Clinical efficacy and predictors of response to dulaglutide in type-2 diabetes.

Aim of this retrospective multicenter observational study was to evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) dulaglutide in a type-2 diabetic real-world population and to determine the factors predicting the response in terms of glycated haemoglobin (HbA1c) and other relevant clinical outcomes. Data for efficacy outcomes, adverse events and drug discontinuation were collected from records of patients with type-2 diabetes treated with once-a-week 1.5 mg of dulaglutide for 12 months in routine clinical practice. Initial analysis included 782 patients and 626 had complete follow-up at 6- and 12-months. There was a significant reduction of HbA1c at 6 months (-1 ± 0.8 %, p < 0.0001), which remained stable at 12-months follow-up (-1 ± 0.9 %, p < 0.0001). The percentage of subjects with HbA1c≤7.0 % increased significantly from 7.2 % at baseline to 52.7 % at 6 months to 55.8 % at 12 months. Predictors of the achievement of HbA1c≤7.0 % were low baseline HbA1c and short duration of diabetes. The reduction of HbA1c was associated with reductions of BMI, waist circumference, fasting plasma glucose and blood pressures. Neither sex nor age had significant effects on any clinical or laboratory outcome. The effects of dulaglutide on HbA1c, BMI and SBP tended to be greater in patients who shifted from dipeptidyl peptidase-IV inhibitors (-0.8 ± 0.8 %) than other GLP-1 RA, even if an improvement of HbA1c reduction (-0.5 %) was also seen in those shifting from other GLP-1 RA. This study confirms that addition of dulaglutide 1.5 mg once a week in real word settings has beneficial effects on both clinical and laboratory outcomes in patients with uncontrolled type-2 diabetes. Dulaglutide has a greater effect on HbA1c in patients with higher baseline values and helps achieve a target HbA1c≤7.0 %, more consistently in patients with lower baseline HbA1c and shorter diabetes duration.

Body composition and pulmonary function in the elderly: a 7-year longitudinal study.

OBJECTIVE: To evaluate over a 7-year follow-up period the relationships between changes in body composition, fat distribution and pulmonary function in a sample of elderly men and women. DESIGN: Longitudinal clinical study. SUBJECTS: A total of 47 women and 30 men aged 71.6+/-2.3 and 71.7+/-2.2 years, respectively, at baseline with body mass index (BMI) values of 24.96+/-3.28 and 27.04+/-3.35 kg m(-2) were followed for 7 years. MEASUREMENTS: Body weight, waist circumference, sagittal abdominal diameter (SAD), fat-free mass (FFM) and fat mass as measured by dual energy X-ray absorptiometry (DXA) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) by spirometry were evaluated at baseline and after a 7-year mean follow-up. RESULTS: In women as in men there were no significant changes in weight, SAD and BMI. A significant decrease in height and FFM was observed in both women and men. Height-adjusted FEV1 and FVC decreased significantly in women and men over the 7-year follow-up. Changes in SAD were the most powerful predictors of 7-year follow-up of FEV1 and FVC after taking into account, respectively, baseline FEV1 and FVC. Linear regression analysis, performed by using 7-year follow-up lung function variables as dependent variables and changes in body composition variables as independent variables, showed that 1 cm SAD increase predicted a decrease in FEV1 and FVC of 31 and 46 ml, respectively, and 1 kg FFM decrease predicted a decrease in FVC of 38 ml. After subdividing our study population into four categories of change in FFM and SAD, patients with decreased FFM and increased SAD showed the highest probability of having a worsening in FEV1 and FVC. CONCLUSION: Increase in abdominal fat and FFM decline are significant predictors of lung function decline in the elderly. Old subjects developing both abdominal fat gain and FFM loss show the highest probability of developing worsening in lung function.

Neuroendocrine features in extreme longevity.

