Trace elements and cognitive impairment: an elderly cohort study.

Dementia is one of the most pressing public health problems with social and economic implication. The form called cognitive impairment non-dementia (CIND)represents a subclinical phase of dementia. Different studies have shown a possible effect of micro- and macro-nutrients on cognitive function. Trace elements, being involved in metabolic processes and redox reactions in the central nervous system (CNS), could influence the cognitive functions. This study evaluated the presence of an eventual correlation between serum trace element concentrations and cognitive function in a group of subjects with CIND and manifest dementia (Alzheimer dementia = AD, and vascular dementia = VaD), and compared them with a control group. Thirty -five patients were enrolled in this study. Each patient underwent a clinical and biochemical examination. We also performed a neuropsychological and functional assessment (the Milan overall dementia assessment = MODA, activities of daily living = ADL, and instrumental activities of daily living = IADL), and a computerized tomographic (CT) cerebral scan. Patients were than divided in 4 groups according to the obtained diagnosis (Controls, CIND, AD, VaD). The presence of any acute or chronic conditions, affecting cognitive functions, was considered as exclusion criteria. A blood sample was collected to determine iron (Fe), zinc (Zn), manganese (Mn), selenium (Se), cobalt (Co), chromium (Cr), copper (Cu),molybdenum (Mo) and aluminium (Al) serum concentrations (chromatographic,spectrophotometric methods). In our cohort we found a positive correlation between cognitive function, expressed as the MODA score, and Se, Cr, Co and Fe serum levels,while a negative correlation was observed between MODA score, Cu and Al serum levels.Moreover, some statistically significant differences in Se, Cr, Co, Cu and Al concentrations were found among the groups. According to these results, we may suppose that Se, Cr and Co protect cognitive function, Cu influences the evolution of cognitive impairment, while Al contributes to the pathogenesis of AD.

Effect of metabolic control on homocysteine levels in type 2 diabetic patients: a 3-year follow-up.

OBJECTIVES: Hyperhomocysteinaemia has emerged as a novel risk factor for cardiovascular disease. The determinants of total homocysteine (tHcy) levels in type 2 diabetic patients (D2p) have not been studied in detail. We examined prospectively the effect of different degrees of metabolic control on plasma tHcy in D2p with preserved kidney function. SUBJECTS AND MAIN OUTCOME MEASUREMENTS: Ninety-five D2p were studied. Clinical parameters, fasting plasma glucose, HbA1c, serum lipids, blood urea nitrogen (BUN) and creatinine, vitamin B12 and folate and tHcy were measured at the baseline and after 36 months. The methylentetrahydrofolate reductase (MTHFR) C677T polymorphism was also determined. Subjects were categorized according to deltaHbA1c into group A (+/-1 point), B (>1 point increase) or C (>1 point decrease). RESULTS: Total homocysteine was reduced in subjects whose HbA1c decreased with time, whilst patients showing a worsened metabolic control had an increased tHcy in respect to baseline. A larger response to the improved metabolic control in terms of tHcy reduction was noted in wild type patients versus those homozygous for the mutation. A multivariate analysis revealed MTHFR polymorphism and HbA1c as strong determinants of changes in tHcy with time. CONCLUSIONS: The findings suggest that in D2p tHcy decreases even with modest improvement of glycaemic control; moreover patients homozygous for the MTHFR C677T mutation show the largest changes in tHcy levels with concomitant changing of HbA1c. These results define a further mechanism through which hyperglycaemia might promote cardiovascular damage in diabetic patients.

Atorvastatin improves metabolic control and endothelial function in type 2 diabetic patients: a placebo-controlled study.

