Maria Rosaria Rizzo

A gender--dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity.

Current literature indicates that elevated IL‐6 serum levels are associated with diseases, disability and mortality in the elderly. In this paper, we studied the IL‐6 promoter genetic variability at –174 C/G locus and its effect on IL‐6 serum levels in a total of 700 people from 60 to 110 years of age, including 323 centenarians. We found that the proportion of homozygotes for the G allele at –174 locus decreases in centenarian males, but not in centenarian females. Moreover, we found that, only among males, homozygotes for the G allele at –174 locus have higher IL‐6 serum levels in comparison with carriers of the C allele. On the whole, our data suggest that those individuals who are genetically predisposed to produce high levels of IL‐6 during aging, i.e. –174 locus GG homozygous men, are disadvantaged for longevity.

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.

Oxidative Stress and Advancing Age: Results in Healthy Centenarians

OBJECTIVE: Our study aims at investigating the degree of oxidative stress in centenarians

Relationships Between Daily Acute Glucose Fluctuations and Cognitive Performance Among Aged Type 2 Diabetic Patients

OBJECTIVE The mean amplitude of glycemic excursions (MAGE) is a significant determinant of overall metabolic control as well as increased risk for diabetes complications. Older individuals with type 2 diabetes are more likely to have moderate cognitive deficits and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for cognitive performance in diabetic patients, we evaluated whether the contributions of MAGE to cognitive status in older patients with type 2 diabetes were independent from the main markers of glycemic control, such as sustained chronic hyperglycemia (A1C), postprandial glycemia (PPG), and fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS In 121 older patients with type 2 diabetes, 48-h continuous subcutaneous glucose monitoring (CSGM) were assessed. MAGE and PPG were evaluated during CSGM. The relationship of MAGE to performance on cognitive tests was assessed, with adjustment for age, glycemic control markers, and other determinants of cognitive status. The cognitive tests were a composite score of executive and attention functioning and the Mini Mental Status Examination (MMSE). RESULTS MAGE was significantly correlated with MMSE (r = 0.83; P < 0.001) and with cognition composite score (r = 0.68; P < 0.001). Moreover, MAGE was associated with the MMSE (P < 0.001) and cognition composite score (P < 0.001) independently of age, sex, BMI, waist-to-hip (WHR) ratio, drug intake, physical activity, mean arterial blood pressure, FPG, PPG, and A1C. CONCLUSIONS MAGE during a daily period was associated with an impairment of cognitive functioning independent of A1C, FPG, and PPG. The present data suggest that interventional trials in older patients with type 2 diabetes should target not only A1C, PPG, and FPG but also daily acute glucose swings.

Lowering fatty acids potentiates acute insulin response in first degree relatives of people with Type II diabetes

Summary 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]

Plasma sex hormones are significantly associated with plasma leptin concentration in healthy subjects

In humans a sexual dimorphism of plasma leptin concentration has been demonstrated but its significance remains to be established. Sex hormones may have a role.

Safety of Type 2 Diabetes Treatment With Repaglinide Compared With Glibenclamide in Elderly People: A randomized, open-label, two-period, cross-over trial

The incidence of type 2 diabetes increases with age (1), and elderly people with this disease may be particularly susceptible to hypoglycemia due to long-acting oral antidiabetic drugs (OADs). The American Geriatric Society clinical guidelines on type 2 diabetes treatment in elderly people report that short-acting hypoglycemic agents are preferable to longer-acting agents (chlorpropramide), which are associated with increased risk of hypoglycemia (2). Repaglinide is an insulin secretagogue with a rapid onset and relatively short duration of action (3,4). Several studies have shown repaglinide to be a safe and effective treatment for type 2 diabetes (5–9). However, few data are available on its use in elderly patients and, in particular, on the incidence of hypoglycemic events. The present study assessed the safety of repaglinide versus glibenclamide in this population, in terms of hypoglycemia and adverse events. This was a 24-week, randomized, open-label, two-period, cross-over comparison between mealtime repaglinide and twice-daily glibenclamide. Patients ( n = 90) were aged ≥65 years and had been previously treated with diet or OADs (mean age 74.6 years, HbA1c [A1C] 7.9%). A subgroup of 37 patients aged ≥75 years was evaluated separately. After screening, previous OAD treatment was discontinued and patients were randomized to first receive either repaglinide (Novonorm; …

