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Purpose: We did a meta-analysis with meta-regression to evaluate the relationship between hemoglobin A1c (A1C) reduction and the primary CV outcome of cardiovascular outcome trials (CVOTs). Methods: We used a random effects meta-analysis of the 12 CVOTs to quantify the effect of A1C reduction on major cardiovascular events (MACE) risk by stratifying the difference in achieved A1C (drug vs placebo) in three strata: A1c < 0.3%, A1c = 0.3% and < 0.5%, and A1c = 0.5%. Results: We found a relation between the reduction in achieved A1C and the hazard ratio reduction for MACE (P = 0.002), explaining almost all (94.1%) the between-study variances: lowering A1C by 0.5% conferred a significant HRR of 20% (95% CI 4–33%) for MACE. Conclusions: Blood glucose reduction may play a more important role than previously thought in reducing the risk of MACE during treatment with the newer glucose-lowering drugs, including peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium–glucose co-transporter-2 inhibitors.

Clinical inertia and medication non-adherence are thought to contribute largely to the suboptimal glycemic control in many patients with type 2 diabetes. The present review explores the relations between A1C targets, clinical inertia and medication non-adherence in type 2 diabetes. We searched PubMed for English-language studies published from 2001 through June 1, 2018. We also manually searched the references of selected articles, reviews, meta-analyses, and practice guidelines. Selected articles were mutually agreed upon by the authors. Clinical inertia is the failure of clinicians to initiate or intensify therapy when indicated, while medication non-adherence is the failure of patients to start or continue therapy that a clinician has recommended. Although clinical inertia may occur at all stages of diabetes treatment, the longest delays were reported for initiation or intensification of insulin. Medication non-adherence to antidiabetic drugs may range from 53 to 65% at 1 year and may be responsible for uncontrolled A1C in about 23% of cases. Reverse clinical inertia can be acknowledged as the failure to reduce or change therapy when no longer needed or indicated. Clinical inertia and medication non-adherence are difficult to address: clinician-and patient-targeted educational programs, more connected communications between clinicians and patients, the help of other health professional figures (nurse, pharmacist) have been explored with mixed results. Both clinical inertia and medication non-adherence remain significant barriers to optimal glycemic targets in type 2 diabetes. Moreover, part of clinical inertia may be a way through which clinicians face current uncertainty in medicine, including some dissonance among therapeutic guidelines. Scientific associations should find an agreement about how to measure and report clinical inertia in clinical practice and should exhort clinicians to consider reverse clinical inertia as a cause of persisting inappropriate therapy in vulnerable patients.

Metabolic diseases are associated with chronic low-grade inflammation, which has been indicated as a potential mediator of endothelial dysfunction and cardiovascular disease. Visceral adiposity is thought to be the starting condition of the inflammatory state through the release of inflammatory cytokines, including TNF-alpha, CRP, and IL-6, which in turn promote endothelial dysfunction, endothelial expression of chemokines (IL-1) and adhesion molecules (ICAM-1, VCAM-1, and P-selectin), and the inhibition of anti-atherogenic factors (adiponectin). Obesity, metabolic diseases, and diabetes, all conditions characterized by abdominal fat, are well-recognized risk factors for sexual dysfunction in both sexes. Evidence from randomized-controlled trials supports the association between inflammatory milieau and erectile dysfunction in men suffering from metabolic diseases, whereas, in women, this has to be confirmed in further studies. A healthy lifestyle based on dietary pattern with high content of whole grain, fruit, nuts and seeds, and vegetables and low in sodium and saturated fatty acids plus regular physical activity may help to modulate the pro-inflammatory state associated with metabolic diseases and the related burden of sexual dysfunctions.

A relationship between thyroid dysfunction and diabetes mellitus has been described by several authors but the role of glycemic variability is still unclear. We planned the present study to evaluate the influence of glycemic variability on thyroid hormones and TSH concentrations in patients with type 1 diabetes mellitus (T1DM). Seventy-seven young patients with T1DM were enrolled and evaluated for basal glucose concentrations, HbA1c, thyroid hormones and TSH concentrations. Glucose variability was investigated by considering the standard deviation of blood glucose readings and by calculating the mean amplitude of glycemic excursions and continuous overlapping net glycemic action (CONGA). The low (LBGI) and high (HBGI) blood glucose indices were also calculated. The correlations between TSH, thyroid hormones, glycemia and HbA1c were studied in patients and in controls, whereas those between TSH, thyroid hormones and indices of glucose variability only in patients. No correlations were observed in T1DM patients between free thyroid hormones and glycemic values, HbA1c and indices of glucose variability, while an inverse correlation was observed between TSH levels and glycemic values (r= −0.27; p= 0.01), CONGA index (r= −0.35; p= 0.001) and HBGI (r= −0.28; p= 0.01) but not with HbA1c (r= −0.1; p= 0.47). Our results suggest a direct action of glycemic excursions on TSH secretion, regardless of variations of thyroid hormone concentrations. Thus, the evaluation of thyroid function through the assay of TSH concentrations in these patients should be made, if possible, by multiple samples on patients in euglycemic state to avoid underestimation or overestimation of thyroid dysfunction due to a wrong diagnosis of euthyroidism or dysthyroidism with consequent inappropriate choice of therapeutic options.

