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Objectives: To evaluate shear stress (SS) and normal pressure (NP) at the tooth-restoration interface of highly-filled flowable resin composite applied to deep margin elevation technique through FEM analysis generated by a microCT scan., Methods: A reference maxillary molar with two class II cavities was prepared according to deep margin elevation protocol. A geometrical model was segmented from a micro-CT scan generating separate volumes of enamel, dentin and restorative materials. The 3D Finite Element (FE) model was subsequently built-up and an axial chewing load was simulated. Data concerning the tooth-restoration interface were analyzed in terms of SS and NP. Different materials and techniques were tested in order to evaluate the effects of the restorative material, the usage of a highly-filled flowable composite as liner and the substrate of the cervical area., Results: Both SS and NP presented similar distribution, but showed significant differences between tested materials. Composites showed more homogeneous behavior in stress distribution compared to ceramic. The use of a highly-filled flowable composite as liner on the cervical margin significantly reduced SS and NP on the cavity floor and the cervical margin area. Lastly, stress distribution in the cavity floor area varied according to the cervical margin substrate: enamel showed a protective role in stress distribution., Significance: Highly-filled flowable resin composites showed encouraging results when applied to deep margin elevation from an interfacial mechanical point of view. Further studies are needed to validate these data and to better define the role of cervical enamel in stress distribution., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects., Methods and Results: Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively. After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences., Conclusion: Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out., Clinical Trial Registration Number: NCT01182948, clinicaltrials.gov., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The relatives role of each component of the glucose-insulin system in determining hyperglycemia in type 2 diabetes is still under debate. Metabolic Control Analysis (MCA) quantifies the control exerted by each component of a system on a variable of interest, by computing the relevant coefficients of control (CCs), which are systemic properties. We applied MCA to the intravenous glucose tolerance test (IVGTT) to quantify the CCs of the main components of the glucose-insulin system on intravenous glucose tolerance., Methods and Results: We combined in vivo phenotyping (IVGTT/euglycaemic insulin clamp) and in silico modeling (GLUKINSLOOP.1) to compute the CCs of intravenous glucose tolerance in healthy insulin-sensitive (n = 9, NGR-IS), healthy insulin-resistant (n = 7, NGR-IR) and subdiabetic hyperglycemic (n = 8, PreT2DM) individuals and in patients with newly diagnosed type 2 diabetes (n = 7, T2DM). Altered insulin secretion and action were documented in NGR-IR and PreT2DM groups, but only 1st phase insulin secretion was significantly lower in T2DM than in PreT2DM (p < 0.05). The CCs changed little in the nondiabetic groups. However, several CCs were significantly altered in the patients (e.g. CCs of beta cell: -0.75 ± 0.10, -0.64 ± 0.15, -0.56 ± 0.09 and -0.19 ± 0.04 in NGR-IS, NGR-IR, PreT2DM and T2DM, respectively; p < 0.01 by MANOVA), and they could not be corrected by matching in silico nondiabetic and T2DM groups for 1st phase secretion., Conclusions: Type 2 diabetes is characterized not only by loss of function of the elements of the glucose-insulin system, but also by changes in systemic properties (CCs). As such, it could be considered a disease of the governance of the glucose-insulin system., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: There has been increasing research interest in parenting by anxious adults; however, little is known about anxiety-subtype effects, or effects of the context in which parenting is assessed., Methods: Two groups of anxious mothers, social phobia (N = 50), generalised anxiety disorder (N = 38), and nonanxious controls (N = 62) were assessed with their 4.9-year-old children in three tasks: two presented threat specifically relevant to each maternal disorder, namely, a social threat task where the child had to give a speech, and a nonsocial threat task where the child had to explore potentially scary objects; the third was a nonthreat task (playing with play dough). Seven parenting dimensions were scored. Effects on parenting of maternal anxiety subgroup and task, and their interactions, were examined, as were effects of earlier child behavioural inhibition and currently manifest anxiety., Results: There were no parenting differences between maternal groups in the nonthreat play-dough task; parenting difficulties in the two anxious groups were principally evident in the disorder-specific challenge. Parenting differences between nonanxious and anxious mothers occurred independently of child characteristics. There was little evidence for particular forms of parenting difficulty being unique to maternal disorder., Conclusions: Anxious mothers' parenting difficulties emerge when occurring under challenge, especially when this is disorder-specific. These effects should be considered in research and clinical practice., (© 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.)

Background: We assessed the risk of coronary heart disease (CHD) in subjects with metabolic syndrome using different reference categories and focusing on the number of traits in the cluster., Methods: For 15 years, we followed 840 subjects from the general population living in Bruneck, northeastern Italy, aged 40-79 years, without CHD at baseline. Metabolic syndrome was diagnosed at baseline using American Heart Association/National Heart, Lung, and Blood Institute criteria. Subjects with the syndrome were compared to subjects without, as well as to subjects without any metabolic abnormality, using Cox models adjusted for sex, age, smoking, and low-density lipoprotein-cholesterol. There were 89 incident CHD cases., Results: In subjects with the metabolic syndrome, the risk of CHD was1.5-fold higher when subjects without the syndrome were the reference category. CHD risk, however, was 12.5-fold higher (95% confidence interval [CI], 1.7-92.7, P=0.014) when subjects without any metabolic abnormality composed the reference category. As compared to subjects with no abnormalities (who had a trivial number of CHD events), the risk increased from subjects with one (hazard ratio 7.6, 95% CI 1.0-56.5, P=0.047) to those with 2, 3, and 4/5 abnormalities (11.6, 1.6-84.9, P=0.016; 12.9, 1.7-96.0, P=0.013; and 10.1, 1.3-79.2, P=0.028), respectively., Conclusions: When compared to the reference category of people without any metabolic abnormality, those with the metabolic syndrome had high cardiovascular risk. However, in the Bruneck population, the risk of CHD seems to be similar in subjects having two or three to five clinical features of metabolic syndrome. Therefore, the clinical utility of identifying subjects with the syndrome using current diagnostic criteria remains uncertain and might be the focus of further specific studies.

Background and Aims: To assess all-cause and cardiovascular mortality in type 2 diabetic individuals according to estimated glomerular filtration rate (eGFR) and albuminuria., Methods and Results: We followed 2823 type 2 diabetic outpatients for a median period of 6 years for the occurrence of all-cause and cardiovascular mortality. eGFR was estimated using the abbreviated Modification of Diet in Renal Disease study equation. At baseline, an eGFR < 60 ml/min/1.73 m² and abnormal albuminuria were present in 22.5% and 26.0% of participants, respectively. During follow-up, a total of 309 patients died, 53% of deaths were secondary to cardiovascular causes. Risks of all-cause and cardiovascular mortality increased progressively with decreasing eGFR and increasing albuminuria. After adjustment for age, sex, body mass index, smoking, hypertension, diabetes duration, hemoglobin A1c, plasma lipids, medications use (hypoglycemic, anti-hypertensive, anti-platelet or lipid-lowering drugs) and albuminuria, the hazard ratios of all-cause and cardiovascular mortality per 1-SD decrease in eGFR were 1.53 (95%CI 1.2-2.0; p < 0.0001) and 1.51 (95%CI 1.05-2.2; p=0.023), respectively. A similar pattern in the risk of all-cause and cardiovascular mortality was seen for albuminuria (1.14, 1.01-1.3, p=0.028 and 1.19, 1.01-1.4, p=0.043 per 1-SD increase in albuminuria, respectively) after adjustment for eGFR and other potential confounders., Conclusions: These findings suggest that both decreasing eGFR and rising albuminuria are associated with all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of traditional risk factors and diabetes-related variables., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Objective: In hyperandrogenic women, hyperinsulinaemia amplifies 17 α-hydroxycorticosteroid intermediate response to ACTH, without alterations in serum cortisol or androgen response to stimulation. The aim of the study is to assess whether acute hyperinsulinaemia determines absolute changes in either basal or ACTH-stimulated adrenal steroidogenesis in these subjects., Design and Methods: Twelve young hyperandrogenic women were submitted in two separate days to an 8 h hyperinsulinaemic (80  mU/m² × min) euglycaemic clamp, and to an 8 h saline infusion. In the second half of both the protocols, a 4 h ACTH infusion (62.5  μg/h) was carried out. Serum cortisol, progesterone, 17 α-hydroxyprogesterone (17-OHP), 17 α-hydroxypregnenolone (17-OHPREG), DHEA and androstenedione were measured at basal level and during the protocols. Absolute adrenal hormone secretion was quantified by measuring C19 and C21 steroid metabolites in urine collected after the first 4 h of insulin or saline infusion, and subsequently after 4 h of concurrent ACTH infusion., Results: During insulin infusion, ACTH-stimulated 17-OHPREG and 17-OHP were significantly higher than during saline infusion. No significant differences in cortisol and androgens response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinaemia than at basal insulin levels (both P < 0.005). Changes in steroid metabolites molar ratios suggested stimulation by insulin of 5 α-reductase activity., Conclusions: These in vivo data support the hypothesis that insulin acutely enhances ACTH effects on both the androgen and glucocorticoid pathways.

Context: Intronic variants of TCF7L2 are confirmed genetic risk factors for type 2 diabetes and are associated to alterations in beta cell function in nondiabetic individuals., Objective: The objective of the study was to test whether TCF7L2 variability may affect β-cell function also in patients with type 2 diabetes., Design: This was a cross-sectional association study., Setting: The study was conducted at a university hospital referral center for diabetes., Patients: Patients included 464 (315 males and 149 females) glutamic acid decarboxylase-negative patients [age: median 59 yr (interquartile range: 52-65); body mass index: 29.3 kg/m(2) (26.5-32.9); fasting plasma glucose: 7.0 mmol/liter (6.1-8.0)] with newly diagnosed type 2 diabetes., Intervention(s): Interventions included frequently sampled oral glucose tolerance test and euglycemic insulin clamp., Main Outcome Measure(s): β-Cell function (derivative control and proportional control); insulin sensitivity; genotypes of the following TCF7L2 single-nucleotide polymorphisms: rs7901695, rs7903146, rs11196205, and rs12255372., Results: Both rs7901695 and rs7903146 diabetes risk alleles were associated with reduced proportional control of β-cell function (P = 0.019 and P = 0.022, respectively). Two low-frequency haplotypes were associated with extreme (best and worst) phenotypes of β-cell function (P < 0.01). No associations between TCF7L2 genotypes and insulin sensitivity were detected., Conclusions: TCF7L2 diabetes risk variants, either as single-nucleotide polymorphisms or as haplotypes, detrimentally influence β-cell function and might play a role in determining the metabolic phenotype of patients with newly diagnosed type 2 diabetes.

Objective: To evaluate the impact of an exercise program organized into supervised walking groups in subjects with type 2 diabetes., Research Design and Methods: Fifty-nine diabetic subjects were randomized to a control group receiving standard lifestyle recommendations or an intervention group assigned to three supervised walking sessions per week and counseling. Changes in metabolic features, weight, 6-min walk test, prescription of antidiabetic medications, and overall physical activity were assessed., Results: Functional capacity and overall physical activity were higher in the intervention group, whereas metabolic changes were not different between groups after 4 months. However, in subjects who attended at least 50% of scheduled walking sessions, changes in A1C and fasting glucose were greater than in control subjects. Discontinuation or reduction of antidiabetic drugs occurred in 33% of these patients versus 5% of control subjects (P<0.05)., Conclusions: Supervised walking may be beneficial in diabetic subjects, but metabolic improvement requires adequate compliance.

Background and Aims: Once-daily (OD) basal insulin glargine (GLA) can be used as part of a multiple daily injection regimen in patients with type 1 diabetes mellitus. This randomized, multicenter study compared GLA+prandial regular human insulin (RHI) with GLA+prandial insulin lispro (LIS) in reducing the incidence of severe nocturnal hypoglycemia at endpoint. In addition, the effects on glycemic control of both treatments were investigated., Methods and Results: Patients (489) previously on neutral protamine Hagedorn (NPH) insulin or GLAR plus RHI/LIS were switched to, or continued on GLA (target fasting blood glucose [FBG]=5.0-6.7 mmol/L [90-120 mg/dL]) for 8 weeks (qualification phase) prior to randomization; patients continued with their previous bolus insulin. Patients (n=395) were then randomized to LIS (n=193) or RHI (n=202) and treated for 16 weeks. The proportion of patients experiencing severe nocturnal hypoglycemia at the end of the study was 1.55% (n=3) in the RHI group and 1.11% (n=2) in the LIS group (p=0.938 between groups); the mean difference was 0.44% (95% CI: -1.77, 2.21), suggesting non-inferiority of RHI versus LIS. At the end of the study, both treatments did not differ with respect to glycemic control, as measured by hemoglobin A(1c) and FBG., Conclusion: These results suggest that GLA+LIS and GLA+RHI treatments were associated with a similar and low rate of severe nocturnal hypoglycemia. Further studies with greater patient sizes are necessary to verify the findings from the current study., (Copyright 2009. Published by Elsevier B.V.)

Objective: There is limited and controversial information on whether anaemia is a risk factor for cardiovascular mortality in type 2 diabetes, and whether this risk is modified by the presence of chronic kidney disease (CKD). We assessed the predictive role of lower hemoglobin concentrations on all-cause and cardiovascular mortality in a cohort of type 2 diabetic individuals., Methods: The cohort included 1153 type 2 diabetic outpatients, who were followed for a mean period of 4.9 years. The independent association of anaemia (i.e., hemoglobin <120 g/l in women and <130 g/l in men) with all-cause and cardiovascular mortality was evaluated by Cox proportional hazards regression models and adjusted for several potential confounders, including kidney function measures., Results: During follow-up, 166 (14.4%) patients died, 42.2% (n=70) of them from cardiovascular causes. In univariate analysis, anaemia was associated with increased risk of all-cause (hazard ratio HR 2.62, 95% confidence intervals 1.90-3.60, p<0.001) and cardiovascular mortality (HR 2.70, 1.67-4.37, p<0.001). After adjustment for age, sex, body mass index, smoking, hypertension, dyslipidemia, diabetes duration, hemoglobin A1c, medication use (hypoglycemic, anti-hypertensive, lipid-lowering and anti-platelet drugs) and kidney function measures, the association of anaemia with all-cause (adjusted HR 2.11, 1.32-3.35, p=0.002) and cardiovascular mortality (adjusted HR 2.23, 1.12-4.39, p=0.020) remained statistically significant., Conclusions: Anaemia is associated with increased risk of all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of the presence of CKD and other potential confounders. The advantage to treat anaemia in type 2 diabetes for reducing the risk of adverse cardiovascular outcomes remains to be demonstrated., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Leprechaunism is a rare congenital syndrome caused by mutations of the insulin receptor gene, transmitted in an autosomal recessive pattern. Insulin growth factor-1 (IGF-1) treatment can be a therapeutic option in this syndrome by its insulin-like effects. Nevertheless, it is of note that IGF-1 has also an angiogenic activity., Methods: Fundus examination by ophthalmoscopy, fluorangiography, and laser treatment were performed., Results: A 17-year-old girl with leprechaunism, under treatment with high doses of insulin, presented a florid diabetic retinopathy. The large neovascularization of the disk regressed after treatment with argon laser panretinal photocoagulation. Five years after treatment, the patient maintained good vision., Conclusions: This clinical case is of interest for 2 reasons: 1) the large retinal neovascularization was likely due to the high insulin dosages; 2) this is the first case in which a sustained regression of retinal neovascularization has been observed after laser treatment in leprechaunism.

Objective: Increased serum C-reactive protein (CRP), an independent predictor of coronary heart disease, was reported in women with polycystic ovary syndrome (PCOS). It remains unclear whether this finding is due to the association between PCOS and either insulin resistance, obesity, or androgen excess, which are all common features of this condition. The aims of this study were to assess whether increased serum CRP is a specific feature of PCOS and to investigate the mechanisms underlying this association., Design and Methods: Serum high-sensitivity CRP (hs-CRP) was measured in 86 hyperandrogenic women (age 21.6+/-4.2 years, body mass index (BMI) 23.6+/-3.5 kg/m2), 50 with PCOS and 36 with idiopathic hyperandrogenism (HA). Thirty-five BMI-matched healthy women were also studied as controls. In these subjects, endocrine and metabolic profiles were assessed. In all hyperandrogenic subjects and 14 controls, insulin sensitivity was measured by the glucose clamp technique. Body fat was measured by bioelectrical impedance., Results: Hs-CRP concentrations were higher in PCOS women (3.43+/-2.01 mg/l) than in HA subjects and healthy women (2.43+/-1.04, P<0.005; and 2.75+/-0.86 mg/l, P<0.05 respectively versus PCOS). In multiple regression analyses, increased serum hs-CRP was independently predicted by higher body fat and lower insulin sensitivity. However, in lean women, serum-free testosterone was an additional, negative, predictive variable., Conclusions: PCOS is accompanied by a low-grade chronic inflammation. Body fat appears the main determining factor of this finding, which is only partly explained by insulin resistance. At least in lean women, androgen excess per se seems to play an additional, possibly protective, role in this association.

Background and Aims: Type 2 diabetes is one of the most important risk factor for the development of chronic kidney disease (CKD). Recently, it has been shown that lower high-density lipoprotein cholesterol (HDL-C) levels predicted the development of microalbuminuria in type 2 diabetic individuals. We have prospectively assessed the effects of plasma HDL-C levels on the incidence of CKD in a large cohort of type 2 diabetic patients., Methods and Results: We followed 1987 type 2 diabetic outpatients with normal or near-normal kidney function at baseline for 5 years for the occurrence of incident CKD defined as glomerular filtration rate < or = 60 mL/min/1.73 m(2) (as estimated by the abbreviated Modified Diet and Renal Disease Study equation). Cox proportional hazards models were used to examine the independent relationship between plasma HDL-C levels and incident CKD. During a median follow-up of 5 years, 11.8% (n=234) of participants developed incident CKD. In multivariate regression analysis, higher HDL-C levels were associated with a lower risk of incident CKD (multiple-adjusted hazard ratio 0.76; 95% coefficient intervals 0.61-0.96; p=0.025) independently of age, gender, body mass index, hypertension, smoking history, diabetes duration, hemoglobin A1c, plasma triglycerides, LDL-cholesterol, presence of diabetic retinopathy, baseline albuminuria, and current use of medications (anti-hypertensive, anti-platelet, lipid-lowering and hypoglycemic drugs)., Conclusions: Higher plasma levels of HDL-C are associated with a lower risk of incident CKD in a large cohort of type 2 diabetic adults independently of numerous confounding factors.

Objective: There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals., Research Design and Methods: The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders., Results: During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12-1.27], P < 0.001) and cardiovascular (1.25 [1.16-1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01-1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not., Conclusions: Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are both associated with insulin resistance.We assessed whether NAFLD is associated with impaired insulin sensitivity in PCOS women independently of age and total adiposity., Subjects and Methods: We enrolled 14 young PCOS women with NAFLD, 14 women with PCOS alone and 14 healthy controls, who were matched for age, body mass index, and total body fat (by bio-impedance analyzer). NAFLD was diagnosed by the surrogate measure of abnormal serum alanine aminotransferase (ALT) concentrations (defined as ALT>19 U/l) after excluding other secondary causes of liver disease (alcohol, virus, and medications). Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp., Results: Insulin sensitivity was markedly decreased (p<0.001) in PCOS women with abnormal ALT levels, whereas it was similar between PCOS women with normal ALT levels andmatched healthy controls (8.3+/-2.5 vs 12.1+/-1.7 vs 13.2+/-1.8 mg/min x kg of fat-free mass, respectively). PCOS women with abnormal ALT levels also had higher plasma triglycerides and lower HDLcholesterol concentrations than those with PCOS alone. There was a strong inverse association between serum ALT levels and insulin sensitivity in the whole group of PCOS women (r=-0.59, p=0.0013)., Conclusions: Abnormal serum ALT levels, as surrogate measure of NAFLD, are closely associated with impaired insulin sensitivity in young PCOS women in a manner that is independent from the contribution of age and total adiposity. Early recognition of NAFLD by radiological imaging tests in this group of young patients is warranted.

Aims: Fasting plasma glucose variability strongly predicts the incidence of cardiovascular events in type 2 diabetic patients. We prospectively assessed whether fasting plasma glucose variability predicts the development/progression of retinopathy in a large cohort of type 2 diabetic outpatients., Methods: In the period 1996-1999, 1019 type 2 diabetic participants (aged 69+/-11 years) in the Verona Diabetes Study underwent at least 3 fasting plasma glucose (FPG) determinations and an eye examination by retinography. Of these, 746 underwent a 2nd eye examination in the period 2000-2004, while 273 did not (102 patients had died before undergoing the 2nd eye examination). For each patient, the mean (M-FPG) and the coefficient of variation of FPG (CV-FPG) were computed., Results: By the 2nd eye examination, 124 patients had either developed new retinopathy (79 patients) or progressed to a more severe degree of retinopathy (45 patients). In a multivariable logistic regression analysis, the development/progression of retinopathy was independently predicted by average glycaemia over time, expressed as glycated haemoglobin (odds ratio [OR] 1.82, 95%CI 1.40-2.38 for 1 SD increase) or M-FPG (OR 1.88, 1.47-2.41), but not by CV-FPG. Among other independent variables, HDL-cholesterol was inversely associated with the development/progression of retinopathy., Conclusions: These results suggest that in elderly type 2 diabetic patients the magnitude of hyperglycaemia, but not fasting plasma glucose variability, strongly predicts the development/progression of diabetic retinopathy independently of other known risk factors.

Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

We evaluated possible interactions between BMI and serum gamma-glutamyltransferase (GGT) concentration and their effects on the prevalence of poor glycemic control and common comorbidities of diabetes. We assessed whether the association of BMI with poor glycemic control, hypertension, atherogenic dyslipidemia (i.e., high triglycerides and/or low high-density lipoprotein (HDL) cholesterol), hypercholesterolemia, and hyperuricemia differed according to serum GGT concentration in a cohort of 3,633 type 2 diabetic individuals. The associations of BMI with different outcome measures were significant, but the associations varied remarkably by GGT concentration. As GGT concentration increased, the association of BMI with atherogenic dyslipidemia and glycemic control strengthened (P = 0.01 and 0.004 for interactions, respectively); in contrast, the association of BMI with hypertension, hypercholesterolemia, and hyperuricemia did not change substantially across GGT quartiles. For example, within the lowest GGT quartile, BMI was not associated with atherogenic dyslipidemia or poor glycemic control, whereas in the highest GGT quartile, the prevalence rates ranged from 62.3 to 74.7% for dyslipidemia and from 75.3 to 83% for poor glycemic control. The results remained unchanged after adjustment for sex, age, alcohol consumption, diabetes duration, and diabetes treatment. In conclusion, our findings show that BMI was associated with atherogenic dyslipidemia and poor glycemic control only when serum GGT activity was in its high-normal range. These findings suggest that obesity itself may not be a sufficient risk factor for atherogenic dyslipidemia or poor glycemic control in people with type 2 diabetes.

Background: Ageing is characterized by a decreased functional reserve, a concept defined as homeostenosis. We assessed the impact of long-term exposure to the average value (mean) or to the variability (coefficient of variation) of fasting glycaemia, body mass index (BMI) and pulse pressure on total mortality in a cohort of type 2 diabetic patients., Methods: Fasting glycaemia, BMI and pulse pressure values were collected over a period of 3 years in 1 319 type 2 diabetic patients who were subsequently followed up for 10 years. For each patient, the means and the coefficients of variation of fasting glycaemia, BMI and pulse pressure were computed. The adverse impact of these risk factors on total mortality was assessed in patients aged < 65 years (n = 565) and in those aged > or = 65 years (n = 754), separately., Results: During the 10 years of follow-up, 438 patients died. In younger diabetic patients, the means of fasting glycaemia [hazard ratio (HR) of III tertile versus I tertile = 2.11, 95% confidence interval (CI): 1.22-3.64], BMI (HR = 1.88, 1.12-3.14) and pulse pressure (HR = 2.36, 1.34-4.16) were independently associated with total mortality, while in older patients they were not. In contrast, the coefficients of variation of glycaemia (HR = 1.56, 1.17-2.08), BMI (HR = 1.34, 1.03-1.75) and pulse pressure (HR = 1.34, 1.03-1.74) independently predicted total mortality only in older patients., Conclusions: Our findings suggest that the variability of fasting glycaemia, body weight and blood pressure (BP) is independently associated with an increased risk of all-cause mortality in older type 2 diabetic patients. Future studies are required to confirm the reproducibility of our findings., (Copyright 2008 John Wiley & Sons, Ltd.)