Low insulin resistance and preserved β-cell function contribute to human longevity but are not associated with TH–INS genes

Tyrosine Hydroxylase (TH) and Insulin (INS) genes lie extremely close in the 11p15.5 chromosomal region. An STR marker of the TH gene had revealed this locus associated with longevity. Thus, it seemed of interest to investigate the association between the TH-STR and INS gene variability (FokI-RFLP) with a phenotypic trait, such as the degree of insulin resistance (IR) and beta-cell function in centenarians (C). We analyzed age-related trajectories of IR and beta-cell function in a large sample (n=466) of individuals whose age ranged from 28 to more than 100 years; furthermore, allele average effects on IR and beta-cell function relevant to TH-STR and INS-FokI polymorphisms were estimated in C. Both IR and beta-cell function increased with advancing age and declined in subjects older than 90 years (p for trend <0.001). C had lower IR (1.5+/-0.7 vs. 3.9+/-1.7, p<0.001) and beta-cell function (26.1+/-8.5 vs. 55.4+/-16, p<0.001) than nC. In nC, but not in C, IR and beta-cell function correlated with the main anthropometric and metabolic confounders. Nevertheless, significant allele average effects by TH-STR and INS-FokI polymorphisms on IR and beta-cell function were not observed in C. In conclusion, C has a lower degree of IR and a preserved beta-cell function in comparison to nC, but the cause of such metabolic differences, which are likely does not lie in this genomic region.

Evidence for Anti-Inflammatory Effects of Combined Administration of Vitamin E and C in Older Persons with Impaired Fasting Glucose: Impact on Insulin Action

Objective: Vitamin E and C given separately improve insulin sensitivity due to an inhibitory effect on oxidative stress and inflammation, however their combined effect on glucose control and inflammation is unknown. To investigate combined effect of Vitamin E and C in elderly with Impaired Fasting Glucose (IFG) on insulin action and substrate oxidation. Design: Controlled-trial administration of Vitamin E (1000 mg/day) and Vitamin C (1000 UI/day) for four weeks. Hyperinsulinemic euglycemic glucose clamp was performed before and following supplementation. Setting: Out-patient clinic. Participants: Thirteen older men with IFG. Main Outcome Parameters: Variations in whole body glucose disposal (WBGD), anti-oxidant, and inflammatory cytokines plasma levels. Results: An increase in plasma Vitamin E (8.3 + 0.8 vs. 64.9 + 2.1 μmol/l; p < 0.001] and C (35.9 + 5.4 vs. 79.4 + 7.4 μmol/l; p < 0.001) was found. Vitamin administration reduced insulin, glucose, lipid, TNF-α and [8-]isoprostane levels. Increase in plasma vitamin E levels correlated with decline in both plasma [8-]isoprostane levels (r = −0.58; p = 0.048) and TNF-α levels (r = − 0.62; p = 0.025), while no correlations were found for Vitamin C. Whole body glucose disposal (WBGD) (22.7 + 0.6 vs. 30.4 + 0.8 mmol × kg-1 × min-1; p = 0.001) and non-oxidative glucose metabolism rose after supplementation. Rise in plasma levels of Vitamin C and E correlated with WBGD. Multivariate linear regression models showed independent associations among the change in Vitamin E and the decline in TNF-α and [8-]isoprostane levels. Conclusions: Combined administration of Vitamin E and C lowered inflammation and improved insulin action through a rise in non-oxidative glucose metabolism.

Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)γ-2 with longevity

Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype. Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long-lived subjects and 250 aged subjects. We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism. In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific.