Antonio Gambardella

Advancing age and insulin resistance: role of plasma tumor necrosis factor-α

In 70 healthy subjects with a large age range, the relationships between plasma tumor necrosis factor-alpha (TNF-alpha) and body composition, insulin action, and substrate oxidation were investigated. In the cross-sectional study (n = 70), advancing age correlated with plasma TNF-alpha concentration (r = 0.64, P < 0.001) and whole body glucose disposal (WBGD; r= -0.38, P < 0.01). The correlation between plasma TNF-alpha and age was independent of sex and body fat (BF; r = 0.31, P < 0.01). Independent of age and sex, a significant relationship between plasma TNF-alpha and leptin concentration (r = 0.29, P < 0.02) was also found. After control for age, sex, BF, and waist-to-hip ratio (WHR), plasma TNF-alpha was still correlated with WBGD (r = -0.33, P < 0.007). Further correction for plasma free fatty acid (FFA) concentration made the latter correlation no more significant. In a multivariate analysis, a model made by age, sex, BF, fat- free mass, WHR, and plasma TNF-alpha concentrations explained 69% of WBGD variability with age (P < 0.009), BF (P < 0.006), fat-free mass (P < 0.005), and plasma TNF-alpha (P < 0.05) significantly and independently associated with WBGD. In the longitudinal study, made with subjects at the highest tertiles of plasma TNF-alpha concentration (n = 50), plasma TNF-alpha concentration predicted a decline in WBGD independent of age, sex, BF, WHR [relative risk (RR) = 2.0; 95% confidence intervals (CI) = 1.2-2.4]. After further adjustment for plasma fasting FFA concentration, the predictive role of fasting plasma TNF-alpha concentration on WBGD (RR = 1.2; CI = 0.8-1.5) was no more significant. In conclusion, our study demonstrates that plasma TNF-alpha concentration is significantly associated with advancing age and that it predicts the impairment in insulin action with advancing age.

Total-body and myocardial substrate oxidation in congestive heart failure

Congestive heart failure is a condition associated with increased plasma norepinephrine levels, which have been demonstrated to impair glucose handling. In the present study, 10 patients suffering from congestive heart failure and 10 healthy age- and body mass index-matched subjects were submitted to a hyperinsulinemic (insulin infusion rate, 0.5 mU/kg.min-1) glucose clamp, while simultaneous D-3H-glucose infusion and indirect calorimetry allowed for determination of glucose turnover parameters and substrate oxidation, respectively. On a separate day, basal local (myocardial) indirect calorimetry was also performed. Our data demonstrate that in congestive heart failure, fasting myocardial glucose oxidation (Gox) was inhibited with a simultaneous increase in lipid oxidation (Lox). In our patients, a significant decrease in total-body insulin-stimulated glucose metabolism (31.0 +/- 0.5 v 20.3 +/- 0.4 mumol/kg.min-1, P < .01) and nonoxidative glucose metabolism (18.9 +/- 1.1 v 11.0 +/- 0.5 mumol/kg.min-1, P < .05) was also found. Such latter changes were also associated with a simultaneous overdrive of Lox (0.4 +/- 0.2 v 1.9 +/- 0.2 mumol/kg.min-1, P < .02) that was correlated with an enhanced availability of plasma free fatty acids (FFAs).

Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectal carcinoma : Final results of the southern italy cooperative oncology group trial 0108

In patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression‐free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5‐fluorouracil/leucovorin (5‐FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5‐FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5‐FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5‐FU/LV in combination with oxaliplatin, especially in older patients.

Glutathione Infusion Potentiates Glucose-Induced Insulin Secretion in Aged Patients With Impaired Glucose Tolerance

Objective –To evaluate the effect of glutathione infusion on β-cell response to glucose in elderly people with impaired glucose tolerance (IGT). Research Desigh and Methods –Ten patients with normal glucose tol-erance and 10 patients with IGT were matched for age (mean ± SE, 72.1 ± 2.8 vs. 71.0 ± 3.4 yr), body mass index (23.1 ± 1.1 vs. 22 ± 2.1 kg/m2), and sex (6/4 vs. 5/5, men/women) underwent glutathione infusion (10 mg/min) under basal conditions and during 75-g oral glucose tolerance tests and intravenous glucose tolerance tests (0.33 g.kg body wt−1.3 min−1). Patients with IGT were also submitted to euglycemic-hyperinsulemic and hyperglycemic glucose clamps. Results –In subjects with normal glucose tolerance, glutathione infusion failed to affect β-cell response to glucose. In contrast, glutathione significantly potentiated glucose-induced insulin secretion in patients with IGT. Furthermore, in the latter group studied by hyperglycemic clamps, glutathione infusion significantly potentiated the beta-cell response to glucose when plasma glucose levels varied between 10 and 15 mM. This effect disappeared at plasma glucose levels <15 mM. No effect of glutathione on insulin clearance and action was observed. Conclusios –Glutathione infusion enhances insulin secretion in elderly people with IGT.