Aims: To assess the association between circulating levels of soluble CD40 ligand (sCD40L), an emerging cardiovascular risk factor, and gamma-glutamyltransferase (GGT) activity concentrations in Type 1 diabetic subjects., Methods: Plasma concentrations of sCD40L and GGT activity, a marker of liver dysfunction, were measured in 54 non-smoking, non-drinking, young Type 1 diabetic patients, who were free of diagnosed cardiovascular disease., Results: When participants were grouped according to tertiles of GGT, plasma sCD40L concentrations steadily increased across GGT tertiles (P = 0.007 for trend). Similarly, plasma sCD40L concentrations were positively correlated with plasma GGT levels in the whole group of participants (r = 0.532; P < 0.0001). In multivariate linear regression analysis, plasma GGT activity levels were positively associated with sCD40L (standardized beta coefficient = 0.342; P = 0.027) independently of age, gender, diabetes duration, glycated haemoglobin, total cholesterol and systolic blood pressure. Further adjustment for the presence of diabetic retinopathy and microalbuminuria did not appreciably attenuate this association., Conclusions: Our findings suggest that there is a strong, graded, relationship between plasma GGT activity and sCD40L concentrations in non-smoking, non-drinking, young Type 1 diabetic individuals. This association appears to be independent of numerous confounding factors. Further studies are required to confirm the reproducibility of these results.

Background and Objectives: Subclinical primary hypothyroidism is highly prevalent in the general population, especially in the elderly. However, the prevalence of subclinical primary hypothyroidism in persons with chronic kidney disease (CKD) not requiring chronic dialysis is not well defined., Design, Setting, Participants, and Measurements: Cross-sectional data from 3089 adult outpatients, who were consecutively referred by general practitioners for routine blood testing over the last two years, were analyzed. Glomerular filtration rate (GFR) was estimated by the abbreviated Modification of Diet in Renal Disease equation. Multivariable logistic regression was used to evaluate the independent association between prevalent subclinical primary hypothyroidism and estimated GFR., Results: Among 3089 adult participants, 293 (9.5%) had subclinical primary hypothyroidism and 277 (9%) had an estimated GFR <60 ml/min per 1.73 m(2). The prevalence of subclinical primary hypothyroidism increased from 7% at an estimated GFR >or=90 ml/min per 1.73 m(2) to 17.9% at an estimated GFR <60 ml/min per 1.73 m(2) (P < 0.0001 for trend). Compared with participants with an estimated GFR >or=60 ml/min per 1.73 m(2), those with estimated GFR <60 ml/min per 1.73 m(2) had an increased odds of subclinical primary hypothyroidism after adjusting for age, gender, fasting plasma glucose, total cholesterol, and triglyceride concentrations., Conclusions: These findings suggest that subclinical primary hypothyroidism is a relatively common condition ( approximately 18%) among persons with CKD not requiring chronic dialysis, and it is independently associated with progressively lower estimated GFR in a large cohort of unselected outpatient adults.

Background: Anaemia associated with chronic kidney disease (CKD) has substantial public health importance. However, the association of haemoglobin concentrations with inflammation in the setting of decreased kidney function is not well established., Methods: We analysed cross-sectional data from 7389 outpatient adults, who were referred by general practitioners for routine blood testing between June 2006 and June 2007. Glomerular filtration rate (eGFR) was estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Multivariable linear regression analysis was used to identify factors independently associated with haemoglobin concentrations across eGFR categories as the main outcome., Results: Of the 7389 participants included in the analytic cohort 2221 (30.1%) participants had eGFR >/=90 mL/min/m(2), 4310 (58.3%) 60-89 mL/min/m(2) and 858 (11.6%) <60 mL/min/m(2). There were significant, graded, increases in high sensitivity C-reactive protein (hs-CRP) and haemoglobin concentrations across eGFR categories independent of age, gender, plasma glucose and lipids (P < 0.0001 for trends). In the multivariable regression analysis, increased hs-CRP concentrations were independently associated with lower haemoglobin concentrations at different stages of eGFR (P < 0.0001 for all). Other independent predictors of lower haemoglobin were older age, female gender and lower eGFR., Conclusions: Our findings suggest that increased plasma hs-CRP concentrations are independently associated with anaemia in the setting of decreased kidney function in a large cohort of unselected adult outpatients.

It is unknown whether chronic kidney disease (CKD) is associated with nonalcoholic fatty liver disease among patients with type 2 diabetes. We followed 1760 outpatients with type 2 diabetes and normal or near-normal kidney function and without overt proteinuria for 6.5 yr for the occurrence of CKD (defined as overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m(2)). During follow-up, 547 participants developed incident CKD. Nonalcoholic fatty liver disease, diagnosed by liver ultrasound and exclusion of other common causes of chronic liver disease, was associated with a moderately increased risk for CKD (hazard ratio 1.69; 95% confidence interval 1.3 to 2.6; P < 0.001). Adjustments for gender, age, body mass index, waist circumference, BP, smoking, diabetes duration, glycosylated hemoglobin, lipids, baseline estimated GFR, microalbuminuria, and medications (hypoglycemic, lipid-lowering, antihypertensive, or antiplatelet drugs) did not appreciably attenuate this association (hazard ratio 1.49; 95% confidence interval 1.1 to 2.2; P < 0.01). In conclusion, our findings suggest that nonalcoholic fatty liver disease is associated with an increased incidence of CKD in individuals with type 2 diabetes, independent of numerous baseline confounding factors.

Dedicated European and US clinical guidelines for type 2 diabetes in the elderly have been released, but they do not specifically address the issue of advanced chronic kidney disease (CKD) in older patients with diabetes. General clinical guidelines have been published on the treatment of patients with diabetic nephropathy (DN), but these address the issue of how to prevent progression and treat advanced DN without distinguishing between different age groups. Elderly patients with diabetes and stages 3 to 4 CKD have particular needs that differ from those of younger patients with the same conditions. This is mainly due to their frailty and shorter life expectancy. Differently tailored therapeutic strategies are needed, which may have less stringent targets; and the use of common drugs should be critically evaluated. The management agenda (metabolic control, low-protein diet, controlling BP, preventing progression of advanced DN, preventing cardiovascular outcomes) for these patients is discussed in light of the limits and perspectives of current guidelines. Intensive, simultaneous management of all items on the agenda may not be feasible for a proportion of older patients, and clinicians may have to give priority to reducing some risk factors rather than others, choosing between different therapies.

We assessed the differential contribution of nonalcoholic steatohepatitis (NASH) and visceral adiposity to nontraditional cardiovascular risk biomarkers in adult men. We enrolled 45 consecutive, overweight, male patients with biopsy-proven NASH, 45 overweight male patients without ultrasound-diagnosed hepatic steatosis, and 45 healthy male volunteers. All participants were matched for age; NASH and overweight patients were also matched for BMI and visceral adiposity (as estimated by abdominal ultrasonography). Nontraditional cardiovascular risk biomarkers were measured in all participants. Plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) activity, and adiponectin were markedly different among the groups; the lowest values (the highest for adiponectin) were in nonobese healthy subjects, intermediate in overweight nonsteatotic patients, and the highest (the lowest for adiponectin) in those with biopsy-proven NASH. The marked differences in these cardiovascular risk biomarkers that were observed between overweight and NASH patients were only slightly weakened after adjustment for age, BMI, smoking, plasma triglycerides, and insulin resistance (IR) as assessed by homeostasis model assessment (HOMA). In multivariate regression analysis, NASH and visceral adiposity predicted cardiovascular risk biomarkers independently of potential confounders. In conclusion, our results suggest that NASH can predict a more atherogenic risk profile in a manner that is partly independent from the contribution of visceral adiposity in adult men.