The aim of this study was to evaluate the prevalence and risk factors associated with female sexual dysfunction (FSD) in young women with type 1 diabetes treated with different intensive insulin regimens. Type 1 diabetic women aged 18–35 years were included in this study if they had stable couple relationship and no oral contraceptive use. All women were asked to complete the Female Sexual Function Index (FSFI) and other validated multiple-choice questionnaires assessing sexual-related distress (Female Sexual Distress Scale, FSDS), quality of life (SF-36 Health Survey), physical activity (International Physical Activity Questionnaire), depressive symptoms (Zung Self-Rating Depression Scale, SRDS) and diabetes-related problems (Diabetes Integration Scale ATT-19). FSD was diagnosed according to a FSFI score higher than 26.55 and a FSDS score lower than 15. The overall prevalence of FSD in diabetic and control women was 20 and 15 %, respectively (P= 0.446). Compared with the continuous subcutaneous insulin infusion group and control women, diabetic women on multiple daily injections (MDI) had lower global FSFI score (P= 0.007), FSDS score (P= 0.045) and domains such as arousal (P= 0.006), lubrication and satisfaction scores (P< 0.001 for both). In the multiple regression analysis, only the mental component summary (P= 0.047) and the SRDS score (P= 0.042) were independent predictors of FSFI score in the overall diabetic women. Young women with type 1 diabetes wearing an insulin pump show a prevalence of sexual dysfunction similar to that of healthy age-matched women, but sexual function was significantly impaired in diabetic women on MDI therapy. Depression and the mental health status were independent predictors for FSD in diabetic women.

Erectile dysfunction (ED) is a common comorbidity of diabetes mellitus, but few studies investigated its prevalence in type 1 diabetes. The objective of this study was to evaluate the prevalence and correlates of ED in young men with type 1 diabetes treated with different intensive insulin regimens. The study population included 151 type 1 diabetic men, aged 18–35 years, and 60 healthy age-matched controls. Ninety-four men were treated with multiple daily injections of insulin (MDI), and the remaining 71 with continuous subcutaneous insulin infusion (CSII). All participants in the study completed the International Index of Erectile function (IIEF-5), and other validated multiple-choice questionnaires assessing quality of life, physical activity, depressive symptoms and diabetes-related problems. The overall prevalence of ED was higher in diabetic men (37%), as compared with controls (6%, P<0.001). ED prevalence rates were similar in both MDI (36%) and CSII (39%) groups (P=0.326); both were higher compared with controls (P<0.001 for both). More than half of diabetic men (58%) had mild ED. Compared with men without ED, diabetic men with ED showed lower weight, body mass index, fasting glucose, insulin dose and high-density lipoprotein cholesterol levels, and higher self-rating depression score (SRDS). In the multiple regression analysis only the SRDS (P=0.032) were independent predictors of IIEF-5 score in the overall diabetic men. Young men with type 1 diabetes treated with MDI or CSII show a higher prevalence of ED, as compared with healthy age-matched men. Depression was associated with ED in diabetic population.

The real efficacy of selenium supplementation in Hashimoto’s thyroiditis (HT) is still an unresolved issue. We studied the short-term effect of l-selenomethionine on the thyroid function in euthyroid patients with HT. Our primary outcome measures were TSH, thyroid hormones, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb) levels and thyroid echogenicity after 6 months of l-selenomethionine treatment. The secondary outcome measure was serum CXCL10 levels. In a placebo-controlled randomized prospective study, we have enrolled untreated euthyroid patients with HT. Seventy-six patients were randomly assigned to receive l-selenomethionine 166 µg/die (SE n= 38) or placebo (controls n= 38) for 6 months. TSH, free T4(FT4), free T3(FT3), TPOAb and CXCL10 serum levels were assayed at time 0, after 3 and 6 months. An ultrasound examination of the left and right thyroid lobe in transverse and longitudinal sections was performed. A rectangular region, the region of interest, was selected for analysis. TSH, FT4, FT3, TPOAb, thyroid echogenicity and CXCL10 were not statistically different between SE and control groups at time 0, after 3 and 6 months. In the SE group, FT4levels were significantly decreased (P< 0.03) after 3 months, while FT3increased (P< 0.04) after 3 and 6 months versus baseline values. In the control group, the FT3decreased after 3 and 6 months (P< 0.02) compared to baseline. The short-term l-selenomethionine supplementation has a limited impact on the natural course in euthyroid HT. Our results tip the balance toward the ineffectiveness of short-term l-selenomethionine supplementation in HT.

To evaluate the Vitamin D status of patients with a single autoimmune disease and of patients with several autoimmune diseases. We enrolled 35 patients with isolated type 1 diabetes mellitus (T1DM), 60 with autoimmune polyendocrine syndromes (APS) including T1DM and 72 control subjects. Among patients with APS, 10 were classified as type 2 (Addison’s disease + T1DM), whereas the other 50 as type 3 (autoimmune thyroid disease + T1DM + other autoimmune diseases). Vitamin D (25-OHD) levels were assessed by a chemiluminescent immunoassay in all patients and controls on samples drawn in the morning of the same months. Both groups of APS and T1DM patients showed 25-OHD levels significantly lower than healthy controls (p< 0.001 for both vs controls), without any significant difference between the two groups (p= 0.80). The highest prevalence of vitamin D deficiency (values <20 ng/ml) was observed in APS type 3 subgroup (8 out of 50 patients, 16 %). Patients with APS present reduced vitamin D circulating levels, but the vitamin D status is not different between patients with single or multiple autoimmune diseases. The kind of autoimmune disease, rather than the association of several autoimmune diseases, may influence negatively the levels of vitamin D. Further prospective studies are needed to clarify if impaired vitamin D level is a causal factor in the pathogenesis of autoimmune diseases or a consequence of them.

