Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients.

Tocilizumab (TCZ) is used for treating moderate-to-severe Covid-19 pneumonia by targeting interleukin-6 receptors (IL-6Rs) and reducing cytokine release. Yet, in spite of this therapy, patients with vs. patients without diabetes have an adverse disease course. In fact, glucose homoeostasis has influenced the outcomes of diabetes patients with infectious diseases. Of the 475 Covid-19-positive patients admitted to infectious disease departments (University of Bologna, University Vanvitelli of Napoli, San Sebastiano Caserta Hospital) in Italy since 1 March 2020, 31 (39.7%) hyperglycaemic and 47 (60.3%) normoglycaemic patients (blood glucose levels ≥140mg/dL) were retrospectively evaluated at admission and during their hospital stay. Of note, 20 (64%) hyperglycaemic and 11 (23.4%) normoglycaemic patients had diabetes (P<0.01). At admission, hyperglycaemic vs. normoglycaemic patients had fivefold higher IL-6 levels, which persisted even after TCZ administration (P<0.05). Intriguingly, in a risk-adjusted Cox regression analysis, TCZ in hyperglycaemic patients failed to attenuate risk of severe outcomes as it did in normoglycaemic patients (P<0.009). Also, in hyperglycaemic patients, higher IL-6 plasma levels reduced the effects of TCZ, while adding IL-6 levels to the Cox regression model led to loss of significance (P<0.07) of its effects. Moreover, there was evidence that optimal Covid-19 infection management with TCZ is not achieved during hyperglycaemia in both diabetic and non-diabetic patients. These data may be of interest to currently ongoing clinical trials of TCZ effects in Covid-19 patients and of optimal control of glycaemia in this patient subset.

Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study.

AIM: Telemonitoring (TM) is a safe and efficient monitoring system for internal cardioverter defibrillator device (ICD) recipients. TM has been used to track info on the clinical status of heart failure patients treated by ICD and/or cardiac resynchronisation therapy defibrillator (CRT-D). The aim of this study was to investigate the impact of TM on clinical outcomes in a population of CRT-D patients with heart failure. METHODS: In a multicentre, randomised study, patients with chronic heart failure, New York Heart Association (NYHA) functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%) have been identified and screened. RESULTS: One hundred and ninety-one patients have been randomised to receive either a CRT-D with TM or a CRT-D with traditional ambulatory monitoring (control group) and completed the 12-month study follow-up. Primary endpoints were all cause death, cardiac death and hospital admission for heart failure. Secondary endpoints were atrial fibrillation, sustained episodes, non-sustained and self terminated ventricular tachyarrhythmia, sustained ventricular tachycardia, and ventricular fibrillation, ICD shocks and percentage of CRT-D responder patients. Univariate analysis identified the following factors predicting hospitalisation: TM, age, chronic kidney disease, hypercholesterolaemia, LVEF and NYHA class. At multivariate analysis, TM was the only factor predicting heart failure hospitalisation (hazard ratio 0.6, 0.42-0.79, 95% CI, p = 0.002), without affecting overall mortality and cardiac deaths events. CONCLUSIONS: Taken together, our data indicate the importance of TM in predicting heart failure hospitalisation in patients treated with CRT-D.

Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors.

OBJECTIVE: Blood glucose fluctuations have been found to be relevant to the progression of atherosclerosis in patients with type 2 diabetes and to be more detrimental for the development of atherosclerosis than the sustained hyperglycemia. We aim at evaluating the effect of blunted daily acute glucose fluctuations by DPP-IV inhibitors on intima-media thickness (IMT), a surrogate marker for early atherosclerosis. METHODS: Data from a 12-week prospective, randomized, open-label parallel group trial with a blinded-endopoint study on 90 patients with DMT2, assessing the role of Dipeptidyl Peptidase-4 inhibition in lowering oxidative stress and inflammation by reducing daily acute glucose fluctuations (MAGE), were included in the present analysis. RESULTS: Administration of both sitagliptin and vildagliptin treatment resulted in a significant decline in IMT. Indeed, vs baseline data Vildagliptin vs Sitagliptin resulted in a greater IMT reduction. After 3 months therapy changes in IMT significantly correlated with changes in MAGE but not with change in HbA1c in the whole population. Only change in MAGE and LDL plasma levels resulted to be independent predictors of the reduced carotid intima-media thickness after adjusting for conventional cardiovascular risk factors in patients with type 2 diabetes. Significant correlations between change in MAGE, change in IMT and change in fasting and interprandial inflammation score and nitrotyrosine plasma levels were found. CONCLUSION: Reduction of glucose excursion due to DPP-IV inhibitors administration, may prevent atherosclerosis progression in patients with type 2 diabetes probably through the reduction of daily inflammation and oxidative stress.