In order to evaluate the effects of some neuro-endocrine changes during aging we have studied adrenal, thyroid and pineal secretion in young, healthy old and centenarians. The number of subjects in each hormone group varied. The following parameters were evaluated: serum levels of cortisol, dehydroepiandrosterone-sulfate (DHEAS), free triiodothyronine (FT3), thyroxine (FT4), reverse triiodothyronine (rT3) and thyroid-stimulating hormone (TSH). Urinary 6-hydroxymelatonin sulfate (aMT6s) and free cortisol were measured twice daily. Centenarians exhibited significantly lower TSH levels together with slightly higher rT3 levels than old controls. These changes could be due to reduced 5'-deiodinase activity occurring also in absence of substantial changes of the nutritional pattern. Morning serum cortisol levels were found to be similar in the 3 age groups, whereas the decline of serum DHEAS levels was well evident also after the ninth decade of life. The cortisol/DHEAS molar ratio, which usually increases with age and considered to be an expression of a neurotoxic pattern of the steroidal milieu in the central nervous system, did not shown any further increase in centenarians. The urinary free cortisol and aMT6s excretion declined with age; however only in centenarians and in young controls aMT6s excretion was significantly higher at night than during the day. These findings suggest that the circadian rhythm of melatonin secretion is maintained in centenarians and, based on the limitations of this study, could be considered one factor in successful aging.

Biochemical evaluation of patients with active acromegaly and type 2 diabetes mellitus: efficacy and safety of the galanin test.

The oral glucose tolerance test, which is considered the gold standard for the diagnosis of active acromegaly, should not be performed in the presence of basal hyperglycemia. Moreover, false-positive responses may occur in patients with diabetes mellitus. Galanin has previously been demonstrated to induce paradoxical inhibition of growth hormone (GH) secretion in most patients with active acromegaly. In this study, we assessed GH response to galanin infusion in a series of 17 consecutive patients with active acromegaly, 7 of whom had coexistent type 2 diabetes mellitus and 10 were without either diabetes mellitus or impaired tolerance to glucose. 6 acromegalic patients with diabetes mellitus (85.7%) and 7 without diabetes (70.0%) showed a decrease in serum GH values during galanin infusion (chi2 0.9; p = 0.6). The GH nadir occurred at a comparable time in the two groups of acromegalic patients. Moreover, the two groups showed no significant difference (p = 0.45) in DeltaGH during galanin infusion. Galanin infusion did not induce any significant change in plasma glucose levels in both diabetic and non-diabetic patients with acromegaly. The results of our study provide evidence that the galanin test may be of value for the diagnosis of acromegaly in patients with type 2 diabetes mellitus.

Relationship among nutritional status, pro/antioxidant balance and cognitive performance in a group of free-living healthy elderly.

AIM: Nutrition plays a role in health promotion and well-being, but there is still a lack of knowledge about nutrition-related risk factors in aging cognitive impairment. The purpose of this project was to evaluate the link between nutritional status, cognitive performance and pro/antioxidant balance in healthy elderly subjects residing in a small metropolitan community. METHODS: The subjects were 69 free-living urban healthy elderly people (41 females and 28 males aged 84+/-7 years, mean +/- standard deviation SD, range 70-89). In this group of elderly subjects an analysis of the diet over the 3 days before the study entry was performed. The nutrients intake for individuals were compared with the Italian Recommended Dietary Allowances (RDA). We also collected residents' background information, nutritional status (Mini Nutritional Assessment, MNA), and data on daily nursing routines in institutions, including nutritional care. Plasma malondialdehyde and erythrocyte glutathione peroxidase activity were evaluated in elderly people as compared to a group of healthy young people (control group) as indices of the oxidative balance. RESULTS: The mean vitamin and mineral intake for participants met the RDAs except for calcium and vitamin D. No difference was observed as regards plasma malondialdehyde between young and elderly subjects: 4.5 (3-6.2) mmol/L vs 4.45 (2.4-5.8) mmol/L respectively, median with range, whereas the latter exhibited higher erythrocyte glutathione peroxidase activity: 16.0 (9.3-48) U/g hemoglobin (Hb) vs 15 (10-35) U/g Hb, respectively, median with range (P<0.05). A significant negative correlation (P<0.05, r=0.24) between dietary intake of vitamin D and malondialdeyde and between dietary intake of vitamin D and poor performance on cognitive tests (P<0.01, r=0.35) was observed. CONCLUSION: In line with previous findings, our results highlighted the potential impact of nutritional factors on cognitive performance in older adults.