Background:Endothelial progenitor cells (EPCs), involved in the repairing mechanisms of vascular damage, are positively correlated to insulin-like growth factor I (IGF-I) concentrations in healthy adults. However, the levels of EPCs and their role in acromegalic patients have never been investigated. Aim:We conducted a cross-sectional study in order to assess the levels of the different phenotypes of circulating EPC in acromegalic patients. Subjects and methods:The study was performed at the Endocrinology Unit of Federico II University and at the Unit of Metabolic Diseases and Endocrinology of the Second University of Naples. Fifty-five acromegalic patients and 65 healthy controls were studied. EPCs were assessed by flow cytometry and IGF-I by immunoradiometric assay. Results:Compared with subjects of the control group, acromegalic patients showed significantly higher levels of EPCs phenotypes expressing KDR antigen [KDR+, cells per 106events, median and interquartile range, 44 (28–67) vs 23 (13–40), p=0.006; CD34+KDR+ 25 (18–38) vs12 (8–17), p<0.001; CD133+KDR+ 17 (13–30) vs8 (6–12), p<0.001; CD34+KDR+CD133+ 16 (12–25) vs8 (6–10), p<0.001]. There was a positive correlations between CD34+KDR+CD133+ cells count and IGF-I in acromegaly group (r=0.79, p<0.001). Conclusions:Acromegalic patients show higher circulating EPCs levels expressing KDR, positively correlated with IGF-I, suggesting a role for IGF-I in regulating the expression of this surface marker in the early phase of EPCs differentiation.

Background:Literature data examining the role of metabolic syndrome and its components in prostate cancer risk are limited and contradictory. Aim:We did a meta-analysis of studies that evaluated the association between metabolic syndrome, its components, and risk of prostate cancer. Subjects and methods:We conducted an electronic search for articles published through September 2012 without restrictions. Every included study was to report risk estimates with 95% confidence intervals for the association between metabolic syndrome and prostate cancer. Results:The final number of papers included in the meta-analysis was 14, all published in English, with 4728 prostate cancer cases. Metabolic syndrome was associated with a 12% increase in prostate cancer risk (p=0.231), that was lower in cohort studies (7 studies, RR=1.04, p=0.791) than other studies (RR=1.23, p=0.125). The association was significant in the 8 European studies (RR=1.30, p=0.034), but not in the 4 U.S. or 2 Asiatic studies. The risk estimates of prostate cancer for higher values of body mass index, dysglycemia or dyslipidemia (high triglycerides, low HDL-cholesterol) were not significant; on the contrary, hypertension and waist circumference >102 cm were associated with a significant 15% (p=0.035) and 56% (p=0.007) greater risk of prostate cancer, respectively. Conclusions:Metabolic syndrome is weakly and non significantly associated with prostate cancer risk, but associations vary with geography. Among single components of the syndrome, hypertension and higher waist circumference are significantly associated with increased risk of prostate cancer.

The metabolic syndrome represents a cluster of several risk factors for atherosclerosis that increases the risk of future cardiovascular events. In this study, we evaluated whether oxidative stress is increased in subjects with the metabolic syndrome. We studied 100 subjects (50 men and 50 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III, and 50 (25 men and 25 women) matched subjects without the syndrome. Insulin sensitivity was assessed with the homeostasis model assessment (HOMA) methods; endothelium-dependent flow-mediated vasodilation (FMD) was evaluated in the right brachial artery with a high-resolution ultrasound machine; oxidative stress was assessed by measuring the circulating levels of nitrotyrosine (NT), considered a good marker for the formation of endogenous peroxynitrite. Compared with control subjects, patients with the metabolic syndrome had greater waist circumference, higher HOMA and systolic pressure values, higher triglyceride and lower HDL-cholesterol levels. NT levels were higher (0.44±0.12 μmol/l, mean±SD) while FMD was lower [7.3 (4.4/9.6), median and interquartile range]in subjects with the metabolic syndrome as compared with control subjects [0.27±0.08 and 11.8 (8.6/14.9), respectively, p<0.001]. There was an increase in NT levels and HOMA score as the number of components of the metabolic syndrome increased. NT levels were associated with waist circumference (r=0.38, p=0.01), triglycerides (r=0.32, p<0.02), systolic blood pressure (r=0.21, p<0.05) and fasting glucose (r=0.24, p<0.05). The oxidative stress that accompanies the metabolic syndrome is associated with both insulin resistance and endothelial dysfunction, providing a connection which is highly deleterious for vascular functions.

The aim of this editorial was to discuss evidence indicating a role for low-grade inflammation as a pathogenetic event of the metabolic syndrome. The metabolic syndrome has emerged as an important cluster of risk factors for atherosclerotic disease. Common features are central (abdominal) obesity, insulin resistance, hypertension, and dyslipidemia, namely high triglycerides and low high-density lipoprotein cholesterol. According to the clinical criteria developed by ATP III, it has been estimated that 1 out of 4 adults living in the United States merits the diagnosis. The presence of the metabolic syndrome is highly prognostic of future cardiovascular events. Chronic inflammation may represent a triggering factor in the origin of the metabolic syndrome: stimuli such as overnutrition, physical inactivity, and ageing would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. Alternatively, resistance to the anti-inflammatory actions of insulin would result in enhanced circulating levels of proinflammatory cytokines resulting in persistent low-grade inflammation. A generally enhanced adipose tissue derived cytokine expression may be another plausible mechanism for the inflammation/metabolic syndrome relationship. The role of adipose tissue as an endocrine organ capable of secreting a number of adipose tissue-specific or enriched hormones, known as adipokines, is gaining appreciation. Although the precise role of adipokines in the metabolic syndrome is still debated, an imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms may be an intriguing working hypothesis. The proinflammatory state that accompanies the metabolic syndrome associates with both insulin resistance and endothelial dysfunction, providing a connection between inflammation and metabolic processes which is highly deleterious for vascular functions.

It has been previously reported that endothelial cells exposed to constant high concentrations of glucose upregulate the expression of adhesion molecules. Moreover, it has been suggested that this phenomenon is related to generation of oxidative stress. It has also been suggested that oxidative injuries, related to high glucose, induce the activation of the enzyme poly ADP ribose polymerase (PARP), which can promote the expression of adhesion molecules and the generation of inflammation. Recent in‐vivoand in‐vitroevidence suggests that oscillation of glucose may play an autonomous and direct role in favoring the development of cardiovascular complications in diabetes. In this study we have investigated the effects of constantly high and intermittently high glucose on nitrotyrosine formation (a marker of nitrosative stress) and adhesion molecule (ICAM‐1, VCAM‐1 and E‐selectin), as well as on interleukin (IL)‐6 expression in human umbilical vein endothelial cells, either in the presence or in the absence of PJ34, a potent inhibitor of PARP. We found that oscillating glucose was more effective in triggering the generation of nitrotyrosine and inducing the expression of adhesion molecules and IL‐6 than stable high glucose. Pharmacological inhibition of PARP suppressed both nitrotyrosine formation, adhesion molecule expression and IL‐6 to the levels seen in the normal glucose conditions. Thus, PARP activation appears to be involved in both promoting nitrosative stress and upregulating adhesion molecules and inflammation in endothelial cells exposed to oscillating high glucose conditions.

ABSTRACT. Erectile and endothelial dysfunction may have some shared pathways through a defect in nitric oxide activity. We evaluated associations between erectile function, endothelial function and markers of systemic vascular inflammation in 80 obese men, aged 35–55 yr, divided into two equal groups according to the presence/absence of erectile dysfunction. Compared with non-obese age-matched men [no.=50, body mass index (BMI)=24±1], obese men (all) had impaired indices of endothelial function as suggested by the reduced mean blood pressure and platelet aggregation responses to L-arginine, and higher circulating concentrations of the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin- 18 (IL-18), as well as C-reactive protein (CRP). The mean erectile function score was 14±4 (range 7–19) in obese men with erectile dysfunction and 23.5±1 (range 22–25) in obese men without erectile dysfunction. Endothelial function showed a greater impairment in impotent obese men as compared with potent obese men. The mean blood pressure and platelet aggregation decreases following Larginine were -1.5±1.1 mmHg and -1.1±1.2%, respectively, in obese men with erectile dysfunction, and -3.4±1.2 mmHg and -5.6±2.1%, respectively, in obese men without erectile dysfunction (p<0.01). Circulating CRP levels were significantly higher in obese men with erectile dysfunction as compared with obese men without erectile dysfunction (p<0.05). Erectile function score was positively associated with mean blood pressure responses to L-arginine and negatively associated with BMI, waist-to-hip ratio (WHR), and CRP. Erectile and endothelial dysfunction associate in obese men and may contribute to their raised cardiovascular risk through impaired nitric oxide availability elicited by a low-grade inflammatory state.

BACKGROUND: Endothelial dysfunction and inflammation are present in both type 2 diabetes mellitus (T2DM) and obesity. In this paper we compared the role of weight loss and of glycaemic control in determining circulating levels of ICAM-1, endothelin-1 (ET-1), and E-selectin in patients with morbid (grade 3) obesity. METHODS AND RESULTS: ICAM-1, E-selectin, and ET-1 were higher in obese patients (n=96) than in lean controls (n=30); among obese patients, the three molecules were higher in T2DM patients (n=26) than in patients with normal (NGT, n=43) or impaired (IGT, n=27) glucose tolerance. Sixty-eight obese patients had a significant weight loss induced by bariatric surgery, and showed a significant decrease in blood glucose, HbA1c and all molecules, so that ICAM-1, E-selectin, and ET-1 were not different in NGT, IGT and T2DM patients, and in lean controls; in 13 patients with a small weight loss induced by diet, changes were not significant, in spite of a significant reduction in blood glucose and HbA1c. At stepwise regression, changes in ICAM-1, ET-1, and E-selectin significantly correlated only with change in body mass index. CONCLUSIONS: These data indicate that weight loss is more important than glycaemic control in regulating circulating levels of ICAM-1, ET-1, E-selectin in morbidly obese subjects.

Obesity is associated with an increased risk of developing atherosclerosis and atherosclerotic lesions are essentially an inflammatory response. The aim of this study was to evaluate the effect of a medically supervised, multidisciplinary weight loss program on endothelial functions and circulating levels of proinflammatory cytokines in obese women. Twenty healthy pre-menopausal obese women and 20 age-matched normal weight women were studied. Endothelial functions were assessed by evaluating the response of blood pressure and platelet aggregation to an intravenous bolus of L-arginine (3 g), the natural precursor of nitric oxide. In obese women, the vascular and rheological responses to L-arginine were significantly lower (p<0.05) at baseline, as compared with non-obese women, indicating endothelial dysfunction; on the contrary, basal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly higher (p<0.01). After one year of a multi-disciplinary program of weight reduction consisting of diet, exercise and liposuction surgery, all obese women lost at least 10% of their original weight (10.5±1.7 kg, range 7.9–13.9 kg). Compared with baseline, sustained weight loss was associated with reduction of cytokine (p<0.01) concentrations and with improvement of vascular responses to L-arginine. In conclusion, a multidisciplinary approach aimed at inducing a sustained reduction of body weight in obese women is feasible and is associated with improvement of endothelial functions and reduction of circulating proinflammatory cytokine concentrations.

Prolonged QT intervals and a reduced fall of nocturnal blood pressure (BP) both predict an increased risk of cardiovascular events in obese subjects. We evaluated circadian BP variations (24-h ambulatory BP monitoring), autonomic function (power spectral analysis of RR interval oscillations) and cardiac repolarization times (QTc-dispersion and QTc interval) in 70 obese women, aged 25–44 yr, grouped by WHR into group A (WHR>0.85, no.=38) and group B (WHR≤0.85, no.=32). Compared with non-obese age-matched women (no.=25, BMI=23±1.8) and obese women of group B, obese women of group A had higher values of QTc-d (p<0.05) and QTc (p<0.05), an altered sympathovagal balance (ratio of low-frequency/high-frequency power, p<0.01), and a blunted nocturnal drop in BP (p<0.01). In group A, QTc-d and the QTc interval correlated with diastolic night BP (p<0.01) and sympathovagal balance (p<0.01). WHR and plasma insulin levels correlated with QT intervals, reduced nocturnal fall in diastolic BP and sympathovagal balance (p<0.01). Prolongation of cardiac repolarization times and the reduction of nocturnal fall in BP coexist in obese women with visceral obesity, and might contribute to their raised cardiovascular risk. Autonomic dysfunction may be the common mechanism for this association.

Fat emulsion infusion is routinely used as a source of calories and essential fatty acids for critically ill patients who may be at risk for acquired ventricular repolarization alterations due either to drugs or electrolyte disturbances. The aim of this study was to evaluate whether acute elevations of plasma free fatty acid concentrations influence the corrected Q-T interval (Q-Tc), Q-Tc dispersion and sympathetic nervous system activity in patients requiring parenteral nutrition. Thirty hospitalized patients (mean±SD: 62±17 yr of age) requiring total parenteral nutrition received an infusion of 10% (500 ml) triacylglycerol emulsion as a source of calories (450 Kcal); on another occasion, and in random order, the same patients received an infusion of 20% (500 ml) triacylglycerol emulsion (900 Kcal). The infusion lasted 8 h and was preceded by a sc injection of heparin (5000 U). Infusions of both 10% and 20% triacylglycerol emulsion increased plasma free fatty acid (p<0.001) and triacylglycerol (p<0.01) concentrations, and was associated with no significant change in mean BP, heart rate, and plasma catecholamines. At baseline, Q-Tc and Q-Tc dispersion were within the normal range (<440 milliseconds for QTc and <40 ms for QTc-d) and did not show any significant change at any time during infusion of triacylglycerol emulsion at both concentrations. In the setting of a balanced parenteral nutrition, acute elevation of plasma free fatty acid concentrations in critically ill patients do not modify ventricular repolarization.

Plasma glucose, insulin, glucagon and growth hormone responses to both oral glucose and iv arginine were evaluated in 15 heroin addicts and 15 control subjects matched for age, sex and weight. The heroin users had an exaggerated rise in plasma glucose concentrations following oral sugar, which persisted until the end of the study (102 ± 5 mg/dl in addicts vs 72 ± 3 mg/dl in controls at 240 min, p<0.01) and significantly lower insulin responses (insulin peak 28 ± 4 μU/ml in addicts vs 67 ± 8 μU/ml in controls, p< 0.01). The inhibitory effect of glucose on glucagon concentrations was less evident in addicts than in controls. The responses of plasma glucose, insulin and glucagon to arginine were not significantly different between addicts and controls, while the growth hormone rise was significantly greater in addicts. These results demonstrate that heroin users have impaired insulin secretion to oral glucose but not to arginine and suggest that: a) the impaired insulin secretion in heroin addicts is not dependent on beta-cell exhaustion, and b) a selective inhibition of glucose-induced insulin secretion is operative in these subjects, as it happens in patients with noninsulin-dependent diabetes mellitus.

Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 ± 0.2 vs 7.7 ± 0.3 vs mmol/l, p< 0.01); better insulin-mediated glucose uptake (35.4 ± 0.5 vs 28.3 ± 0.4 μmol/kg fat free mass per min, p< 0.01), acute insulin response (68 ± 4.4 vs 46 ± 7.3 mU/l, p< 0.01) and respiratory quotient (0.81 ± 0.02 vs 0.77 ± 0.03, p< 0.05); and a rise in the plasma glucagon (164 ± 63 vs 134 ± 72 ng/l, p< 0.05), growth hormone (1.31 ± 0.13 vs 0.97 ± 0.21 μg/l, p< 0.03) and cortisol (325 ± 41 vs 284 ± 139 nmol/l, p< 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration (p< 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 ± 5.1 vs 71 ± 5.3 mU/l, p< 0.01) and the insulin-mediated glucose uptake (27.4 ± 0.4 vs 36.7 ± 0.5 μmol/kg fat free mass per min, p< 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake. [Diabetologia (1998) 41: 1127–1132]Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 ± 0.2 vs 7.7 ± 0.3 vs mmol/l, p< 0.01); better insulin-mediated glucose uptake (35.4 ± 0.5 vs 28.3 ± 0.4 μmol/kg fat free mass per min, p< 0.01), acute insulin response (68 ± 4.4 vs 46 ± 7.3 mU/l, p< 0.01) and respiratory quotient (0.81 ± 0.02 vs 0.77 ± 0.03, p< 0.05); and a rise in the plasma glucagon (164 ± 63 vs 134 ± 72 ng/l, p< 0.05), growth hormone (1.31 ± 0.13 vs 0.97 ± 0.21 μg/l, p< 0.03) and cortisol (325 ± 41 vs 284 ± 139 nmol/l, p< 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration (p< 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 ± 5.1 vs 71 ± 5.3 mU/l, p< 0.01) and the insulin-mediated glucose uptake (27.4 ± 0.4 vs 36.7 ± 0.5 μmol/kg fat free mass per min, p< 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake. [Diabetologia (1998) 41: 1127–1132]

Abstract. This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3–10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2(10 μg/min) and glucose disappearance rates were reduced (P< 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2infusion. The inhibitory effect of prostaglandin E2on glucoseinduced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2on glucose-induced insulin secretion in man.

We evaluated the effect of insulin on platelet function, blood viscosity, and filterability in healthy subjects and in patients with Type 2 (non‐insulin‐dependent) diabetes mellitus. Fifteen diabetic patients were free from cardiovascular complications (group A), while the other 15 patients had both clinical and measured evidence of coronary or peripheral vascular disease (group B); 15 non‐diabetic subjects served as controls. On blood samples taken without stasis, maximal platelet aggregation to 1.25 μmol l−1ADP, blood and plasma viscosity, and blood filterability were measured in basal conditions, and after incubation of blood, plasma or platelet‐rich plasma with insulin at two physiological concentrations (120 and 480 pmol l−1). Compared with healthy subjects, the diabetic patients of group B had higher values of blood (p< 0.01) and plasma (p< 0.05) viscosity, and platelet aggregation response to ADP (p< 0.01), as well as lower values of blood filterability (p< 0.01). The diabetic patients of group A had values intermediate between normal subjects and the patients of group B. In non‐diabetic subjects, insulin significantly decreased platelet aggregation and blood viscosity at low shear rates (22.5 s−1) (p< 0.01 for both), and had no significant effects on other parameters. In the diabetic patients of group A, insulin decreased blood viscosity at high (225 s−1) rates of shear (p< 0.01) and increased blood filterability (p< 0.01). The effects of insulin were not dose‐related. In the diabetic patients of group B, none of the parameters evaluated was significantly influenced by insulin. Type 2 diabetic patients present many abnormalities of the rheologic properties of blood. The beneficial effects of insulin on platelet aggregation and blood viscosity are not evident in Type 2 diabetic patients, especially those with vascular complications and this may be relevant to the development of those complications. © 1997 John Wiley & Sons, Ltd.

OBJECTIVE: To compare the effects of the ACE inhibitor perindopril and the beta-blocker carvedilol on blood pressure and endothelial functions in NIDDM patients with hypertension. RESEARCH DESIGN AND METHODS: We conducted a double-blind randomized trial in 26 patients with NIDDM and mild hypertension. A 4-week run-in placebo period preceded the active 12-week treatment with perindopril (4-8 mg daily) or carvedilol (25-50 mg daily). Endothelial functions were assessed by evaluating the hemodynamic (mean blood pressure, leg blood flow) and rheological (platelet aggregation, blood viscosity, and blood filterability) responses to an intravenous bolus of 3 g L-arginine, the natural precursor of nitric oxide. RESULTS: Both perindopril and carvedilol significantly reduced mean blood pressure (P < 0.001) and increased leg blood flow (P < 0.05) to the same extent; blood filterability remained unchanged in both perindopril- and carvedilol-treated groups. Carvedilol reduced platelet aggregation and blood viscosity significantly (P < 0.05) but perindopril did not. Before treatment, the hemodynamic and rheologic responses to L-arginine were significantly lower in patients (P < 0.05-0.01) than in 20 nondiabetic nonhypertensive control subjects. After 12 weeks of treatment, both drugs normalized the hemodynamic responses to L-arginine. Platelet aggregation response to L-arginine was ameliorated by carvedilol and remained unchanged in the perindopril group. CONCLUSIONS: At the doses used, both drugs effectively reduce blood pressure and normalize the hemodynamic responses to L-arginine. The implications of the ameliorated endothelial function for the poor cardiovascular outlook of the NIDDM hypertensive patient need further assessment.

To evaluate whether beta-cell hyperfunction characterizes glucose intolerant states per seindependent of fasting glycemia, we conducted a case-control study among 430 subjects who were classified, by NDGG criteria, as having normal glucose tolerance (n=230, 130M/130F), nondiagnostic tolerance (NDT, n=100, 50M/50F) and impaired glucose tolerance (IGT, n=100, 50M/50F). Thirty-four subjects (17M/17F) with normal glucose tolerance were matched by age, sex, body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose and HbA1c with 30 NDT (15M/15F) and 30 IGT (15M/15F) subjects. The continuous and significant increase in insulin and C-peptide levels across categories of glucose tolerance (from normal to NDT to IGT) was no longer evident in the case-control study: at a fasting plasma glucose ranging from 5.2–5.5 mmol/L (HbA1c was 5%) the concentration of fasting C-peptide was 0.793±225 nmol/L (mean±SD) in subjects with normal glucose tolerance, 0.805+200 nmol/L in NDT and 0.807±231 nmol/L in IGT subjects (p=NS). Similarly, plasma concentrations of triglycerides and blood pressure values were similar when subjects of different categories were compared at the same level of glycemia. Sixteen normal subjects were rendered mildly hyperglycemic by a 24-h glucose infusion to match the fasting glucose level of NDT (1 mg/kg/min) and IGT (2 mg/kg/min) subjects. At the same fasting glucose level, normal subjects presented elevations of fasting C-peptide significantly (p<0.01) higher than subjects belonging to the NDT and IGT categories. In conclusion, overweight people with impaired glucose tolerance present beta-cell hyperfunction in the fasting state which, however, is largely inappropriate for the prevailing glucose level; in these persons, glucose intolerance per seis not associated with hyperinsulinemia.

The effect of nifedipine, a calcium antagonist, on carbohydrate metabolism and insulin secretion was evaluated in patients who required treatment with this drug. 20 subjects underwent two oral glucose tolerance tests (100 g), one under basal conditions, and the other after ten days of treatment with nifedipine 30 mg/day by mouth, in three divided doses. 10 subjects had normal glucose tolerance; in them nifedipine administration reduced the insulin response to oral glucose in the first 60 min, but improved glucose tolerance. The other 10 subjects had impaired glucose tolerance and nifedipine treatment resulted in a further reduction both of insulin secretion and glucose tolerance. No such effects were seen in the placebo (weight- and disease-matched) group. The mechanism by which nifedipine influences carbohydrate metabolism and insulin secretion is discussed.

Summary: The effect of the calcium antagonist nicardipine on insulin secretion and glucose homoeostasis was investigated in elderly hypertensives with and without diabetes mellitus; 15 patients with essential hypertension for at least 10 years and normal glucose tolerance according to standard criteria (Group I) and 15 elderly hypertensive patients affected by Type 2 diabetes mellitus and on treatment with diet or oral drugs (Group 2).In the basal state, all patients were submitted to an oral glucose tolerance test (OGTT, 75 g) and an iv arginine test (30 g), on two different days and in random order. The same tests were repeated after one month of treatment with nicardipine 60 mg/day, in three spaced doses, the last being given 1 h before the post-treatment test. Nicardipine did not change overall glucose homoestasis, as assessed by haemoglobin Alc and fructosamine, nor did it significantly affect the plasma insulin response either to glucose or arginine in Groups 1 and 2. Only the glucagon response to arginine was significantly reduced in diabetic hypertensives. Small, non-significant variations in the metabolic and hormonal parameters were seen in additional two groups of patients (Groups 3 and 4), matched with Groups 1 and 2 for age, sex and diseases, who took capsules containing placebo.Thus, nicardipine did not produce any significant over-all alteration in glucose homoestasis when given to elderly diabetic or nondiabetic hypertensive subjects.

The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin.

Plasma and erythrocyte magnesium levels were measured by atomic absorption spectrometry in 12 healthy subjects and 12 moderately obese patients with Type 2 (non-insulin-dependent) diabetes mellitus. Basal plasma and erythrocyte magnesium levels were significantly lower in diabetic patients than in control subjects. In vitro incubation in the presence of 100 mU/l insulin significantly increased magnesium erythrocyte levels in both control subjects (p<0.001) and patients with diabetes (p<0.001). However, even in the presence of 100mU/l insulin, the erythrocyte magnesium content of patients with Type 2 diabetes was lower than that of control subjects. The in vitro dose-response curve of the effect of insulin on magnesium erythrocyte accumulation was shifted to the right when red cells of diabetic patients were used, with a highly significant reduction of the maximal effect. Such reduction of the maximal effect of insulin suggests that the impairment of insulin-induced erythrocyte magnesium accumulation observed in Type 2 diabetic patients results essentially from a post-receptor defect. In the diabetic patients, the Δ increase in erythrocyte magnesium levels (calculated as the net increase between basal and 100 mU/l insulin-induced erythrocyte magnesium levels) was negatively correlated with plasma insulin levels (r=−0.86; p<0.001) and with body mass index (r=−0.90; p<0.001); it was positively correlated with the glucose disappearance constant Kgafter intravenous glucose injection (r=0.79; p<0.01), with the amount of glucose required to keep euglycaemia despite hyperinsulinaemia in a glucose clamp (r=0.88; p<0.001), and with the metabolic clearance rate of glucose during the clamp (r=0.82; p<0.001). These results demonstrate that insulin-induced erythrocyte magnesium accumulation is impaired in patients with Type 2 diabetes and that such defect is correlated to impaired insulin-mediated glucose disposal in these patients.

In 14 normal subjects, treatment with acetylsalicylic acid (ASA, 3.2 g daily for 3 days) a well known inhibitor of prostaglandin synthesis, caused a slight but significant decrease (p<0.05) in basal plasma glucose levels; by contrast, basal insulin rose from 5±1 to 8±1 μU/ml (p<0.01) after ASA. Pretreatment with ASA augmented the early insulin response to a standard IV glucose tolerance test (25 g) in 7 normal subjects (p<0.05 at 2 min; p<0.02 at 5 min; p<0.01 at 10 min). No significant changes were detected in the rate of glucose utilization. 7 additional subjects received a standard arginine test without and with ASA pretreatment. Arginine stimulated insulin levels were increased after ASA (p<0.01 at 15 min; p<0.05 at 30 min; p<0.05 at 45 min), whereas glucose values were lower than under basal conditions at all times, with significant differences at 105 (p<0.02) and 120 (p<0.05) min. A possible role of prostaglandins upon the insulin responses to glucose and arginine is discussed.