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease in type 2 diabetes. Currently, there is a lack of information on associations between NAFLD and microvascular complications of diabetes. We assessed the associations between NAFLD and both chronic kidney disease (CKD) and retinopathy in a large cohort of type 2 diabetic individuals using a cross-sectional design., Methods: Prevalence rates of retinopathy (by ophthalmoscopy) and CKD (defined as overt proteinuria and/or estimated GFR

Background: The effect of insulin on glucose, protein metabolism, circulating fatty acids (FFA), potassium (K(+)) and C-peptide concentrations were investigated in a 12-year-old girl with leprechaunism. The mutations do not affect the insulin-receptor binding affinity and insulin-stimulated auto-phosphorylation of the receptor., Methods: The subject was studied with a primed-continuous infusion of [6,6 - (2)H(2)] glucose and [1-(13)C] leucine during a basal period followed by two steps of insulin infusion (1 and 10 mU/kg/min) of 2 h each, during which plasma glucose level decreased from 131 to 115 and then to 95 mg/dL., Results: Whole body glucose disposal was virtually unaffected by insulin, slightly decreasing from 21 micromol/kg/min in the basal period to 20 and to 19 micromol/kg/min during the two steps of insulin infusion, respectively. The endogenous leucine flux, an index of proteolysis, was completely insensitive to insulin, being 182, 189 and 180 micromol/kg/min, in the three periods, respectively. The FFA concentration (an indirect index of lipolysis) decreased from 1135 to 799 during step 1. During step 2 the FFA concentration rebounded to 917 micromol/L. The concentration of K(+) decreased from 4.2 to 3.2 mmol/L and an infusion of 20 mEq/h of KCl was necessary to prevent further hypokalemia (final value 3.3 mmol/l). The C-peptide concentration declined from 1.85 to 0.97 and then to 0.29 pmol/mL., Conclusions: The dissociation of control exerted by insulin on K+ uptake and on beta-cell secretion may rely on a differential expression and folding of the mutated receptors in the different insulin target tissues., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Objective: Although overt thyroid dysfunction is associated with some liver abnormalities, there is a dearth of information on liver function tests across thyroid function tests. We assessed the relationship between serum liver enzyme activity and thyroid function tests in a cohort of adult individuals., Design, Patients and Measurements: We performed a retrospective analysis on the database of the Clinical Chemistry Laboratory at the Verona University Hospital to retrieve results of serum liver enzyme activities [alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT)] and thyroid function tests (TSH and free T4), which have been performed on the whole cohort of outpatient adults consecutively referred by general practitioners for routine blood testing during the last 3 years., Results: Cumulative results for serum GGT, ALT and TSH concentrations were retrieved for 10 292 (68.3% females) outpatient adults with a wide range of age and thyroid function tests. Subjects were categorized according to serum TSH concentrations as follows: < 0.1, 0.1-0.35, 0.36-4.5, 4.6-10 and >10 mU/l. Serum GGT and ALT concentrations increased steadily across the increasing TSH categories (P < 0.0001 for trends), ranging from mean values of 36 to 62 U/l for GGT and from 29 to 41 U/l for ALT, respectively. Similarly, there was a negative, graded, relationship between serum GGT and ALT concentrations and free T4 categories. The results did not change after adjusting for gender, age, lipids and fasting glucose concentrations., Conclusions: Our findings suggest that hypothyroidism and thyroid function tests, even within the reference range, are associated with slightly increased serum GGT and ALT activity concentrations.

Aims: We investigated the association of diabetic retinopathy with the risk of incident cardiovascular disease (CVD) events in a large cohort of Type 2 diabetic adults., Methods: Our study cohort comprised 2103 Type 2 diabetic outpatients who were free of diagnosed CVD at baseline. Retinal findings were classified based on fundoscopy (by a single ophthalmologist) to categories of no retinopathy, non-proliferative retinopathy and proliferative/laser-treated retinopathy. Outcomes measures were incident CVD events (i.e. non-fatal myocardial infarction, non-fatal ischaemic stroke, coronary revascularization procedures or cardiovascular death)., Results: During approximately 7 years of follow-up, 406 participants subsequently developed incident CVD events, whereas 1697 participants remained free of diagnosed CVD. After adjustment for age, body mass index, waist circumference, smoking, lipids, glycated haemoglobin, diabetes duration and medications use, patients with non-proliferative or proliferative/laser-treated retinopathy had a greater risk (P < 0.001 for all) of incident CVD events than those without retinopathy [hazard ratio 1.61 (95% confidence interval 1.2-2.6) and 3.75 (2.0-7.4) for men, and 1.67 (1.3-2.8) and 3.81 (2.2-7.3) for women, respectively]. After additional adjustment for hypertension and advanced nephropathy (defined as overt proteinuria and/or estimated glomerular filtration rate < or = 60 ml/min/1.73 m(2)), the risk of incident CVD remained markedly increased in those with proliferative/laser-treated retinopathy [hazard ratio 2.08 (1.02-3.7) for men and 2.41 (1.05-3.9) for women], but not in those with non-proliferative retinopathy., Conclusions: Diabetic retinopathy (especially in its more advanced stages) is associated with an increased CVD incidence independent of other known cardiovascular risk factors.

Aims: The purpose of the study was to determine long-term cardiovascular autonomic adaptation to moderate endurance aerobic exercise in people with Type 2 diabetes in order to test the hypothesis of an enhanced vagal drive., Methods: We analysed the power spectral density of heart rate cyclic variations at rest, while lying, and while standing in 12 sedentary, non-smoking, Type 2 diabetic individuals. Testing was performed before and after a 6-month, supervised, progressive, aerobic training programme, twice weekly. Heart rate variability was assessed by autoregressive power spectral analysis (PSA); this method allows reliable quantification of low-frequency (LF) and high-frequency (HF) components, which are considered to be under mainly sympathetic and purely parasympathetic control, respectively., Results: In 10-min electrocardiogram recordings, mean RR intervals values lying and standing were similar before and after physical exercise. Likewise, total heart rate variability, expressed as total power spectral density (PSD), was not altered by exercise. In contrast, on standing, the HF component, expressed in normalized units, was significantly higher (20.1 +/- 4 vs. 30.4 +/- 5, P < 0.01), whereas the LF component was significantly lower (68.1 +/- 7 vs. 49.8 +/- 8, P < 0.01) after exercise; hence, on standing, the LF/HF ratio, reflecting the sympathetic vs. parasympathetic balance, was markedly lower (16.2 +/- 11 vs. 5.2 +/- 3.2, P = 0.003). No significant exercise-related changes in these PSA components were observed on lying., Conclusions: A twice-weekly, 6-month, moderate, aerobic exercise programme, without a concomitant weight loss diet, is associated with significant improvements in cardiovascular autonomic function in overweight, non-smoking, Type 2 diabetic individuals.

Objective: The purpose of this study was to evaluate whether insulin resistance is associated to cardiovascular disease (CVD) and to understand whether this association can be explained by traditional and novel CVD risk factors associated with this metabolic disorder., Research Design and Methods: We examined a sample representative of the population of Bruneck, Italy (n = 919; aged 40-79 years). Insulin-resistant subjects were those with a score in the top quartile of the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR). Risk factors correlated with insulin resistance included BMI, A1C, HDL cholesterol, triglycerides, blood pressure, high-sensitivity C-reactive protein (hsCRP), fibrinogen, oxidized LDL, vascular cell adhesion molecule-1 (VCAM-1), and adiponectin. Subjects without CVD at baseline were followed up for 15 years for incident CVD, a composite end point including fatal and nonfatal myocardial infarction and stroke, transient ischemic attack, and any revascularization procedure., Results: During follow-up, 118 subjects experienced a first symptomatic CVD event. Levels of HOMA-IR were higher at baseline among subjects who developed CVD (2.8) compared with those remaining free of CVD (2.5) (P < 0.05). Levels of HOMA-IR also were significantly correlated (P < 0.05) with most CVD risk factors we evaluated. In Cox proportional hazard models, insulin-resistant subjects had an age-, sex-, and smoking-adjusted 2.1-fold increased risk (95% CI 1.3-3.1) of incident symptomatic CVD relative to non-insulin-resistant subjects. After sequential adjustment for physical activity and classic risk factors (A1C, LDL cholesterol, and hypertension) as well as BMI, HDL cholesterol, triglycerides, and novel risk factors, including fibrinogen, oxidized LDL, hsCRP, VCAM-1, and adiponectin, the association between HOMA-IR and incident CVD remained significant and virtually unchanged (hazard ratio 2.2 [95% CI 1.4-3.6], P < 0.001)., Conclusions: HOMA-estimated insulin resistance is associated with subsequent symptomatic CVD in the general population independently of all classic and several nontraditional risk factors. These data suggest that insulin resistance may be an important target to reduce CVD risk.