Erectile dysfunction and angiographic extent of coronary artery disease in type II diabetic patients.

Some studies observed an association between erectile dysfunction (ED) and coronary artery disease (CAD) extent in the general population, but others did not. There are no specific studies in diabetic populations. The aim of the present study was to evaluate whether ED is correlated with the extent of angiographic CAD in a large group of type II diabetic patients. We recruited 198 consecutive type II diabetic males undergoing an elective coronary angiography to evaluate chest pain or suspected CAD. Presence and degree of ED were assessed by the International Index Erectile Function - 5 (IIEF-5) questionnaire. ED was considered present, when IIEF-5 score was < or =21. Moreover, each domain of IIEF-5 was considered. Angiographic CAD extent was expressed both by the number of vessels diseased and by the Gensini scoring system. The percentage of subjects with ED was significantly higher (45.8 versus 15.8%; P=0.0120) in patients with (n=179) than in those without (n=19) significant angiographic CAD (stenosis of the lumen > or =50%). No significant association of CAD extent with presence of ED, total IIEF-5 score and each domain of IIEF-5 was observed. Our study shows that ED was significantly more prevalent in type II diabetic males with angiographic CAD than in those with normal arteries. However, no correlation was found between the extent of angiographic CAD and the presence or the severity of ED.

Lipoprotein(a), apolipoprotein(a) polymorphism and coronary atherosclerosis severity in type 2 diabetic patients.

BACKGROUND: Few and conflicting data are available in the literature on the association between Lp(a) levels and the severity of coronary artery disease (CAD) in diabetic patients. In addition, no studies took into account the role of apo(a) polymorphism. The purpose of the present study was to analyse the association of the degree of coronary atherosclerosis with Lp(a) levels and apo(a) polymorphism in a large group of type 2 diabetic patients. METHODS: The study population consisted of 227 consecutive type 2 diabetic patients undergoing a routine coronary angiography to evaluate chest pain or suspected CAD. The patients were subdivided into four subgroups according to the number of coronary arteries diseased: normal arteries (n=26), mono-vessel disease (n=67), bi-vessel disease (n=54) and multi-vessel disease (n=80). RESULTS: Lp(a) levels (normal arteries: 14.6+/-19.6 mg/dl; mono-vessel disease: 19.0+/-16.4 mg/dl; bi-vessel disease: 19.3+/-15.1 mg/dl; multi-vessel disease: 26.5+/-16.8 mg/dl; p<0.001) and the percentages of patients with at least one isoform of low molecular weight (normal arteries: 23.1%; mono-vessel disease: 38.8%; bi-vessel disease: 75.9%; multi-vessel disease: 81.2%; p<0.001) were significantly correlated with increasing number of coronary vessels diseased. Multiple logistic regression analysis showed that both Lp(a) levels (OR: 1.31; 95% CI: 1.02-4.11) and apo(a) polymorphism (OR: 3.43; 95% CI: 1.67-7.05) were independent predictors of CAD severity. CONCLUSIONS: Our data suggest that Lp(a) levels and apo(a) polymorphism may be reliable predictors of CAD severity in type 2 diabetic patients.

No effect of atypical antipsychotic drugs on weight gain and risk of developing type II diabetes or lipid abnormalities among nursing home elderly patients with Alzheimer's disease.