Poor glycaemic control in type 2 diabetes patients reduces endothelial progenitor cell number by influencing SIRT1 signalling via platelet-activating factor receptor activation.

AIMS/HYPOTHESIS: Downregulation of levels of endothelial progenitor cells (EPCs) during in-vitro short-term exposure to high glucose concentrations relates to reduced activity of silent information regulator 1 (SIRT1) and increased synthesis of platelet-activating factor (PAF). We investigated the possible relationship between PAF and SIRT1 pathways in EPCs during altered glucose homeostasis. METHODS: SIRT1 and PAF receptor (PAF-R) levels were determined by western blot, RT-PCR and confocal laser-scanning microscopy. In-vivo experiments were performed on 48 type 2 diabetic patients (25 with poor glycaemic control and 23 with good glycaemic control) and 20 control individuals. In-vitro experiments with the PAF-R antagonist CV3988 were performed on EPCs isolated from leucocyte-rich buffy coat of healthy human donors. RESULTS: Decreased SIRT1 protein levels were observed in EPCs from type 2 diabetic patients compared with control individuals (p < 0.01). Notably, the SIRT1 level was consistently lower in patients with poor glycaemic control than in those with good glycaemic control (p < 0.01). Diabetic patients also showed an upregulation of PAF-Rs; this response occurred to a greater extent in individuals with poor glycaemic control than in those with good glycaemic control. In-vitro experiments confirmed that EPCs respond to PAF stimulation with decreased SIRT1 protein and SIRT1 mRNA levels. Moreover, reduction of SIRT1 levels and activity were abolished by CV3988. CONCLUSIONS/INTERPRETATION: These findings unveil a link between PAF and SIRT1 pathways in EPCs that contributes to the deleterious effect of hyperglycaemia on the functional properties of EPCs, crucial in diabetes and peripheral vascular complications.

-94 ins/del ATTG NFKB1 gene variant is associated with lower susceptibility to myocardial infarction.

BACKGROUND AND AIMS: An imbalance of Nuclear Factor Kappa B (NFкB) and Inhibitor Kappa B (IкB) is involved in various human diseases including atherogenesis. We aimed to evaluate the relationship between NFKB1 and NFKBIA polymorphism and susceptibility to myocardial infarction (MI). METHODS AND RESULTS: Genotyping was performed for NFKB1 and NFKBIA gene variants in 253 subjects (86 patients affected by myocardial infarction and 167 control subjects). In 40 patients, biopsy specimens were taken from the left ventricle area of presumed ischemia for p50, p65 and IкBα quantification. The allele frequency and genotype distribution of NFKBIA gene polymorphism did not differ between MI and control group while control subjects had a higher D allele frequency of -94 ins/del ATTG NFKB1 polymorphism, compared to the MI group (P<0.001; OR=0.304; 95% CI=0.177-0.522). Subjects carrying the D allele had significantly lower plasma fibrinogen and CRP (C-reactive protein) levels compared to no carriers (P<0.05). Fibrinogen-genotype interaction was found to have a significant effect on susceptibility to myocardial infarction. Myocardial p50 (r=0.627; P=0.012) and p65 (r=0.683; P=0.005) levels significantly correlated with plasma fibrinogen levels while subjects carrying the D allele of the NFкB1 gene variant had lower myocardial p50 (P=0.007) and p65 (P=0.009) levels compared to no carriers. CONCLUSION: -94 ins/del ATTG NFKB1 gene variant may contribute to lower MI susceptibility via the potential reduction of activated NFкB which in turn is related to plasma inflammatory marker reduction.

Leukocytes of exceptionally old persons display ultra-short telomeres.

With a view to understanding the association between leukocyte telomere length and the human lifespan, we performed genome-wide telomere length analyses by the terminal restriction fragment length (TRFL) and single molecule telomere length analysis (STELA) of the X and Y chromosomes in leukocytes of exceptionally old (aged 90-104 yr) and younger (aged 23-74 yr) individuals. We found that the mean TRFL of 82 exceptionally old individuals was within a range projected by age-dependent TRFL attrition of 99 younger individuals. However, compared with the younger individuals, exceptionally old persons exhibited peaking of the TRFL distribution with overrepresentation of ultra-short telomeres. These findings were confirmed by the STELA. Women had longer mean TRFL than men (6.10 vs. 5.86 kb), and exceptionally old women exhibited fewer ultra-short telomeres than exceptionally old men. Our results have implications for gerontological studies of the limitation of lifespan in humans.

Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.

BACKGROUND: Postprandial plasma glucose (PPG) excursion is a significant determinant of overall metabolic control as well as an increased risk for diabetic complications. Older persons with type 2 diabetes mellitus (DM2) are more likely to have moderate cognitive deficits and neurophysiologic and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for tissue/organ damage in diabetics, the authors hypothesized that PPG excursion is associated with a decline in cognitive functioning and that a tighter control of PPG may prevent cognitive decline. METHODS: Two groups of aged diabetic patients were randomly selected to be treated with repaglinide (n = 77) or glibenclamide (n = 79). RESULTS: Coefficient of variation of PPG (CV-PPG) was associated with Mini-Mental State Examination (MMSE) scores (r = -0.3410; p < 0.001) and a composite score of executive and attention functioning (r = -0.3744; p < 0.001) after adjusting for multiple confounders. Both groups showed a significant decline in hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), but only the repaglinide group demonstrated a significant decline of CV-PPG over time. In models investigating the change in cognitive functioning over time, adjusted for HbA1c and CV-FPG, a decline in cognitive functioning was observed only in the glibenclamide group (p < 0.001). After adjusting for CV-PPG, the authors no longer found a decline in executive and attention functioning composite score (p = 0.085) or the MMSE (p = 0.080) with glibenclamide. CONCLUSIONS: Exaggerated postprandial glucose (PPG) excursions are associated with a derangement of both global, executive, and attention functioning. A tighter control of PPG may prevent cognitive decline in older diabetic individuals.

Repaglinide has more beneficial effect on cardiovascular risk factors than glimepiride: data from meal-test study.

Aim our study is to compare the effects of repaglinide vs glimepiride administration on cardiovascular risk factors after meal test. Thus, after 2 weeks washout period, a 3-month randomised, cross-over parallel group trial of repaglinide (1 mg x 2/day) vs glimepiride (2 mg/day) in 14 patients with type 2 diabetes "naive" on diet treatment was made. Both treatments significantly declined plasma glucose, total-cholesterol, LDL-cholesterol, triglycerides, PAI-1, PAP levels and increased HDL-cholesterol. Lowering in plasma PAI-1 and PAP levels was significantly greater in repaglinide group. Furthermore, repaglinide administration resulted in a significant decrease in fasting plasma free fatty acids, fibrinogen, thrombin-antithrombin complex and reaction product of malondialdehyde with thiobarbituric acid (TBARS) levels, in absence of significant difference in fasting plasma insulin levels. Decrease in plasma TBARS levels correlated with the decrease in Plasminogen Activator Inhibitor-1 (r = 0.72; P < 0.003) and free fatty acids concentrations (r = 0.62; P < 0.01). Analysis of the insulin and glucose concentrations throughout the meal test revealed that AUC for glucose (758 +/- 19 vs 780 +/- 28 mg/Lxmin; P = 0.02) was significantly lower after repaglinide than glimepiride administration despite similar AUC for insulin (2327 +/- 269 vs 2148 +/- 292 mU/Lxmin; P = 0.105). At time 120' of meal test, repaglinide vs glimepiride administration was associated with a significant decline in plasma triglycerides, free fatty acids, fibrinogen, Plasminogen Activator Inhibitor-1, plasmin-alpha(2)-antiplasmin complex, thrombin-antithrombin complex, TBARS levels and increase in plasma HDL-cholesterol levels. In repaglinide group a negative correlation between insulin secretion during 1st phase of meal-test and plasma TBARS levels (r = -0.55; P < 0.03) at time 120' was found. Such correlation was lost after adjusting for changes in postprandial hyperglycaemia (r = -0.48; P < 0.09). In conclusion, our results support the hypothesis that repaglinide is more efficient than glimepiride on controlling for postprandial glucose excursion and may have beneficial effect on reducing cardiovascular risk factors.

Is dermolipectomy effective in improving insulin action and lowering inflammatory markers in obese women?