Background/objective: Previous studies conducted both in the general and diabetic population have shown that pulse pressure (PP) can predict mortality from cardiovascular diseases. The aim of the present study was to investigate the relationship between PP and specific cardiovascular mortality, i.e. from cerebrovascular and ischemic heart diseases, in a well-characterized cohort of type 2 diabetic patients., Methods: A cohort of 1,128 known type 2 diabetic patients 56 to 74 years of age with at least 2 blood pressure measurements for each year between 1984-1986 was followed-up for ten years to assess specific causes of death. The analyses were carried out by using the mean and the coefficient of variation (CV) of PP., Results: By the end of the 10-year follow-up period, 375 patients (178 male, 197 female) had died (33%). The mean PP resulted as an independent predictor of all causes and cardiovascular mortality. Remarkably, the mean PP, but not the CV of PP, was highly predictive of mortality from cerebrovascular diseases. The risk of cerebrovascular mortality rose by 86% with a 10 mm Hg increase in mean PP. PP turned out to be the most important predictor of cerebrovascular mortality among various pressure indexes (mean, systolic and diastolic pressure)., Conclusion: The mean pulse pressure, but not the coefficient of variation is a strong predictor of cardiovascular mortality, mainly from cerebrovascular diseases, in type 2 diabetic patients., (Copyright 2007 S. Karger AG, Basel.)

Background and Aims: Some plasma biomarkers of inflammation and endothelial dysfunction have been recently recognized as important cardiovascular risk factors. Currently, there is little information about the effects of aerobic exercise training on these biomarkers in older adults with type 2 diabetes. We have therefore assessed the effects of a twice-weekly moderate, aerobic exercise programme, without a concomitant weight loss diet, on plasma inflammatory and endothelial dysfunction biomarkers in older type 2 diabetic patients., Methods and Results: A group of 16 sedentary, overweight, non-smoking, older patients with type 2 diabetes volunteered to participate in a 6-month, supervised, progressive, aerobic training study, two times per week. Plasma levels of hs-C-reactive protein (hs-CRP), soluble tumour necrosis factor (TNF)-alpha receptors, P-selectin and intercellular adhesion molecule-1 (ICAM-1) were measured before and after physical training. While hs-CRP and soluble TNF-alpha receptors remained essentially unaffected by physical training, plasma concentrations of P-selectin (P<0.001) and ICAM-1 (P<0.01) markedly decreased; physical training also increased HDL cholesterol by 12% (P<0.05) and decreased uric acid levels by approximately 33% (P=0.021). Body weight, waist circumference, blood pressure, haemoglobin A1c, plasma triglyceride and LDL cholesterol concentrations did not change. Interestingly, the exercise-induced changes in ICAM-1 and P-selectin levels remained significant after adjustment for the percent variations of body weight, waist circumference, haemoglobin A1c, HDL cholesterol and uric acid concentrations., Conclusions: A twice-weekly, 6-month, progressive aerobic-training programme, without a concomitant weight loss diet, is associated with significant decreases in circulating P-selectin and ICAM-1 levels and with a less atherogenic lipid profile in overweight, non-smoking, older type 2 diabetic individuals.

Background and Aim: The aim of this trial was to evaluate the effect of doxazosin as add-on therapy in patients with hypertension not adequately controlled on current antihypertensive therapy, and impaired glucose metabolism. The effect of doxazosin administered as add-on therapy was to be considered significant both from clinical and statistical viewpoints if the proportion of patients with adequate control of blood pressure (BP<130/85 mmHg) would be at least 30% after 16 weeks of combined therapy., Method and Results: It was an open, multicenter phase IV study, lasting 19 weeks: 3-week qualifying/placebo run-in period+16-week dose titration/add on therapy period, involving 264 out-patients (158 m and 106 f; mean age+/-SD: 60.9+/-8.6 years; mean BMI+/-SD: basal 29.5+/-5.1, final 30.2+/-4.6) with blood pressure still >130/85 mmHg in spite of the antihypertensive treatment (ACE inhibitors 44%, AT II antagonists 21%, Ca antagonists 12%, other drugs 8%, polytherapy 15%) and affected by type 2 diabetes (n=219), impaired fasting glucose (IFG; n=16) or impaired glucose tolerance (IGT; n=29). Following a run-in, 3-week qualifying phase during which placebo was added to ongoing antihypertensive treatment, 16-week treatment with doxazosin was added at dosages from 1 up to 8 mg/day. Main outcome measures were: the percentage of patients with blood pressure <130/85 mmHg at the end of treatment; the effects of the combination therapy on glyco-lipidic metabolism: fasting plasma glucose, fasting insulin, glycated hemoglobin, insulin resistance (HOMA-R), plasma lipids; and the effect on the 10-year CHD risk (Framingham equation)., Results: 35% of patients were responsive (BP<130/85 mmHg) to add-on treatment with doxazosin (CI 90%: 30.3%-40.4%; P<0.05, stat. an. intention to treat). During the run-in phase with placebo, mean SBP/DBP (+/-SD) decreased from 155.6+/-13.2/91.8+/-6.8 mmHg (Week -3) to 151.9+/-12.9/90.1+/-7.2 mmHg (Week -1) and to 151.2+/-11.5/90.1+/-6.9 mmHg (Week 0). During add-on treatment with doxazosin, mean SBP/DBP (+/-SD) further decreased to 144.9+/-15.2/86.3+/-8.3 mmHg (Week 4), 139.7+/-15.3/83.4+/-7.9 mmHg (Week 8), 135.5+/-14.3/81.7+/-7.6 mmHg (Week 12) and 136.4+/-14.5/81.0+/-7.0 mmHg (Week 16). Overall, mean BP changes reached a plateau of about -15 mmHg (SBP) and -9 mmHg (DBP) after 16 weeks of treatment; at each visit the mean decreases from baseline were statistically significant. The following mean values of metabolic parameters were reduced during the study: fasting plasma glucose (-4.1mg/dl; -2.8%), fasting insulin (-2 microU/ml; -12.3%; P<0.05), glycated hemoglobin (-0.12%; -1.7%), HOMA-R (-1.03; -18.2%; P<0.05), total cholesterol (-1.85 mg/dl; -1.1%), LDL cholesterol (-1.35 mg/dl; -0.8%) and triglycerides (-5.64 mg/dl; -2.4%); mean HDL cholesterol increased (+1.79 mg/dl; +3.9%; P<0.01). At the end of study treatment, the percentage of patients with lab values returned within normal ranges, in comparison with basal values, was statistically significant (P<0.05) for the following parameters: fasting plasma glucose (6.3%), fasting insulin (7.5%), LDL cholesterol (6.0%). Ten-year CHD risk (+/-SD) decreased from 16.4+/-7.8% to 13.6+/-7.4% (final vs. basal: -2.87+/-3.9; -17%; P<0.01). Six patients (2.3%) reported 8 adverse drug reactions: dizziness (3), edema (2), headache (2), asthenia (1). In one out of these 6 patients, in whom doxazosin was associated to the ACE inhibitor quinapril, adverse reaction (peripheral edema) led to treatment withdrawal., Conclusion: In patients not responsive to antihypertensive treatment and concomitantly affected by impaired glucose metabolism, achievement of target BP was obtained in more than one third of cases after 16-week add-on treatment with doxazosin. Changes in glyco-lipidic parameters and reduction of 10-year CHD risk observed during the study, although of moderate extent, confirm the overall favourable effect of antihypertensive combinations including doxazosin.