AIM: Weight gain and the risk of developing alterations in lipid and glucose metabolism are possible side effects of atypical antipsychotic therapy in young and adult patients. The objective of this study was to examine whether elderly patients with Alzheimer's disease (AD) gain weight or develop disturbances in lipid and glucose metabolism while being treated with atypical antipsychotic drugs. METHODS: This retrospective study identified 36 out of 99 patients (mean age: 75.4+/-7.1, 27 female, 9 males) who were taking risperidone (N=9, mean dosage: 1.42+/-0.49 mg/day), olanzapine (N=17: 4.42+/-1.10 mg/day), and quetiapine (N=10: 75+/-27 mg/day) over a 12 months period. Anthropometric parameters, mini nutritional assessment (MNA), total, HDL and LDL cholesterol, triglycerides, glycaemia were assessed at baseline (T0) and 12 (T1) months. RESULTS: Body weight (BMI=23+/-5 vs 23+/-5), MNA score (21+/-4 vs 21+/-4), blood glucose (5.7+/-2 vs 4.9+/-0.9 mmol/L) or total cholesterol (4.9+/-1.1 vs 4.3+/-0.7 mmol/L), HDL cholesterol (1.3+/-0.3 vs 1.1+/-0.3 mmol/L), LDL cholesterol (3.3+/-0.7 vs 3 +/- 0.4 mmol/L), triglycerides (1.1+/-0 vs 1+/-0.3 mmol/L) did not reveal treatment-induced changes in the patients evaluated (T0 vs T1). CONCLUSION: These results suggest that the treatment with low-dose of atypical antipsychotic drugs is not associated with weight gain or increase the risk of developing type II diabetes or abnormalities of lipid metabolism among elderly patients with AD, who were residing in long-term nursing home.

Involvement of hormonal circadian secretion in the growth of HIV-infected children.

OBJECTIVE: To evaluate the circadian secretion of hormones involved in the regulation of growth in childhood, namely growth hormone, insulin-like growth factor (IGF)-I, cortisol, adrenocorticotropin hormone (ACTH), and thyroid-stimulating hormone (TSH) in HIV-infected children. DESIGN: The circadian secretory pattern of growth hormone, IGF-I, cortisol, ACTH and TSH was evaluated in 14 HIV-infected children; 13 healthy age- and sex-matched children were chosen as controls. METHODS: Sampling was performed every 4 h from 0400 h to 2000 h and every 2 h from 2000 h to 0400 h. Rhythmometric data were analysed by single and population mean cosinor methods and by analysis of variance. RESULTS: A statistically significant circadian rhythm for growth hormone, IGF-I and cortisol was detectable in HIV-seropositive children, but the mean basal IGF-I levels were below the normal range for age in 12 patients. A statistically significant circadian rhythm was not detectable for ACTH or TSH. CONCLUSION: These results show that there is a loss of the physiological regulation of growth hormone-IGF-I axis and a modification of 24 h TSH profile in our HIV-infected children. These abnormalities might be involved in the altered growth mechanism leading to the failure to thrive that is a peculiar feature of HIV-infected children.

Dehydroepiandrosterone sulfate enhances natural killer cell cytotoxicity in humans via locally generated immunoreactive insulin-like growth factor I.

Experimental and clinical investigations suggest the hypothesis that dehydroepiandrosterone sulfate (DHEAS) can positively influence natural killer (NK) immunity via locally produced insulin-like growth factor I (IGF-I) from NK cells. In the present study, the NK cell cytotoxicity (NKCC) and IGF-I levels in the supernatant of NK cells were studied at baseline and after exposure to various molar concentrations of DHEAS (from 10(-5)-10(-8) mol/L x mL/7.75 x 10(6) NK cells) in healthy subjects of young and old age. DHEAS-induced NKCC was also determined after DHEAS coincubation with somatostatin-14 (10-6) mol/L x mL/7.75 x 10(6) NK cells) and with interleukin-2 (IL-2; 100 IU/mL x 7.75 x 10(6) NK cells). NK cells were previously isolated by Ficoll-Hypaque density gradient and then by immunomagnetic procedure; the purity obtained was 97 +/- 1%. NKCC was determined against K562 tumoral targets. We observed that the increase in NKCC after DHEAS exposure was dose dependent and was correlated with the amount of IGF-I released in the supernatant of cultured NK cells. NKCC and IGF-I generation from NK cells were more elevated in healthy elder subjects than in healthy young subjects. The coincubation of DHEAS with somatostatin-14 significantly suppressed NKCC and IGF-I release from NK in both groups, whereas higher NKCC was found after DHEAS plus IL-2 exposure than after incubation with DHEAS alone. Taken together, this study suggests a role for NK-generated IGF-I in the modulation of NKCC by DHEAS in humans. Although DHEAS may contribute to the IL-2-mediated NKCC, its activity on NK cytolytic function can be dependent on a autocrine mechanism (IGF-I-mediated), probably independent of cytokine activation. The higher NKCC response to DHEAS found in old subjects than in younger might counterbalance the age-dependent decline in circulating DHEAS, thus contributing to maintain the pattern of NK immunity during aging.