OBJECTIVE: Obesity is a major risk factor for coronary heart disease, and surgical treatment of obese patients as part of a multidisciplinary approach seems to provide faster results than diet therapy. The aim of this study was to evaluate the effect of dermolipectomy on insulin action and inflammatory markers in 20 obese women. PATIENTS: At baseline and 40 days after dermolipectomy, 20 obese women underwent indirect calorimetry and hyperinsulinaemic glucose clamp. Twenty obese nonsmoking females (age range 25--40 years) volunteered for the study. All subjects had a stable body weight for 2 months before the study. No patient was affected by cardiovascular and/or pulmonary disease, type 2 diabetes, thyroid dysfunction, acute or chronic hepatitis, renal insufficiency or cancer. No patients was receiving any drug therapy and all measurements were made during the follicular phase of the menstrual cycle. RESULTS: At baseline, fat mass (FM) correlated with plasma triglycerides (r=.58, P<0.009), free fatty acids (FFA) (r=0.73, P<0.001), insulin (r=0.70, P<0.002), leptin (r=0.55, P<0.01), adiponectin (r=-0.32, P<0.02) and resistin (r=0.31, P<0.01), insulin sensitivity (IS) (r=-0.59, P<0.005) and respiratory quotient (Rq) (r=0.62, P<0.002). With regard to inflammatory markers, FM was significantly correlated with plasma interleukin (IL)-6 (r=0.71, P<0.001), IL-10 (r=-0.67, P<0.002), tumour necrosis factor-alpha (TNF-alpha) (r=0.78, P<0.001) and soluble IL-6 receptor (sIL-6r) (r=-0.65, P<0.003). Dermolipectomy resulted in a significant decline in total FM of 2.3+/- 0.2 kg. A significant decline in BMI was also observed (30.0+/- 0.08 vs. 31.1+/- 0.7 kg/m(2)). After 40 days a significant decline in plasma resistin (P<0.001) and inflammatory markers and an increase in plasma adiponectin (P<0.03) were observed. Those metabolic changes were accompanied by a significant improvement in insulin-mediated glucose uptake (P<0.001), substrate oxidation and degree of inflammation. Changes in FM following dermolipectomy correlated with the changes in IS (P<0.01), substrate oxidation and FFA (P<0.001). CONCLUSIONS: In obese patients, dermolipectomy is associated with weight lost, improved glucose handling and lower inflammatory markers.

Role of interaction between variants in the PPARG and interleukin-6 genes on obesity related metabolic risk factors.

The combined effect of Peroxisome proliferator-activated receptor gamma (PPARG) Pro/Ala and interleukin-6 G174C gene variants, was evaluated in 429 Caucasian subjects in order to determine whether subjects carrying both variants were at different risk for obesity. In particular, the combined contribution of these two variants (both independent and interaction effects) to the total variation of obesity-related factors was estimated. All subjects were genotyped for codon 12 Pro/Ala locus variability and for the interleukin-6-174 C/G promoter polymorphism. Subjects with the Ala variant had significantly lower BMI, insulin resistance, triglyceride levels than those without. Furthermore, subjects with Ala variant had significantly lower IL-6 levels (0.88 +/- 0.9 vs 1.61 +/- 2.25 pg/ml; p = 0.041). In contrast, the IL6-C variant was significantly associated with lower plasma IL-6 and with lower total cholesterol levels but was not significantly associated with any other obesity risk factors. Indeed, subjects carrying both PPARG and IL-6 gene variants, had a clearly more favourable profile of obesity related risk factors than subjects with one variant, having Ala+/C+ carriers lower BMI (22.8 +/- 2.3 vs 24.14 +/- 1.9; f = 5.31; p < 0.005), insulin resistance (1.49 +/- 0.70 vs 2.13 +/- 0.92; f = 4.342; p = 0.038) and triglyceride levels (79.15 +/- 32.9 vs 98 +/- 6.73 mg/dl; f = 3.120; p < 0.005). These findings suggest that the effect of the two genetic variants on 'obesity related' factors is additive.

Resting metabolic rate and respiratory quotient in human longevity.