Several pieces of evidence support a role of inflammatory processes in the pathogenesis of atherosclerosis; it is also known that endothelial dysfunction is the initial lesion of the atherosclerotic process. Among other markers of endothelial dysfunction, some adhesion molecules seem to play an interesting role. The aim of the present study was to evaluate the effect of atorvastatin vs placebo on some indexes of leukocytes adhesion in a group of Type 2 diabetic patients. Twenty-five Type 2 diabetic patients free from microangiopathic complications and with LDL-cholesterol lower than 180 mg/dl were randomized to receive either atorvastatin (T2DA) or placebo (T2Dp) for twelve months. BMI, fasting plasma glucose, glycated hemoglobin (HbA1c), albumin excretion rate (AER), lipid profile, and serum concentrations of vascular cell adhesion molecule-1 (VCAM1), E-selectin and cadherin-5 were measured at baseline and at the end of the follow-up. At T0 E-selectin was 16 +/- 6 ng/ml in T2DA and 17 +/- 13 in T2Dp; VCAM1 was 413 +/- 112 ng/ml in T2DA and 411 +/- 112 in T2Dp. At T12 VCAM1 and E-selectin did not vary in T2Dp, while a significant reduction was observed in T2DA (VCAM1 275 +/- 104 ng/ml and E-selectin 8 +/- 3 ng/ml; p < 0.001 and p < 0.01, respectively). T2DA also showed a reduction of total and LDL cholesterol and an improved glycemic control respect to T2Dp. Hypolipidemic therapy was the strongest independent predictor of the cytokines variations along the time. These results confirm the role of statins in modulating endothelial function also in Type 2 diabetes, outlining a therapeutic role of these molecules probably independent from the hypolipidemic effect.

Role of diabetes in influencing leptin concentration in elderly overweight patients.

BACKGROUND: Leptin, the product of the ob gene, could have a significant role in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus. However, it is still debated whether different degrees of glucose tolerance may affect plasma leptin concentrations in obese patients. OBJECTIVE: To investigate whether diabetes might influence leptin concentrations in obese patients. METHODS: We evaluated clinical parameters, anthropometric measures, and sex hormones, fasting plasma leptin, glucose and insulin concentrations in 100 elderly obese diabetic patients and 100 obese non-diabetic control individuals matched for age and sex. RESULTS: After adjustment for age and fat mass, plasma leptin concentrations did not differ between diabetic and non-diabetic obese individuals, in both men and women. In all patients leptin was significantly related to body mass index, fat mass and the homeostasis model insulin resistance index; moreover we observed a significant relationship with fasting plasma glucose and age in diabetic obese women, and with blood pressure values and testosterone concentrations in diabetic obese men. Multiple regression analysis revealed age and fasting plasma glucose to be the only independent determinants of fasting plasma leptin in diabetic obese women. CONCLUSIONS: These data suggest that leptin concentrations do not differ between obese diabetic and obese non-diabetic elderly patients. Among correlates of the metabolic syndrome, systolic pressure seems to be related to leptin only in men. In the postmenopausal or andropausal status, sex hormones are related to leptin concentrations only in diabetic men; in diabetic women, however, high glucose seems to be relevant in maintaining the same leptin concentrations as in non-diabetic women with similar degree of obesity.

Plasma homocysteine, methylenetetrahydrofolate reductase mutation and carotid damage in elderly healthy women.

Plasma homocysteine (Hcy) is an independent vascular risk factor. Its remethylation to methionine is regulated by the activity of the enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR). A C-to-T substitution at nucleotide 677 of the MTHFR gene is frequently associated to hyperhomocysteinemia. In this study, we evaluated the relationship among MTHFR C677T polymorphism, Hcy and some ultrasonographic parameters at the level of carotid arteries in 120 elderly women with normal ECG, normal blood pressure values, total cholesterol <250 mg/dl, normal glucose tolerance, normal albumin excretion rate. In all subjects, we measured Hcy by HPLC, MTHFR mutation by polymerase chain reaction followed by HinfI digestion and intima-media thickness (IMT), peak velocity of the systolic flow (SP(V)), end-diastolic velocity (ED(V)) and resistance and pulsatility indexes of intracranial circulation (RI and PI) by ultrasound imaging. Twenty-eight women were homozygotes for the wild type allele (Ala/Ala), 72 were heterozygotes (Ala/Val) and 20 were homozygotes for the mutation (Val/Val). Groups were comparable for age, blood pressure values and plasma lipid levels. Hcy was higher in Val/Val group; moreover, after adjustment for confounding factors, Val/Val had significantly greater IMT and ED(V) (P<0.001 and P<0.05, respectively). Logistic analysis revealed that Val/Val genotype was the strongest risk factor for IMT (OR 30.8, 95% CI 2.82-335.6). Our results show that, in elderly healthy women, Val/Val homozygosity for C677T mutation in MTHFR gene could identify subjects at risk for asymptomatic carotid atherosclerotic impairment.

The relationship of plasma glucose and electrocardiographic parameters in elderly women with different degrees of glucose tolerance.