Hemorheological changes and overproduction of cytokines from immune cells in mild to moderate dementia of the Alzheimer's type: adverse effects on cerebromicrovascular system.

An association between hemorheological alterations (i.e., whole-blood and plasma hyperviscosity, reduced erythrocyte deformability, increased red cell aggregation, hyperfibrinogenemia and increased acute-phase protein levels) and the mild stage of senile dementia of the Alzheimer's type (DAT) was suggested in the present study. In particular, hyperfibrinogenemia and the increase of erytrhocyte aggregation were correlated with the increased generation and release of TNF-alpha and IFN-gamma (spontaneous release and IL-2-modulated release) from natural killer (NK) lymphocytes (CD16+, CD56+, CD3- cells) of patients with DAT; whereas a normal cytokine release from NK cells was found in healthy old subjects and in patients with vascular dementia (VaD). The in vitro and in vivo administration of the hemorheologic drug pentoxifylline (PTX) significantly reduced spontaneous and IL-2-modulated cytokine overproduction from NK cells (in vitro effects with 500 U/ml and 1000 U/ml/NK cells) and improved all the hemorheological parameters. Taken together, these data suggest that disturbances of cerebrovascular flow and of hemorheology could be considered a negative component related to the pathogenesis and progression of DAT neurodegeneration. The association between hemorheological changes and alterations of TNF-alpha and IFN-gamma release from NK may indicate a potential immunorheologic mechanism associated with cerebrovascular damage in DAT and could suggest the use of vascular protective drugs as support of the main pharmacological and non-pharmacological therapy of AD.

Increased natural killer cell cytotoxicity in Alzheimer's disease may involve protein kinase C dysregulation.

Increased cytokine-mediated cytotoxic natural killer (NK) cell activity has recently been demonstrated in patients with senile dementia of the Alzheimer's type (SDAT). In the present study, we evaluated whether protein-kinase C (PKC), a main regulatory enzyme involved in the mechanism of exocytosis by NK cells, has a role in the cytotoxic response of NK cells (during IL-2 and IFN-beta exposure) from SDAT patients. Our data demonstrate the presence of an increased cytotoxic response by NK cells to IL-2 (mean increase +102%) and IFN-beta (mean increase +132%) in SDAT patients in comparison with healthy elderly subjects (+75% and +88% for IL-2 and IFN-beta, respectively). A smaller suppression of NK cytotoxicity after cortisol was also observed in SDAT (mean decrease -24%) than in the control group (-44%). The NK cell activity of SDAT patients was inversely correlated with the cognitive status as evaluated by the analysis of MMSE (Mini Mental State Examination) score. A comparison of young and elderly healthy subjects revealed no variations in NK cell activity. A physiological decrease in cytosolic PKC activity was demonstrated in healthy old subjects after IL-2 and IFN-beta incubation, but not in SDAT patients, while no variations in kinase activity were observed after cortisol incubation. The decreased activity with cytokines was associated with reduced levels of PKC alpha and betaII isoforms. An alteration in cytokine-mediated NK cell activity associated with PKC dysregulation is therefore suggested to occur in patients with SDAT. These changes may indicate the existence of an immunological component to the pathogenesis and progression of the disease.

Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection.

The circadian rhythms of plasma growth hormone (GH), insulin-like growth factor type I (IGF-I), cortisol, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin (PRL) were evaluated in 13 HIV-seropositive patients (8 males and 5 females; mean age [+/-SD], 30 +/- 5 years), classified as CDC C2. Sixteen clinically healthy subjects (9 males and 7 females; mean age [+/-SD], 32 +/- 8 years) were chosen as control group. Samples were taken every 4 hr from 04:00 to 20:00 and every 2 hr from 20:00 to 04:00. Plasma GH was evaluated by IRMA procedure, plasma IGF-I by RIA (after separation of soluble IGF-I from IGF-I-binding proteins, using acid-ethanol extraction), plasma cortisol by a solid-phase RIA, plasma ACTH by double-antibody RIA, and serum TSH and serum PRL by a solid-phase two-site fluoroimmunometric assay. Rhythmometric data were analyzed by single and population mean cosinor analysis; the comparison of the parameters of the rhythm between patients and controls was carried out by the mesor test and the amplitude-acrophase Hotelling test. Alterations of the circadian pattern of GH, IGF-I, cortisol, ACTH, TSH, and PRL were demonstrated in HIV-seropositive patients. In fact, the circadian profiles of these hormones were clearly flattened and no statistically significant 24-hr rhythm was detectable (with the exception of cortisol). These results are consistent with the hypothesis that alterations of the circadian temporal structure may already be present in HIV-seropositive patients without wasting and infectious complications.

Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia.

The simultaneous evaluation of the circadian rhythm of plasma melatonin and ACTH and of serum cortisol and DHEAS represents a clinically reliable tool to appreciate the neuroendocrine changes occurring in physiological and pathological brain aging.A selective impairment of the nocturnal melatonin secretion has been observed in elderly subjects, being significantly related either to the age or to the severity of dementia. A significant increase of serum cortisol levels during evening- and night-times was found in elderly subjects, particularly if demented, when compared to young controls. Besides, both the circadian amplitude of cortisol rhythm and the nocturnal cortisol increase were significantly reduced in relation either to age or to cognitive impairment. By comparison to vascular dementia, patients with Alzheimer's disease exhibited the highest cortisol concentrations throughout the 24h. The sensitivity of the hypothalamic-pituitary-adrenal axis to the steroid feedback was significantly impaired in old subjects and particularly in the demented ones. The serum DHEAS levels were significantly lower in elderly subjects and even more in demented patients than in young controls. Consequently, a significant increase of the cortisol/DHEAS molar ratio was evident when going from young controls to healthy elderly subjects and to demented patients. In conclusion, the aging process affects many neuroendocrine functions resulting in subtle but clinically relevant consequences; the occurrence of senile dementia seems to play an additive role.

Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates.

The aim of this review was to examine the evidence for age-related changes of the hypothalamic-pituitary-adrenal (HPA) axis in both physiological and pathological aging, on the basis of the many data in the literature, as well as of our personal findings. A statistically significant circadian rhythmicity of serum cortisol was maintained in elderly subjects, even if with a reduced amplitude of the 24 h fluctuations and a trend to an increase of the serum levels in the evening and at night-time, in comparison with young controls. Furthermore, an age-related impairment of HPA sensitivity to steroid feedback was present in elderly people. The occurrence of senile dementia amplified the changes already present in physiological aging. While the cortisol secretion was generally well maintained in aging, the adrenal production of dehydroepiandrosterone and of its sulfate (DHEAS) exhibited an age-related decline. Therefore, the cortisol/DHEAS molar ratio was significantly higher in elderly subjects and even more in demented ones, than in young controls. Due to the opposite effects of cortisol and DHEAS on the brain and particularly on the hippocampal region, the imbalance between glucocorticoids and androgens occurring in physiological and even more in pathological aging, may have adverse effects on the function of this region, whose key role in learning and memory is well known.

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study.

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.

Overproduction of IFN-gamma and TNF-alpha from natural killer (NK) cells is associated with abnormal NK reactivity and cognitive derangement in Alzheimer's disease.

Alterations of natural killer (NK) function can be involved in the neuroimmune mechanism of neurodegeneration in dementia of the Alzheimer's type (DAT). NK cell cytotoxicity (NKCC) and the generation and release of IFN-gamma and TNF-alpha (spontaneous and modulated by IL-2) from pure NK cells (CD 16+, CD 56+, CD 3-) were studied together with circulating IFN-gamma and TNF-alpha levels and cognitive function in 22 old patients with DAT and 15 healthy old subjects. Higher (p < 0.001) IL-2 modulated NKCC (with IL-2 50 U/mL and 100 U/mL) was demonstrated in DAT patients (+35% and +99% from baseline) than in healthy subjects (+6% and +76% from baseline). Increased spontaneous and IL-2-induced release of IFN-gamma and TNF-alpha from NK cells were found in DAT patients compared to healthy subjects (p < 0.001), whereas no difference of serum IFN-gamma and TNF-alpha was demonstrated between DAT and control groups. Significant negative correlations among the spontaneous release of IFN-gamma and TNF-alpha from NK and the decrease of the score of cognitive function (MMSE) were found in patients with DAT. In conclusion, alterations of NKCC control and NK-derived cytokine release in DAT could be involved in the neuroinflammatory mechanism related to the progression of neurodegeneration and dementia.

Variability of interactions between neuroendocrine and immunological functions in physiological aging and dementia of the Alzheimer's type.

A link between neuroendocrine and immunological changes has been suggested in the pathophysiology of dementia of the Alzheimer's type (DAT). Healthy young and old subjects and patients with DAT were recruited to evaluate the chrononeuroendocrine organization of cortisol, GH, and melatonin (MLT) secretions. The study was carried out together with the evaluation of natural killer (NK) cell function: cytotoxic activity (NKCC) and TNF-alpha and IFN-gamma release after exposure to IL-2 (100 U/mL). Moreover, a cerebral morphometric analysis of hippocampus and temporal lobe (MRI) was performed. The activation of hypothalamo-pituitary-adrenal (HPA) axis and the decrease of GH, and MLT nocturnal peaks were associated with normal NKCC and TNF-alpha/IFN-gamma in healthy elderly subjects, whereas in DAT patients the same neuroendocrine changes occurred together with abnormal NKCC (spontaneous and IL-2/IFN-beta-modulated) and with alterations of TNF-alpha/INF-gamma generation from NK. Moreover significant correlations among the increase of NKCC and TNF-alpha and the decrease of cognitive function were found in the DAT group. These correlations were associated with the impairment of nocturnal GH and MLT levels and with the relatively higher serum cortisol concentrations. Moreover, the impairment of cortisol suppression after dexamethasone (1 mg orally at 23:00) was significantly correlated with the increase of spontaneous release of TNF-alpha and with IL-2-modulated NKCC. Finally the imunoneuroendocrine alterations found in DAT were associated with the reduction of cerebral volume in hippocampus and temporal lobes. Taken together these data indicate that the immunoneuroendocrine balance is maintained in physiological aging, whereas NK immune dysregulation in DAT could contribute to altering the neuroendocrine functions and to extend the progression of neurodegeneration and dementia.

Exercise-induced microalbuminuria in patients with active acromegaly: acute effects of slow-release lanreotide, a long-acting somatostatin analog.