Significant changes in body composition, body fat distribution, and resting metabolic rate (RMR) occur with aging. Interestingly, studies on human longevity pointed out that long-lived subjects are less prone to the anthropometrics and metabolic derangement normally observed in the elderly. Indeed, the relationship between energy expenditure and longevity has been poorly investigated. Thus, energy expenditure parameters of 28 long-lived subjects were assessed and compared with those of 26 adults and 27 younger elderly. All subjects enrolled were female. In the whole population, RMR was negatively correlated with age (P < 0.05), waist to hip ratio (WHR) (P < 0.001), fat mass (P < 0.001), and percent body fat (P < 0.03); respiratory quotient (Rq) displayed an age-related decrease (P < 0.001) and was negatively correlated with WHR (P < 0.001) and fat-free mass (FFM) (P < 0.006). In multivariate analysis, both RMR and Rq had FFM, WHR, but not body mass index as significant and independent determinants. Splitting the whole study group into subgroups according to age, long-lived subjects had oxygen volume, carbon dioxide volume, and Rq significantly higher than aged subjects but lower than adult subjects. In addition, long-lived subjects had total volume of expired air and RMR greater than aged subjects but not different from ones found in adults. In long-lived subjects, Rq was negatively correlated with percent body fat (P < 0.02), plasma glucose (P < 0.05), free fatty acid (P < 0.05), and WHR (P < 0.05), whereas RMR was negatively correlated with WHR (P < 0.05). No significant associations of RMR and Rq with FFM were found. In conclusion, our data demonstrate that human longevity seems protected toward an age-related decline. It is likely that the lack of the anthropometrics derangement may preserve long-lived subjects from the age-related decrease in energy metabolism.

Repaglinide is more efficient than glimepiride on insulin secretion and post-prandial glucose excursions in patients with type 2 diabetes. A short term study.

OBJECTIVES: To compare the effect of Repaglinide vs Glimepiride on glucose- and meal-induced insulin secretion and on meal-test induced postprandial glucose excursions. METHODS: After 2 weeks washout period, a 3-Month randomised, cross-over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with type 2 diabetes "naive" in diet treatment was made. RESULTS: Both R and G significantly but similarly lowered fasting glucose levels and improved fasting plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/- 34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120'; p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/- 0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G administration. In the meal test, R therapy produced a more rapId induction of insulin secretion during the first part. In fact, the mean rise in insulin secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R). Consequently, glucose spike at 60 min was higher in G group compared to glucose spike at 45 min in R group (p=0.002). CONCLUSIONS: Our study demonstrates that R is more efficient that G on improving glucose- and meal- induced insulin secretion as well as on controlling for postprandial glucose excursion.

Cardiovascular risk in type 2 diabetics and pharmacological regulation of mealtime glucose excursions.

In type 2 diabetic patients mealtime glucose fluctuations are important determinants of overall glucose control and overall risk of diabetes cardiovascular complications. In fact, acute elevation of plasma glucose concentrations trigger an array of tissue response that may contribute to development of such vascular complications since it may result in a thrombophilic condition, causes endothelial dysfunction (possibly through a reduction of nitric oxide availability) and is responsible for non-enzymatic glycation and production of free- radicals with ensuing oxidative stress. To keep post-prandial glucose with narrow range, metiglinide analogues drugs have been developed. In particular, repaglinide and nateglinide seem the most useful ones. In fact, both drugs improve 1(st) phase insulin release but they do not affect the total daily amount of insulin released by the pancreas. Due to the mechanism of action and to pharmacokinetic properties, repaglinide and nateglinide allow diabetic patients to get a more tight metabolic glucose control with a contemporary reduction in the cases of severe hypoglycaemia. In conclusions, repaglinide and nateglinide are new and powerful pharmacological tools not only for achieving a better metabolic glucose control but also for preventing the development of diabetes-related cardiovascular complications.

Low insulin resistance and preserved beta-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.

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.

Role of free fatty acids on cardiac autonomic nervous system in noninsulin-dependent diabetic patients: effects of metabolic control.