Plasma glucose has been regarded as a risk factor for macrovascular complications in diabetes, but less is known about its role in the development of cardiac impairment other than coronary heart disease (CHD). The aim of our study was to determine the relationship between basal and post-OGTT (Oral Glucose Tolerance Test) plasma glucose levels and some ECG parameters in a group of elderly women with normal or impaired glucose tolerance (IGT). One-hundred and one women with normal fasting glucose (<6.0 mmol/L) and no familial history or clinical signs of CHD and diabetes underwent an OGTT and a resting ECG. Based on the degree of glucose tolerance, we identified 24 women with a diagnostic OGTT for either IGT or diabetes; the 77 women (age range 52-88 years) with normal glucose tolerance were further divided into two groups according to their post-OGTT area under the curve (AUCG): below and above the median value (32 and 45 women, respectively). Basal plasma glucose and insulin levels, as well as lipid profile and percent of hypertensive patients were similar in the three groups. Mean corrected QT (QTc) was prolonged as a function of progressive worsening of glucose tolerance even after adjustment for possible confounding factors (p=0.03). A similar relationship was apparent when post-OGTT plasma glucose peak (GP) was considered. In a multiple regression analysis, AUCG and GP were the only factors independently related to both QTc and Sokolow index. Our observations suggest that, even in the presence of a normal glucose tolerance, plasma glucose concentrations during an OGTT are associated with peculiar ECG signs potentially combined with an increased risk of sudden death, arrhythmias, or cardiovascular mortality.

alpha2-adrenoceptor regulation of the hypothalamic-pituitary-adrenocortical axis in obesity.

BACKGROUND: Abdominal obesity is associated with hyper-responsiveness of the hypothalamic-pituitary-adrenocortical (HPA) axis to stimulatory neuropeptides and to stress. Catecholamines are involved in the regulation of the HPA axis, particularly during stress, via alpha-adrenoceptor modulation. DESIGN: In this study, we investigated the effects of pre-treatment with an alpha2-adrenoceptor agonist, clonidine (2 microg/kg over 10 minutes) and antagonist, yohimbine (0.125 mg/kg bolus, followed by 0. 001 mg/kg/minutes per 90 minutes infusion) on the HPA axis, measured by ACTH and cortisol response to combined CRH (human, 100 microg) plus AVP (0.3 IU) administration, and on noradrenalin (NA) and adrenalin (A) blood levels, in a group of obese women with abdominal (A-BFD) or peripheral (P-BFD) body fat distribution and in nonobese controls. RESULTS: During the control CRH + AVP test the ACTH but not the cortisol response was higher (P < 0.05) in obese A-BFD women than in controls, with minor and transient variations of NA levels. Neither the control test nor clonidine or yohimbine influenced basal or post CRH + AVP A concentrations. Clonidine pretreatment similarly and significantly decreased NA levels in all women and, compared to the control test, marginally influenced the ACTH response to CRH + AVP. Conversely, during yohimbine infusion NA levels steadily and similarly increased to values more or less double baseline values in all groups. Compared to the control test, however, the ACTH response to the CRH + AVP test performed during yohimbine infusion significantly decreased in the control subjects whereas a tendency to a further increase occurred in the obese groups and, specifically, in the A-BFD group significantly (P < 0.05) more than in the P-BFD group. CONCLUSIONS: This study shows that alpha2-adrenoceptor regulation of the HPA axis is different in obese and nonobese women, particularly in stressed conditions. We suggest that the abnormal ACTH response to CRH + AVP challenge with increased noradrenergic tone may represent a specific pathophysiological aspect of the abnormal response to stress or to other specific stimulatory factors in obese women, particularly those with abdominal body fat distribution.

Serum leptin in obese women with polycystic ovary syndrome is correlated with body weight and fat distribution but not with androgen and insulin levels.