Metabolic aspects of the extreme longevity

Starting from young to very old subjects, aging is associated with a progressive remodeling. Such an age-dependent remodeling process mainly affects anthropometrics, endocrine and thus, also metabolic factors. Interestingly, it occurs in some individuals successfully, while in others unsuccessfully. Centenarians in good health conditions are a very selected group of subjects representing an exceptional condition. Why the centenarians reach the extreme human life span is still unknown. Thus, in this article we will review the best known causes of age-related insulin resistance, outline the main metabolic differences between aged subjects and healthy centenarians, underline the clinical relevance of insulin resistance in the elderly and finally, we will try to propose a unifying hypothesis for explaining the development of insulin resistance with aging.

Mean arterial blood pressure and serum levels of the molar ratio of insulin-like growth factor-1 to its binding protein-3 in healthy centenarians.

OBJECTIVE Healthy centenarians have a greater molar ratio of plasma insulin-like growth factor-1 to insulin-like growth factor binding protein-3 than that of aged subjects. We investigated the question of whether differences in mean arterial pressure and in this plasma ratio were related in healthy centenarians. SUBJECTS AND METHODS We studied 52 subjects in total, 30 aged subjects (70-99 years) and 22 healthy centenarians (> 100 years) to determine differences in mean arterial pressure, endothelial function and intracellular cation levels. RESULTS In the healthy centenarians, the molar ratio of fasting plasma insulin-like growth factor-1 to its binding protein-3 was significantly correlated with mean arterial pressure (r = -0.66, P < 0.001). Baseline (19.3 +/- 1.5 versus 27.6 +/- 2.2 mumol/l, P < 0.05) and L-arginine-stimulated percentage increases in the plasma total nitrate: nitrite ratio (67 +/- 3.4 versus 48 +/- 4.5%, P < 0.03) were greater in the healthy centenarians than in the aged subjects. An L-arginine bolus elicited an increase in forearm blood flow which was correlated with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.79, P < 0.001) and with the fasting erythrocyte magnesium concentration (r = 0.80, P < 0.001) in healthy centenarians. Both correlations remained significant (P < 0.01) after adjustment for sex, body mass index and the waist: hip ratio. Moreover, the fasting plasma molar ratio of insulin-like growth factor-1 to its binding protein-3 was correlated with the percentage increase in forearm blood flow (r = 0.59, P < 0.005) and with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.54, P < 0.009) in healthy centenarians. The centenarians had higher baseline total erythrocyte magnesium and lower calcium concentrations than the aged subjects. The addition of insulin growth factor-1 to the incubation medium increased the total intracellular erythrocyte magnesium content and decreased the calcium content in both groups of subjects. Nevertheless, the percentage increase in total erythrocyte magnesium (33 +/- 3.8 versus 12 +/- 3.4%, P < 0.03) and decline in intracellular calcium (17 +/- 2.8 versus 8 +/- 3.1%, P < 0.02) concentrations were greater in the healthy centenarians than the aged subjects. CONCLUSION In healthy centenarians, insulin-like growth factor-1 may preserve endothelial function and modulate the intracellular cation content, thus contributing to a lower mean arterial pressure than that in aged subjects.

Screening of depressive symptoms in young-old hemodialysis patients: Relationship between beck depression inventory and 15-item geriatric depression scale

Aims: We studied the relationship between the Beck Depression Inventory (BDI) and the 15-item Geriatric Depression Scale (GDS-15) in young–old hemodialysis and hospitalized patients in order to evaluate the possible usefulness of GDS-15 in hemodialysis patients. Methods: Thirty-one hospitalized and 31 young–old hemodialysis patients aged 65–74 (young–old) were enrolled in the study. Comprehensive geriatric assessment (Mini Mental State Examination (MMSE), BDI, GDS-15, Cumulative Illness Rating Scale (CIRS) and Activities of Daily Living (ADL)) was made for all patients. The internal consistency between BDI and GDS-15 was evaluated with Cronbach’s α coefficient. Sensitivity, specificity and receiver operating characteristic (ROC) curves for GDS-15 were determined using BDI as the standard. Results: In the hospitalized group, the prevalence of depressive symptoms, as evaluated by BDI (≧14) and GDS-15 (≧6), were 29 and 32%, respectively. In the hemodialysis group, the prevalence of depressive symptoms, as evaluated by BDI and GDS-15, were 61 and 58%, respectively. A significantly positive correlation between the BDI and GDS-15 was found in hospitalized (r = 0.808; p < 0.001), hemodialysis (r = 0.692; p < 0.001) and both patient groups together (r = 0.777; p < 0.001). The area under the ROC curve was 0.99 in the hospitalized and 0.95 in the hemodialysis groups. The ROC curves indicate a best effectiveness cutoff point (balancing sensitivity and specificity) of ≧6 for GDS-15 compared to BDI. Conclusions: The GDS-15 could be a useful instrument for evaluating depressive symptoms in young–old hemodialysis patients.

