1, 2, ≥ 3), and timing of consuming the most caloric snack (morning, afternoon, evening). RESULTS: A minority of participants (13/400, 3.3%) did not consume any snacks; 5/13 (38.5) of them were overweight/obese. Among snackers (387/400), overweight/obesity prevalence was 10.4%, 14.4%, 20.5%, respectively, in those consuming <15%, 15% to 10%, and >20% of their energy intake from snacks. In a Poisson regression model, the overweight/obesity relative risks (RRs) were 1.35 (95% confidence interval [CI] 0.58-3.15) and 2.32 (1.10-4.89) for 15% to 20% and >20% calories/day from snacks, respectively. Overweight/obesity prevalence (from 9.6% to 22.6%) was correlated with snacking frequency (RR 2.20, 95% CI 0.92-5.27, and RR 4.17, 95% CI 1.60-10.9, for 2 and ≥ 3 snacks per day, respectively). The most caloric snacks were consumed in the morning (180/387) and afternoon (179/387); 28.6% of the predominantly evening snackers (28/387) were overweight/obese (RR 3.12, 95% CI 1.17-8.34). CONCLUSIONS: Increased snacking calories, frequency, and evening snacking are independently associated with overweight/obesity in Italian middle-school adolescents.

The effect of age and NT-proBNP on the association of central obesity with 6-years cardiovascular mortality of middle-aged and elderly diabetic people: the population-based Casale Monferrato study.

BACKGROUND: Among people with type 2 diabetes the relationship between central obesity and cardiovascular mortality has not been definitely assessed. Moreover, NT-proBNP is negatively associated with central obesity, but no study has examined their combined effect on survival. We have examined these issues in a well-characterized population-based cohort. METHODS AND FINDINGS: Survival data of 2272 diabetic people recruited in 2000 who had no other chronic disease have been updated to 31 December 2006. NT-proBNP was measured in a subgroup of 1690 patients. Cox proportional hazards modeling was employed to estimate the independent associations between cardiovascular and all-cause mortality and waist circumference. Mean age was 67.9 years, 49.3% were men. Both age and NT-proBNP were negatively correlated with waist circumference (r = -0.11, p<0.001 and r = -0.07, p = 0.002). Out of 2272 subjects, 520 deaths (221 for CV mortality) occurred during a median follow-up of 5.4 years. Central obesity was not associated with CV mortality (hazard ratio, HR, adjusted for age, sex, diabetes duration, 1.14, 95% CI 0.86-1.52). NTproBNP was a negative confounder and age a strong modifier of this relationship (p for interaction<0.001): age<70 years, fully adjusted model HR = 3.52 (1.17-10.57) and age ≥70 years, HR = 0.80 (0.46-1.40). Respective HRs for all-cause mortality were 1.86 (1.03-3.32) and 0.73 (0.51-1.04). CONCLUSIONS: In diabetic people aged 70 years and lower, central obesity was independently associated with increased cardiovascular mortality, independently of the negative effect of NT-proBNP. In contrast, no effect on 6-years survival was evident in diabetic people who have yet survived up to 70 years.

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients.

OBJECTIVE: Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory. DESIGN: We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic. METHODS: All 1277 patients treated with sulphonylureas during 19961997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause-specific mortality), including several potential confounders. RESULTS: Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HR=0.30; 95% CI 0.16-0.55, and HR=0.48; 95% CI 0.29-0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HR=0.40; 95% CI 0.22-0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrollment. CONCLUSIONS: Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucose-lowering effect and strongly advocate for further investigation.

N-terminal probrain natriuretic peptide is a stronger predictor of cardiovascular mortality than C-reactive protein and albumin excretion rate in elderly patients with type 2 diabetes: the Casale Monferrato population-based study.

OBJECTIVE: To study whether N-terminal probrain natriuretic peptide (NT-proBNP) is a short-term independent predictor of both all-cause and cardiovascular (CV) mortality in type 2 diabetic patients and to establish whether albuminuria and C-reactive protein (CRP) affect this relationship. RESEARCH DESIGN AND METHODS: The prospective study included 1,825 type 2 diabetic patients from the population-based cohort of the Casale Monferrato study. CV risk factors, preexisting CVD, and NT-proBNP levels were evaluated at baseline. All-cause and CV mortality were assessed 5.5 years after baseline examination. Multivariate Cox proportional hazards modeling was used to estimate mortality hazard ratios (HRs). RESULTS: During the follow-up period, 390 people died (175 for CVD) out of 9,101 person-years of observations. A significantly increased mortality risk by quartiles of NT-proBNP was observed (test for trend, P < 0.001). NT-proBN P values >91 pg/mL conferred HRs of 2.05 (95% CI 1.47-2.86) for all-cause and 4.47 (2.38-8.39) for CV mortality, independently of CV risk factors, including CRP and albumin excretion rate (AER). The association was also significant for modest rises in NT-proBNP levels and in patients without microalbuminuria and CVD at baseline (upper quartiles HRs 3.82 [95% CI 1.24-13.75]) and 3.14 [1.00-9.94]). Albuminuria and NT-proBNP had an additive effect on mortality, though the association was stronger for NT-proBNP. CONCLUSIONS: NT-proBNP is a strong independent predictor of short-term CV mortality risk in elderly people with type 2 diabetes, including those without preexisting CVD. This association is evident even in people with slightly increased values, is not modified by CRP, and is additive to that provided by AER.