Leptin is a hormone produced in the adipose tissue and its concentrations in peripheral blood are significantly correlated with the amount of body fat. Whether other factors, including the pattern of body fat distribution and several hormones (such as insulin, sex steroids, and glucocorticoids), may be involved in the regulation of circulating blood leptin levels is controversial. Women with the polycystic ovary syndrome (PCOS) are hyperandrogenic and most of them are characterized by hyperinsulinemia, insulin resistance, and obesity, particularly the visceral phenotype. To assess the potential contribution of anthropometric factors, androgens, and insulin in determining leptin levels, we examined their relationship with body-mass index (BMI), visceral (VAT) and subcutaneous (SAT) adipose tissue areas, basal androgen levels, and fasting and glucose-stimulated (AUC) insulin in different groups of obese women with PCOS (n = 23) and of age-matched obese (n = 16) and non-obese (n = 10) otherwise healthy controls. The VAT/SAT ratio was measured as a parameter of body fat distribution. Serum leptin levels were significantly higher in obese PCOS women than in obese and normal-weight healthy controls and, within the controls, in the obese than in the non-obese group. In all women considered together, and in each group separately, leptin concentrations were highly significantly correlated with BMI. In addition, after adjusting for BMI, both VAT and the VAT/SAT ratio were positively and significantly correlated with leptin. Partial correlations with the VAT/SAT ratio remained significant in both the obese PCOS group and in controls considered separately, whereas the correlation with the SAT value was significant only in the control group. After adjusting for BMI, no correlation between leptin, androgens and fasting or stimulated (like AUC) insulin was found. These findings indicate that leptin levels in obese women with PCOS are higher than those observed in obese and non-obese controls. Moreover, they suggest that, other than BMI, the pattern of body fat distribution may be an independent factor related to circulating leptin levels, which, on the contrary, do not appear to be related to either androgen or insulin concentrations.

Secretion of major adrenal androgens following ACTH administration in obese women with different body fat distribution.

To investigate whether obese female subjects with abdominal obesity may have adrenal androgen hypersecretion, we examined two groups of women with abdominal (n = 12) and peripheral (n = 13) obesity (defined by body mass index and waist-to-hip ratio) and a group of seven healthy normal-weight women. All subjects underwent the following protocol study that included a) baseline determination of major adrenal androgens, b) an ACTH test, performed by administering two boli of ACTH (Synacthen, 0.2 microg/Kg BW, e.v.), at 90 min intervals, with blood samples taken for cortisol and androgens, c) an oral glucose tolerance test, performed by administering glucose (75 gr), with blood samples taken for glucose and insulin determination. Each woman also underwent a control saline study. We then investigated the relationships between basal and stimulated androgen levels, body weight and fat distribution and fasting and stimulated insulin levels. Although basal cortisol levels were similar, their increase (as AUC) after the ACTH test was higher in women with abdominal obesity than in the other groups. On the contrary, there were no significant differences in basal and stimulated serum levels of dehydroepiandrosterone, androstenedione and 17-hydroxyprogesterone among the three groups. Fasting and stimulated (as AUC) insulin levels were significantly higher (p < 0.05) in women with abdominal obesity than in those with peripheral obesity and controls. No significant correlation was present between basal and stimulated androgen levels and body mass index, the waist-to-hip ratio or basal and stimulated cortisol values. Therefore, our data indicate that adrenal androgen secretion following low-dose ACTH administration in premenopausal women does not seem to be a function of body fat mass, fat distribution and insulin levels, nor does it correlate with the capacity of the adrenal glands to secrete cortisol in both basal and stimulated conditions.

Leptin and the hypothalamic-pituitary-adrenal axis activity in women with different obesity phenotypes.

OBJECTIVE: Women with visceral obesity may have hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since glucocorticoids are involved in the expression of the ob gene, this study was carried out to investigate the relationship between serum leptin and the activity of the HPA axis in women with different obesity phenotypes. DESIGN: Cross sectional clinical study. SUBJECTS: Fifteen obese (Body Mass Index BM128 kg/m2) women and ten normal weight control women (BM126 kg/m2) were included in the study. MEASUREMENTS: Body fat distribution was defined by CT scan at the L4-L5 level. Baseline blood samples were obtained for hormone concentrations. The activity of the HPA axis was evaluated by measuring ACTH and cortisol blood levels after combined iv administration of corticotropin releasing factor (100 microg) + arginine-vasopressin (0.3 IU). RESULTS: Baseline cortisol, ACTH, and androgen levels were similar in all groups, whereas leptin levels were significantly higher in the obese groups than in normal weight controls, without any significant difference between women with different obesity phenotypes. Incremental areas of ACTH and cortisol were significantly higher in women with visceral obesity than in those with subcutaneous obesity and controls. No significant correlation was found between the activity of the HPA axis and leptin concentrations. Leptin showed a highly significant correlation with BMI and subcutaneous fat and a weak but significant correlation with visceral fat and the visceral-to-subcutaneous fat ratio. CONCLUSION: Women with different obesity phenotypes had similar serum leptin concentrations but different HPA axis activity, and there was no correlation between them.