Decreased heart rate variability (HRV) is a risk factor for cardiovascular mortality. Elevated plasma free fatty acid (FFA) levels decrease HRV in healthy subjects. Thus, we investigated the effect of changes in plasma FFA levels on HRV, in non-insulin-dependent diabetes (NIDDM) patients. Thirty NIDDM patients free from diabetic neuropathy volunteered for a study made by two phases. In study A, changes in HRV along a 10% lipid emulsion infusion + heparin (n = 15) or saline infusion (control study; n = 15) were investigated. In study B, all patients (n = 30) underwent further determination of HRV after 3 months of improved metabolic control achieved by intensified insulin treatment. In study A, lipid emulsion infusion increased plasma FFA (P < 0.001) and catecholamine concentrations (P < 0.005), mean arterial blood pressure (P < 0.005), low frequency/high frequency (LF/HF) ratio (P < 0.001). Delta plasma FFA levels correlated with delta LF/HF ratio (r = 0.57; P < 0.02). Along with saline infusion, metabolic and cardiovascular parameters remained unchanged throughout the test. In study B, improved metabolic control lowered fasting plasma glucose (P < 0.005), FFA (P < 0.001), norepinephrine (P < 0.02), epinephrine (P < 0.04), and glycosylated hemoglobin levels (P < 0.001), mean arterial blood pressure(P < 0.05), and LF/HF ratio (P < 0.001). Again percent decline in plasma FFA correlated with the percent change in LF/HF ratio (r = 0.72; P < 0.001). In a multivariate analysis, percent changes in LF/HF ratio were associated with percent changes in plasma FFA independently of gender and percent changes in body mass index, waist/hip ratio, plasma norepinephrine, epinephrine, glycosylated hemoglobin, and daily insulin therapy. Our study demonstrates that changes in plasma FFA levels may have a parallel effect on cardiac sympathetic/parasympathetic nervous system balance in NIDDM patients.

Age-related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians.

It is widely known that advancing age is associated with impaired glucose handling. A unifying hypothesis explaining the relationship between aging and insulin resistance might encompass four main pathways, namely: (a) anthropometric changes (relative and absolute increase in body fat combined with a decline in fat free mass) which could be the anatomic substrate for explaining the reduction in active metabolic tissue; (b) environmental causes, mainly diet style and physical activity; (c) neuro-hormonal variations [decline in plasma dehydroepandrosterone sulphate (DHEAS) and IGF-1]; and finally (d) the rise in oxidative stress. Indeed previous studies have also investigated the occurrence and the degree of insulin resistance in healthy centenarians. Such data demonstrated that age-related insulin resistance is not an obligatory finding in the elderly and that healthy centenarians have a preserved insulin action compared to aged subjects. Why insulin action is preserved in centenarians is still not known. Nevertheless, a possible approach to the question is to outline the centenarians' anthropometric, endocrine and metabolic characteristics in order to design a clinical picture of such metabolic "successful aging". According to the remodeling theory of age, the preserved insulin action in centenarians might be the net result of the continuous adaptation of the body to the deleterious changes that occur over time. Nevertheless, only future longitudinal studies specifically designed to investigate the relationship between extreme old age and degree of insulin sensitivity will provide a conclusive answer with regard to the pathophysiology of adaptive metabolic changes occurring in the elderly.

Elevated plasma fatty acid concentrations stimulate the cardiac autonomic nervous system in healthy subjects.

BACKGROUND: Fatty acids have been shown to stimulate the sympathetic nervous system in rats. Power spectral analysis of heart rate variability (HRV) is a safe and useful tool with which to evaluate cardiac autonomic nervous system (ANS) activity. Whether changes in plasma fatty acid concentrations affect the sympathetic nervous system or HRV in humans is unknown. OBJECTIVE: We investigated the possible changes in HRV after a significant increase in plasma fatty acid concentration. DESIGN: Subjects were randomly assigned to receive an infusion of lipid emulsion (10% triacylglycerol emulsion for 180 min) + heparin (a bolus of 200 U followed by 0.2 U*min(-)(1)*kg body wt(-)(1); n = 20) or 0.9% NaCl (for 180 min; n = 10). RESULTS: Lipid emulsion + heparin infusion was associated with a rise in plasma epinephrine and norepinephrine concentrations. The rise in plasma fatty acid concentration was associated with a significant decline in the RR interval (P: < 0.03) and in total power (P: < 0.03). Analysis of the different components of HRV showed that lipid emulsion + heparin infusion stimulated low- frequency (LF) components (P: < 0.03 at the second hour and P: < 0. 01 at the third hour) and inhibited high-frequency (HF) components (P: < 0.03 at the second and third hours). Consequently, the LF-HF ratio was significantly stimulated (P: < 0.03 at the second hour and P: < 0.01 at the third hour). Such results persisted, although attenuated, when the study was repeated in association with a propranolol infusion (n = 8). CONCLUSION: Elevated plasma fatty acid concentrations may stimulate cardiac autonomic nervous system activity.