In the presence of increased levels of fibrinopeptide A, decreased antithrombin III biological activity, and thrombin-antithrombin III complex levels are seen in diabetic patients. Induced-hyperglycaemia in diabetic and normal subjects decreased antithrombin III activity and thrombin-antithrombin III levels, and increased fibrinopeptide A plasma levels, while antithrombin III concentration did not change; heparin was shown to reduced these phenomena. In diabetic patients, euglycaemia induced by insulin infusion restored antithrombin III activity, thrombin-antithrombin III complex and fibrinopeptide A concentrations; heparin administration had the same effects. These data stress the role of a hyperglycaemia-dependent decrease of antithrombin III activity in precipitating thrombin hyperactivity in diabetes mellitus.

This study aimed at evaluating the influence of furosemide upon insulin and glucagon responses to arginine in healthy subjects. For this purpose, six normal subjects received two consecutive arginine pulses (3 g), 60 min apart, before and after the administration of furosemide (40 mg, IV). The acute insulin response (mean change from 3–10 min) to the second arginine pulse was significantly inhibited by furosemide (mean increase: 14.8 ±3.0 μU/ml versus 11.7±2.5 μU/ml, p<0.01). By contrast, the acute glucagon response was significantly increased (mean increase: 77±18 pg/ml versus 105±21 pg/ml, p<0.01). No significant changes in plasma glucose levels occurred. In control experiments, in which saline rather than furosemide was administered, the acute insulin and glucagon response to the first arginine pulse did not differ from that observed with the second pulse. The effect of furosemide on insulin and glucagon secretion might be mediated through enhanced release of endogenous prostaglandin E.

This study aimed at evaluating a possible relationship between cholesterol levels and ventricular electrical instability in human beings. Forty subjects (26 males and 14 females, mean age±SD 50.3±3.7 yr) with isolated hypercholesterolemia (≥240 mg/dl) were selected from a population of 250 patients who attended the outpatient department of our institution for symptomatic extrasystolic activity (ventricular premature complexes >3,000/24 h). Subjects were randomly assigned to receive either simvastatin 40 mg/d or placebo for 3 consecutive months. After treatment, subjects in the simvastatin group presented a significant decrease of total cholesterol and LDL-cholesterol (p<0.001) and an increase of HDL-cholesterol levels (p<0.01), associated with a reduction of both QTc dispersion (p<0.001) and ventricular premature complexes (p<0.001). None of these changes were observed in the placebo group. At baseline, there was a relationship between cholesterol levels, ventricular premature complexes (VPC) (r=0.33, p<0.05) and QTc dispersion (r=0.41, p<0.01). After treatment, reductions in serum cholesterol levels correlated with decreases of both VPCs (r=0.37, p<0.01) and QTc dispersion (r=0.49, p<0.01). In subjects with isolated hypercholesterolemia simvastatin may reduce the cardiovascular risk associated with ventricular electrical instability.

Increased factor VII levels have been reported in Type 1 (insulin-dependent) diabetic subjects. A direct correlation between fasting plasma glucose and factor VII level was found to exist in both diabetic and normal subjects. Induced-hyperglycaemia was able to increase factor VII levels in both diabetic patients and normal control subjects while, when euglycaemia was achieved in diabetic patients, factor VII values returned to normal range. This study shows that the level of factor VII may be directly conditioned by circulating blood glucose and, therefore, stresses the role of hyperglycaemia in conditioning coagulation abnormalities in diabetes mellitus.

The effects of non-enzymatic glycation on heparin cofactor II activity, at glucose concentrations which might be expected in physiological or diabetic conditions have been evaluated in this study. Radiolabelled glucose incorporation was associated with a loss of heparin cofactor anti-thrombin activity. The heparin cofactor heparin and dermatan sulfatedependent inhibition of thrombin was significantly reduced, showing a remarkable decrease of the maximum second order rate constant. This study shows that heparin cofactor can be glycated at glucose concentrations found in the blood, and that this phenomenon produces a loss of heparin cofactor-antithrombin activity. These data suggest, furthermore, a possible link between heparin cofactor glycation and the pathogenesis of thrombosis in diabetes mellitus.

This study concerns the synthesis of gel materials based on carbon nanotubes dispersed strontium-modified hydroxyapatite (Sr-HA) at different compositions obtained by sol–gel technology and their influence on human-bone-marrow-derived mesenchymal stem cells. Furthermore, an evaluation of the influence of nanotubes and Strontium on physico-chemical, morphological, rheological and biological properties of hydroxyapatite gel was also performed. Morphological analysis (scanning electron microscopy) shows a homogeneous distribution of modified nanotubes in the ceramic matrix improving the bioactive properties of materials. The biological investigations proved that Sr-HA/carbon nanotube gel containing 0–20 mol (%) of Sr showed no toxic effect and promote the expression of early and late markers of osteogenic differentiation in cell culture performed in basal medium without osteogenic factors. Finally, the SrHA/carbon nanotube gels could have a good potential application as filler in bone repair and regeneration and may be used in the osteoporotic disease treatment.