Low-Dose Iloprost Infusion Improves Insulin Action in Aged Healthy Subjects and NIDDM Patients

OBJECTIVE To investigate the effect of iloprost infusion on insulin action. RESEARCH DESIGN AND METHODS Thirteen healthy subjects and 13 non-insulin-dependent diabetes mellitus (NIDDM) patients matched for age (68.2 ± 0.5 vs. 67.9 ± 0.5 years, NS), gender ratio (7 men:6 women vs. 6 men:7 women), body weight, body fat distribution, arterial blood pressure, and plasma triglycéride levels (1.89 ± 0.09 vs. 1.87 ± 0.08 mmol/l, NS) were studied. In eight healthy subjects and eight NIDDM patients, we studied insulin action by euglycemic glucose clamp (insulin infusion rate 2 mU · kg−1 · min−1) along with saline and iloprost delivery (0.7 ng · kg−1 · min−1). In the other five subjects of each group, forearm blood flow and insulin-mediated glucose uptake during saline and iloprost infusion (0.7 ng · kg−1 · min1) were investigated. RESULTS Iloprost infusion improved insulin-stimulated whole-body glucose uptake and oxidative and nonoxidative glucose metabolism in both study groups. Forearm blood flow under basal conditions and with insulin infusion (2 mU · kg−1 · min−1) did not show any significant difference from that during saline and iloprost infusion (0.7 ng · kg−1 · min−1) in healthy subjects and diabetic patients. CONCLUSIONS Iloprost infusion improves insulin action in healthy subjects and NIDDM patients.

A hyaluronic acid‐based compound inhibits fibroblast senescence induced by oxidative stress in vitro and prevents oral mucositis in vivo

Virtually all patients receiving radio‐ and chemotherapy for cancer develop oral mucositis, a severe and highly debilitating condition. The onset of mucositis is thought to involve the production of reactive oxygen species (ROS) in the submucosa. Here we investigated a possible protective effect of a commercial formulation of hyaluronic acid (HA) enriched with amino acids (Mucosamin®) against the damage induced by oxidative stress both in vitro and in vivo. Transient exposure of normal human oral fibroblasts to hydrogen peroxide (H2O2) led to irreversible senescence, as demonstrated by sustained increase in the levels of p16INK4A and SA‐βGal. Conditioned media from senescent fibroblasts induced detrimental effects on keratinocytes, as shown by reduced metabolic activity and migration capability. Pre‐treatment with Mucosamin® prevented H2O2‐induced, but not TGF‐β‐induced, fibroblast senescence with a concomitant reduction of fibroblast‐induced loss of keratinocyte vitality and functional activity. Finally, data from a case‐series of patients undergoing radio/chemotherapy strongly suggested that prophylactic use of the hyaluronic acid‐based compound in the form of a spray may be effective in preventing the onset of oral mucositis. J. Cell. Physiol. 230: 1421–1429, 2015.

Alexithymia and cancer-related fatigue: a controlled cross-sectional study.

AIMS AND BACKGROUND The study aims to investigate the alexithymia construct in patients with a recent or longtime diagnosis of cancer as well as in healthy people, and whether alexithymia and fatigue are linked in the mentioned groups. METHODS A first group, diagnosed less than 3 months previously (n = 63), and a second group whose cancer diagnosis dated back more than 30 months (n = 53), matched for sex, age, educational level and cancer site were assessed. Matched healthy controls (n = 50) were also evaluated. Alexithymia was assessed with the Toronto Alexithymia Scale-20, while fatigue was assessed with the Brief Fatigue Inventory. RESULTS Alexithymia scores were higher in the recently diagnosed group than in the group with a longtime cancer diagnosis (t = 2.18, P < 0.05). Both groups had higher scores than controls (t = 4.3, P < 0.001; t = 2.01, P < 0.05). Alexithymic subjects were 45.6% in the recently diagnosed and 21.4% in the longtime diagnosed group (Chi(2) = 6.3, P < 0.05) and 18% in controls. Fatigue was more severe in patients with a longtime diagnosis compared with recently diagnosed patients (t = 7.079, P = 0.000). A weak but significant association between fatigue and alexithymia was found in recently diagnosed patients (r = 0.27.2; P < 0.05). CONCLUSIONS Our study confirms that alexithymia scores are higher in cancer patients than in controls. The study suggests that alexithymia could be considered a dynamic reaction to illness in recently diagnosed patients, declining during subsequent phases. High fatigue rates in patients with a longtime diagnosis of cancer underline the role of the long course of illness in the perception of fatigue. The association between fatigue and alexithymia was weak in the recently diagnosed group and not significant in patients with a longtime diagnosis, in whom fatigue was an important complaint.