Serum levels of heat shock protein 27 in patients with acute ischemic stroke.

Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.

Obesity is associated with lower mortality risk in elderly diabetic subjects: the Casale Monferrato study.

The relationship between obesity and mortality in people with type 2 diabetes has not been definitely assessed. We have examined this issue in a well-characterized population-based cohort of Mediterranean diabetic people. Standardized anthropometric data from the population-based Casale Monferrato Study have been prospectively analyzed. The cohort included 1,475 people (62.6% aged ≥65 years) who had been recruited in 1991 and followed-up to December 31, 2006. Cox proportional hazards modeling was employed to estimate the independent associations between all-cause and cardiovascular mortality and BMI. Out of 1,475 people, 972 deaths occurred during a 15-year follow-up. Cox regression analyses showed that with respect to BMI <24.2 kg/m(2), values of 30.0 kg/m(2) and over were associated with lower all-cause and cardiovascular mortality risk (HR = 0.68, 95% CI 0.56-0.85, P for trend = 0.001; HR = 0.59, 0.44-0.80, P for trend = 0.002), independently of classical and new risk factors. As interaction between age and BMI was significant, we performed a stratified analysis by age, providing evidence that our finding was entirely due to a significant protective effect of BMI of 30.0 kg/m(2) and over in the elderly (all-cause mortality HR = 0.75, 95% CI 0.58-0.96; cardiovascular mortality HR = 0.67, 95% CI 0.45-0.95). In contrast, obesity was not significantly associated with mortality risk in diabetic subjects aged <65 years. Results were confirmed even excluding from the analysis individuals who died within 2 years of follow-up, smokers and those with CHD. In Mediterranean diabetic people aged ≥65 years, obesity is significantly associated with lower 15-year mortality risk. In contrast, it was not significantly associated with mortality risk in diabetic subjects aged <65 years. As more than two-thirds of people with type 2 diabetes are elderly, our findings, if confirmed, could have clinical implications.

Early life socioeconomic indicators and risk of type 1 diabetes in children and young adults.

OBJECTIVE: To examine the potential role of 2 early-life socioeconomic indicators, parental education, and crowding index, on risk of type 1 diabetes (T1DM) in patients up to age 29 years to test heterogeneity by age at onset according to the hygiene hypothesis. STUDY DESIGN: The study base was 330 950 individuals born from 1967 to 2006 who resided in the city of Turin at any time between 1984 and 2007. Data on their early life socioeconomic position were derived from the Turin Longitudinal Study; 414 incident cases of T1DM up to age 29 years were derived from the Turin T1DM registry. RESULTS: Socioeconomic indicators had opposing effects on risk of T1DM in different age at onset subgroups. In a Poisson regression model that included both socioeconomic indicators, there was a 3-fold greater risk of T1DM (relative risk 2.91, 95% CI 0.99-8.56) in children age 0-3 years at diagnosis living in crowded houses. In the 4- to 14-year subgroup, a low parental educational level had a protective effect (relative risk 0.50, 95% CI 0.29-0.84), and the effect of crowding nearly disappeared. In the 15- to 29-year subgroup, neither crowding nor parental educational level was clearly associated with the incidence of T1DM. CONCLUSIONS: We provide evidence of heterogeneity by age at onset of the association between early-life socioeconomic indicators and the risk of T1DM. This finding is consistent with the hypothesis that infectious agents in the perinatal period may increase the risk, whereas in the following years they may become protective factors (hygiene hypothesis).

Circulating anti-Hsp70 levels in nascent metabolic syndrome: the Casale Monferrato Study.