Objective: Hyperinsulinemia is often associated with several metabolic abnormalities and increased blood pressure, which are risk factors for cardiovascular disease. It has been hypothesized that insulin resistance may underlie all these features. However, recent data suggest that some links between insulin resistance and these alterations may be indirect. The aim of our study was to further investigate this issue in a sample of young hyperandrogenic women, who often show insulin resistance and other metabolic abnormalities typical of the insulin resistance syndrome., Research Design and Methods: We tested the hypothesis of a single factor underlying these features by principal component analysis, which should recognize one component if a single mechanism explains this association. The analysis was carried out in a sample of 255 young nondiabetic hyperandrogenic women. Variables selected for this analysis included the basic features of the insulin resistance syndrome and some endocrine parameters related to hyperandrogenism., Results: Principal component analysis identified four separate factors, explaining 64.5% of the total variance in the data: the first included fasting and postchallenge insulin levels, BMI, triglycerides, HDL cholesterol, and uric acid; the second, BMI, blood pressure, and serum free testosterone; the third, fasting plasma glucose, postchallenge glucose and insulin levels, serum triglycerides, and free testosterone; and the fourth, postchallenge plasma insulin, serum free testosterone, and gonadotropin-releasing hormone agonist-stimulated 17-hydroxyprogesterone., Conclusions: These results support the hypothesis of multiple determinants in the clustering of abnormalities in the so-called insulin resistance syndrome.

Non-alcoholic liver steatosis is associated with metabolic syndrome and type 2 diabetes. The prevalence of this condition in type 2 diabetes is estimated to be between 28 and 55%. Non-alcoholic liver steatosis is not a benign disease because of its potential progression to liver fibrosis, cirrhosis and cancer. The Verona diabetes study, a population-based observational study, on 7148 type 2 diabetic patients after 5 years of follow-up has reported an increased risk of death from gastrointestinal diseases, particularly from chronic liver cirrhosis. Moreover, in the same population after 10 years of follow-up a higher risk of mortality from liver cancer was observed and this risk increased significantly in obese patients (body mass index >30 kg/m2). Of note is that obese diabetic patients suffer an even higher prevalence of non-alcoholic liver steatosis. In conclusion, the Verona diabetes study showed an increased risk of mortality from liver cirrhosis and liver cancer in type 2 diabetic patients. Diverse pathophysiological mechanisms can be responsible, i.e. higher alcohol consumption, hepatitis and others but, considering the high prevalence of non-alcoholic liver steatosis in these patients, it is plausible to hypothesize that non-alcoholic liver steatosis may play a significant role in predisposing the liver of diabetics to chronic diseases.

Objectives: To examine the association between nonalcoholic hepatic steatosis (HS) and the activity of the hypothalamo-pituitary-adrenal (HPA) axis, as evaluated by a low-dose dexamethasone suppression test, in obese subjects., Design and Patients: In a cross-sectional study, we examined 54 obese, otherwise healthy, individuals with a negligible or zero daily alcohol consumption., Measurements: HS (by ultrasonography), glucose tolerance status (by oral glucose load), insulin resistance [by homeostasis model assessment (HOMA)] and 1.0 mg postdexamethasone (postdex) suppression cortisol levels were measured., Results: Subjects with nonalcoholic HS (n = 39) had markedly less suppressed circulating cortisol levels than those without HS (n = 15) (21.9 +/- 2.6 vs. 11.0 +/- 1.4 nmol/l, P < 0.001). In addition, subjects with nonalcoholic HS had significantly higher values of HOMA-insulin resistance score and circulating liver enzymes than their counterparts without HS. Age, body mass index (BMI), waist/hip ratio, plasma glucose concentration (both at fasting and after glucose load), lipids and blood pressure values did not differ significantly between the groups. Females were more represented among those without HS. The marked differences in postdex suppression cortisol levels that were observed between the groups were little affected by adjustment for sex, age, BMI, waist/hip ratio, HOMA-insulin resistance score, plasma lipids and liver enzyme levels. Similarly, in a logistic regression analysis, cortisol levels significantly predicted the presence of nonalcoholic HS (P = 0.032), independently of potential confounders., Conclusions: These results suggest that nonalcoholic hepatic steatosis is closely correlated with a subtle, chronic activation of the HPA axis in obese, otherwise healthy, individuals.

Aim: To validate the Italian version of the World Health Organization (WHO)-Well-Being Questionnaire (WBQ) and the WHO-Diabetes Treatment Satisfaction Questionnaire (DTSQ) in Type 1 and Type 2 diabetic patients., Methods: The cultural adaptation of the questionnaires was performed by using standard forward/backward techniques. Internal consistency reliability was estimated by Cronbach's alpha coefficient. Construct validity was evaluated using the Short Form-36 (SF-36) Health Status Questionnaire. Finally, the discriminative properties of the questionnaires were evaluated relative to the patients' characteristics. The questionnaires were administered to a random sample of patients identified in twelve outpatient diabetes clinics., Results: Overall, 412 subjects were recruited, of whom 96 (23%) with Type 1 diabetes. Item-scale correlations were >0.40 for all the items. Cronbach's alpha coefficient was 0.86 for the WHO-DTSQ and ranged between 0.79 and 0.91 for the WHO-WBQ. High correlations were found between WHO-WBQ scales and the mental dimensions of the Short Form-36 (SF-36) questionnaire, but not between WHO-DTSQ and SF-36 scores. Women, obese subjects, those with longer diabetes duration and multiple complications showed a worse quality of life in all of the four areas of the WHO-WBQ. In Type 2 diabetic subjects, SF-36 scores, but not WHO-WBQ scores, were able to discriminate the population according to the treatment modalities. Lower levels of treatment satisfaction were related to female gender, longer diabetes duration, insulin treatment, presence of diabetes complications and HbA1c levels >7.0%. The flexibility of the treatement was perceived as a major problem even among patients treated with oral agents., Conclusions: The WHO-DTSQ can be considered as a valuable instrument to be used internationally for the description of diabetes treatment satisfaction. The WHO-WBQ also shows adequate psychometric properties, but additional data are needed to clarify whether it is more sensitive than SF-36, the most widely used generic instrument.

Background and Aim: Hepatic steatosis has recently been associated with insulin resistance and other metabolic abnormalities as a possible feature of the metabolic syndrome, but it is still uncertain how hepatic steatosis and insulin sensitivity are connected. Furthermore, obesity is a well characterized insulin resistant condition that is often associated with hepatic steatosis. The aim of this study was to verify whether hepatic steatosis further worsens insulin sensitivity in obese subjects by comparing the degree of insulin sensitivity in obese subjects with normal glucose tolerance on the basis of the presence or absence of hepatic steatosis., Methods and Results: We analyzed 86 obese patients whose alcohol intake was less than 20 g/day and who showed no signs of viral hepatopathy. All of the subjects had normal glucose tolerance as shown by an oral glucose tolerance test. Insulin resistance was estimated using the homeostasis model assessment (HOMA) method and the diagnosis of steatosis was determined by an ultrasound scan of the liver. The subjects were comparable in terms of body mass index (BMI), lipid profile and serum uric acid levels; those with hepatic steatosis were slightly older and tended to have higher systolic blood pressure and fasting glycemia levels. The HOMA values were significantly higher in the group with hepatic steatosis (4.48 +/- 2.22 vs 3.11 +/- 1.47, p=0.002). There was no linear correlation between HOMA and alanine aminotransferase (ALT) levels, but a close linear correlation between HOMA and BMI (r=0.40; p<0.001). The effect of hepatic steatosis on HOMA remained significant after adjusting for age and gender (covariance analysis, p=0.006). When BMI was added to the covariance analysis, hepatic steatosis retained its statistical significance., Conclusion: Our data suggest that hepatic steatosis can increase insulin resistance independently of obesity.