Recent clinical studies have demonstrated an increase of urinary albumin excretion (UAE) at rest in acromegalic patients and, on the other hand, a reduced UAE in patients with growth hormone (GH) deficiency. Physical exercise is known to induce abnormal UAE in patients with diabetes, probably unmasking early glomerular alterations. The effect of exercise on UAE in acromegaly is not known. Moreover, the effect of acute but sustained GH inhibition in acromegaly on UAE at rest and after exercise has never been studied. The aim of our study was to evaluate the acute short-term effects of slow-release lanreotide (SR-L), a long-acting somatostatin analog, on UAE and alpha1-microglobulinuria (A-1-M), a marker of renal tubular damage, at rest and after exercise in 7 normotensive patients with active acromegaly and normal renal function (4 males and 3 females; mean age, 53 +/- 3.1 years; body mass index [BMI], 27.3 +/- 1.1 kg/m2) at baseline and 7 and 14 days after SR-L injection (30 mg). Two of the acromegalic patients were microalbuminuric at rest, and in other 3 cases, UAE was in the borderline range (10 to 20 microg/min). At baseline in the acromegalic subjects, we found a significant increase in UAE at rest with respect to 7 normal subjects considered as a control group. GH and insulin-like growth factor-1 (IGF-1) were also reduced compared with baseline 7 and 14 days after SR-L injection (GH, 13.4 +/- 7.3 and 13.61 +/- 7 v 18.5 +/- 9.3 microg/L, P < .05; IGF-1, 230 +/- 53 and 255 +/- 54 v 275 +/- 64 microg/L). Concomitantly, we observed a significant decrease of UAE at rest and after exercise and 7 and 14 days after SR-L injection as compared with baseline values (27.3 +/- 20.5 and 18.2 +/- 13.7 v 35.3 +/- 12.8 microg/min, P < .05; exercise, 48.5 +/- 24.1 and 18.6 +/- 6.8 v68.3 +/- 39.7 microg/min, P < .05). A-1-M always remained in the normal range (< 12 mg/L) both at rest and after exercise. We can thus conclude that in acromegaly, submaximal exercise induces abnormal increases in microalbuminuria. We hypothesize that this phenomenon may be due to the functional glomeruler involvement. SR-L can significantly reduce UAE at rest and after exercise in the short-term in acromegaly, probably via a decrease in circulating GH levels.

Evaluation of the circadian profiles of serum dehydroepiandrosterone (DHEA), cortisol, and cortisol/DHEA molar ratio after a single oral administration of DHEA in elderly subjects.

Aging is associated with a selective decline in circulating levels of dehydroepiandrosterone (DHEA) and its sulfate, with no major changes in cortisol secretion. In young subjects, serum levels of both DHEA and cortisol are regulated according to a circadian rhythm, and an age-related attenuation of DHEA, but not cortisol, circadian rhythmicity has been reported. Several trials have evaluated the effects of DHEA supplementation in elderly subjects, although the results are still controversial. However, no data are available on the 24-hour profile of DHEA circulating levels in elderly subjects with DHEA administration. In the present study, we evaluated the circadian rhythms of DHEA, cortisol, and the cortisol/DHEA molar ratio in old subjects treated with either placebo (old-PL) or a single 50-mg dose of DHEA (old-D), both administered orally at 0700 hours. For each variable, the circadian profiles were compared with those obtained in young control subjects. The group of young subjects displayed a circadian rhythm for both DHEA and cortisol serum concentrations but no rhythm for the cortisol/DHEA molar ratio. In the old-PL group, the circadian rhythm of DHEA was completely abolished, whereas significant rhythms for both cortisol and the cortisol/DHEA molar ratio were observed. Particularly, at each time point, the cortisol/DHEA molar ratio was significantly higher in these subjects versus the young group. In the old-D group, the circadian rhythm of DHEA was completely restored and was comparable to that observed in the young group. Analogous to the observations in young subjects, the profile of the cortisol/DHEA molar ratio in old-D subjects did not display any circadian rhythmicity, the values being almost completely comparable to those observed in young controls. Our data demonstrate that the circadian rhythm of DHEA is totally abolished in elderly subjects. A single 50-mg dose of DHEA administered orally at 0700 hours restores the circadian rhythmicity of serum DHEA and almost completely normalizes the 24-hour profile of the cortisol/DHEA molar ratio in old subjects without affecting the cortisol circadian rhythm.