The metabolic syndrome (MetS) confers an increased risk of both type 2 diabetes and cardiovascular diseases (CVD). Heat shock protein 70 (Hsp70), an intracellular polypeptide, can be exposed on the plasma membrane and/or released into the circulation, eliciting both native and immune responses that may contribute to vascular damage. Our aim was to assess if serum anti-Hsp70 antibody levels were cross-sectionally associated with uncomplicated MetS. A cross-sectional case-control study from the nondiabetic cohort of the Casale Monferrato Study was performed. Subjects with established CVD and/or abnormal renal function were excluded. Case subjects (n = 180) were defined as those fulfilling the criteria for the diagnosis of MetS. Control subjects (n = 136) were completely free of any component of the MetS. Serum anti-Hsp70 levels were measured by immunoenzymatic assay. We found that anti-Hsp70 antibody levels were significantly higher in cases than in control subjects [122.6 (89.5-155.6) vs 107.1 (77.3-152.4) µg/ml, p = 0.04], even after age and sex adjustment. In logistic regression analysis, higher levels of log-anti-Hsp70 conferred greater odds ratio (OR) for MetS, independently of age and sex. There was a statistically significant trend of ORs across quartiles of anti-Hsp70 and values greater than 108.0 µg/ml conferred a 77% increased OR of MetS as compared with values in the lower quartiles. The strength of the association slightly decreased after further adjustment for apolipoprotein B, smoking, and albumin excretion rate. In conclusion, our results show that serum anti-Hsp70 antibody levels are independently associated with nascent MetS.

Prognostic implications for insulin-sensitive and insulin-resistant normal-weight and obese individuals from a population-based cohort.

BACKGROUND: There are few prospective data on the prognosis of insulin-sensitive and insulin-resistant normal-weight (NW) or obese individuals. OBJECTIVES: The estimated liver fat content, incidences of hyperglycemia and cardiovascular disease, and all-cause and cardiovascular mortality rates were investigated in a population-based cohort of 1658 individuals who were categorized according to BMI and insulin resistance as defined by HOMA-IR values ≥2.5 and the presence of metabolic syndrome. DESIGN: This was a prospective cohort study with a 9-y follow-up. Anthropometric values, blood pressure, and blood metabolic variables were measured, and information on vital status was collected from demographic files at follow-up. RESULTS: A total of 137 of 677 NW individuals (20%) were classified as insulin resistant and normal weight (IR-NW), and 72 of 330 obese individuals (22%) were classified as insulin sensitive and obese (IS-obese). Incidences of diabetes, impaired fasting glucose, and cardiovascular events were 0.4%, 6.3%, and 3.3%, respectively, in insulin-sensitive and normal-weight (IS-NW) individuals (reference category); 5.8%, 10.2%, and 6.6%, respectively, in IR-NW individuals; and 5.6%, 8.3%, and 8.3%, respectively, in IS-obese individuals. In a multiple logistic regression model, risks of incident hyperglycemia and cardiovascular events increased in both groups compared with in the reference category [HR (95% CI): 2.54 (1.42, 4.55) and 1.98 (0.86, 4.54) in IR-NW subjects; 2.16 (1.01, 4.63) and 2.76 (1.05, 7.28) in IS-obese subjects]. The estimated liver fat content significantly increased during follow-up only in the IR-NW group in the same model. Cardiovascular mortality was 2-3-fold higher in IR-NW and IS-obese than in IS-NW individuals in a Cox regression model. CONCLUSIONS: Our data refute the existence of healthy obese phenotypes because IS-obese individuals showed increased cardiometabolic risk. The existence of unhealthy NW phenotypes is supported by their increased risk of incident hyperglycemia, fatty liver, cardiovascular events, and death.

Increased QT interval dispersion predicts 15-year cardiovascular mortality in type 2 diabetic subjects: the population-based Casale Monferrato Study.

OBJECTIVE: To evaluate the predictive role of increased corrected QT (QTc) and QT interval dispersion (QTd) on all-cause and cardiovascular mortality in a large, unselected type 2 diabetic population. RESEARCH DESIGN AND METHODS: The prospective study included 1,357 type 2 diabetic patients from the Casale Monferrato Study. At baseline, QTc intervals >0.44 s and QTd intervals >0.08 s were considered abnormally prolonged. Both all-cause and cardiovascular mortality were assessed 15 years after the baseline examination. RESULTS: During the follow-up period, 862 subjects per 12,450 person-years died. Multivariate analysis showed that the hazard ratio (HR) of cardiovascular mortality was significantly increased in subjects with prolonged QTd (1.26 [95% CI 1.02-1.55]) and was only slightly reduced after multiple adjustments. Conversely, prolonged QTc did not increase the HRs for all-cause or cardiovascular mortality. CONCLUSIONS: Increased QTd predicts cardiovascular mortality after a long-term follow-up period in a large, unselected population of type 2 diabetic subjects.