Incidence rates and risk factors for type 2 diabetes in low-risk populations are not well documented. We investigated these in white individuals who were aged 40-79 years and from the population of Bruneck, Italy. Of an age- and sex-stratified random sample of 1,000 individuals who were identified in 1990, 919 underwent an oral glucose tolerance test (OGTT) and an assessment of physiological risk factors for diabetes, including insulin resistance (homeostasis model assessment, HOMA-IR), and postchallenge insulin response (Sluiter's Index). Diabetes at baseline by fasting or 2-h OGTT plasma glucose (World Health Organization criteria, n = 82) was excluded, leaving 837 individuals who were followed for 10 years. Incident cases of diabetes were ascertained by confirmed diabetes treatment or a fasting glucose >or=7.0 mmol/l. At follow-up, 64 individuals had developed diabetes, corresponding to a population-standardized incidence rate of 7.6 per 1,000 person-years. Sex- and age-adjusted incidence rates were elevated 11-fold in individuals with impaired fasting glucose at baseline, 4-fold in those with impaired glucose tolerance, 3-fold in overweight individuals, 10-fold in obese individuals, and approximately 2-fold in individuals with dyslipidemia or hypertension. Incidence rates increased with increasing HOMA-IR and decreasing Sluiter's Index. As compared with normal insulin sensitivity and normal insulin response, individuals with low insulin sensitivity and low insulin response had a sevenfold higher risk of diabetes. Baseline impaired fasting glucose, BMI, HOMA-IR, and Sluiter's Index were the only independent predictors of incident diabetes in multivariate analyses. We conclude that approximately 1% of European white individuals aged 40-79 years develop type 2 diabetes annually and that "subdiabetic" hyperglycemia, obesity, insulin resistance, and impaired insulin response to glucose are independent predictors of diabetes.

Aims: To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects., Methods: Subjects with the Metabolic Syndrome, defined by WHO criteria, were identified in a large sample of non-insulin-treated Type 2 diabetic patients examined within the Verona Diabetes Complications Study (n = 946). At baseline and after a mean of 4.5 years follow-up, cardiovascular disease (CVD) was assessed by medical history, physical examination, electrocardiogram (ECG) and echo-duplex of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were scrutinized in order to identify CVD deaths. In statistical analyses, CVD was considered as an aggregate end-point, including fatal and non-fatal coronary, cerebrovascular and peripheral vascular disease as well as ischaemic ECG abnormalities and vascular lesions at the echo-duplex., Results: The proportion of subjects with the Metabolic Syndrome was very high (92.3%). At the baseline, 31.7% of subjects were coded positive for CVD, which was more prevalent in subjects with the Metabolic Syndrome (32.9 vs. 17.8%, P = 0.005). Among subjects free of CVD at the baseline (n = 559), CVD events during the follow-up were significantly increased in patients with the Metabolic Syndrome as compared with those without it (19.9% vs. 3.9%, P < 0.001). Multiple logistic regression analysis showed that, along with sex, age, smoking and HbA1c, the presence of the Metabolic Syndrome independently predicted prevalent (OR 2.01, P = 0.045) and incident CVD (OR 4.89, P = 0.031)., Conclusions: In Type 2 diabetes, the presence of the Metabolic Syndrome is associated with an almost 5-fold increase in CVD risk.

Objectives: The present study aimed at evaluating the prevalence of the Metabolic Syndrome and at identifying its additional clinical features., Research Design and Methods: Within a prospective population-based survey examining 888 subjects aged 40-79 y, subjects were identified fulfilling the WHO and the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria for diagnosing the Metabolic Syndrome. In these subjects and in the rest of the sample (controls), several metabolic and nonmetabolic biochemical parameters were compared., Results: The prevalence of the Metabolic Syndrome by WHO criteria was 34.1% (95% CI 31.0-37.2) and by NCEP-ATPIII criteria 17.8% (15.5-20.3). The prevalence was significantly higher in older subjects and in those less physically active. Subjects with the Metabolic Syndrome either by WHO or by NCEP-ATPIII criteria showed higher levels of oxidized low-density lipoprotein, apolipoprotein B, urate, leptin, fibrinogen, leukocytes, erythrocyte sedimentation rate, GOT, gamma-GT and soluble endothelial adhesion molecules (E-selectin, vascular adhesion molecule-1 and intercellular adhesion molecule-1) and lower apolipoprotein A concentrations. Insulin resistance, as assessed by the Homeostasis Model Assessment, increased with the increase in the number of traits composing the syndrome found within the single individual. Subjects with insulin resistance had more pronounced abnormalities in several parameters, including the additional features of the syndrome (eg fibrinogen and soluble adhesion molecules)., Conclusions: The Metabolic Syndrome occurs very frequently in the general population aged 40-79 y, and is associated with several additional metabolic and nonmetabolic abnormalities that likely contribute to an increased cardiovascular risk. Insulin resistance seems to play a major role in classic and additional abnormalities featuring the Metabolic Syndrome.

To compare efficacy and tolerability of combination treatment with metformin and sulfonylurea with each of these drugs alone in the treatment of type 2 diabetes, 88 type 2 diabetic subjects (hemoglobin A1c [HbA1c] levels, 8.0%+/-1.0%; age, 57.3+/-7.1 years; body mass index [BMI]. 27.0+/-2.6 kg/m2; diabetes duration, 9.8+/-8.2 years; means +/- SD) were randomly assigned to double-blind treatment with metformin (500 to 3,000 mg/d), glibenclamide (5 to 15 mg/d), or their combination (metformin 400 to 2,400 mg/d + glibenclamide 2.5 to 15 mg/d) for 6 months. Thereafter, groups were crossed over for the following 6 months. Thus, each patient received metformin or glibenclamide alone, and the combination treatment. Doses were titrated to obtain HbA1c levels < or = 6.0% and fasting plasma glucose levels less than 140 mg/dL. Eighty patients concluded both treatment periods and were included in the analysis of treatment efficacy. In patients receiving metformin or glibenclamide alone, the maximal dose was reached in 21 and 25 patients, respectively; 8 and 15 of these subjects, respectively, required the maximal dose when they were on the combination treatment. During the study, 4 (10.0%) subjects receiving metformin, 7 (17.1%) receiving glibenclamide, and 31 (39.2%) receiving the combination treatment reached HbA1c levels < or = 6.0%. Moreover, when efficacy of the combination treatment on glycemic control was compared with that of single-drug therapies in each individual patient, the combination was significantly more effective than either metformin or glibenclamide (HbA1c after treatment, 6.1%+/-1.1% v 7.3%+/-1.4%, and 6.5%+/-0.7% v 7.6%+/-1.5%, respectively, both P<.0001). In conclusion, combination treatment with metformin and sulfonylurea is more effective than these drugs alone in improving glycemic control in type 2 diabetes, while also allowing a reduction of the dosage of each drug.

Objective: The aim of the present work was to compare mortality from site-specific malignancies in type 2 diabetic patients with those in the general population., Research Design and Methods: Mortality from site-specific cancers was assessed in a population-based cohort of 7,148 type 2 diabetic patients from Verona (Northern Italy) during a 10-year follow-up (1987-1996) by reviewing death certificates. Standardized mortality ratio (SMR) data were computed using as reference mortality rates in the general population of Verona., Results: During follow-up, 641 patients (378 men and 263 women) died of malignancies. The most common causes of death among site-specific malignancies were digestive tumors both in men (140 of 378, 37.0%) and women (105 of 263, 39.9%), respiratory tumors in men (103 of 378, 27.2%), and tumors of the reproductive system in women (79 of 263, 30.0%). A slight increase in the overall mortality from malignancies was observed in diabetic patients and achieved statistical significance in women (observed/expected = 1.16, 95% CI 1.02-1.30; P = 0.019) but not in men (observed/expected = 1.07, 0.97-1.19; P = 0.163). Excess mortality from hepatic cancer (SMR = 1.86, 1.44-2.38) was observed in both men and women. In addition, women with diabetes experienced a higher mortality from pancreatic tumors (observed/expected = 1.78, 1.13-2.67) and breast tumors (observed/expected = 1.40, 1.06-1.81). Excess mortality from breast cancer was confined to obese women with diabetes., Conclusions: Mortality from site-specific malignancies is different in type 2 diabetic patients than in the general population. Better control of body weight seems necessary to prevent the excess mortality from breast cancer in women.