Luigi Cattin

Hyperleptinemia prevents increased plasma ghrelin concentration during short-term moderate caloric restriction in rats

BACKGROUND & AIMS Ghrelin is an orexigenic hormone secreted by the stomach. Increased plasma ghrelin concentration was reported during diet-induced weight loss in obese humans, suggesting that ghrelin contributes to adaptive increment in appetite associated with caloric restriction. Leptin reduces spontaneous food intake and body weight in rodents. The current study tested the hypothesis that increased plasma leptin prevents the potential increase in plasma ghrelin concentration during moderate caloric restriction in lean rats. METHODS Six-month-old male rats (body weight, 367 +/- 9 grams) were randomly assigned to one of the following treatments (8 rats each) for 1 week: (1) leptin subcutaneous infusion to induce moderate hyperleptinemia and moderate caloric restriction (-26% of ad libitum), (2) vehicle infusion and pair feeding, and (3) vehicle infusion and ad libitum feeding. RESULTS Leptin-treated (-19 +/- 5 grams) and pair-fed (-19 +/- 2) rats lost weight compared with ad libitum-fed rats (-3 +/- 1, P < 0.05). Compared with control (6.8 +/- 0.7 ng/mL), plasma leptin was higher in leptin-treated (18.6 +/- 0.9 ng/mL, P < 0.01) rats and lower in pair-fed rats (4.3 +/- 0.4 ng/mL, P < 0.05). Plasma ghrelin was substantially higher in calorie-restricted than control rats (2505 +/- 132 pg/mL vs. 1790 +/- 134 pg/mL, P < 0.01), and leptin treatment (1625 +/- 117 pg/mL) completely prevented this change. Plasma ghrelin concentration was negatively correlated with body weight changes in calorie-restricted and control (r = -0.75, P < 0.01) but not in leptin-treated rats (P > 0.8). CONCLUSIONS Moderate hyperleptinemia prevents an increase of plasma ghrelin during moderate short-term caloric restriction. Satiety-inducing effects of leptin include suppression of gastric orexigenic signals and disruption of a potential feedback mechanism between body weight changes and plasma ghrelin in lean adult rats.

Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with Type I diabetes mellitus

Aims/hypothesis. We tested the hypothesis that silent coeliac disease is more frequent than expected in both patients with Type I (insulin-dependent) diabetes mellitus and their first-degree relatives. We evaluated how the presence of other autoimmune disorders in diabetic patients and their first-degree relatives is related to silent, unrecognized coeliac disease. Methods. Sera from 491 subjects with Type I diabetes, 824 relatives and 4000 healthy control subjects were screened for anti-endomysial antibodies and all those subjects who tested positive for anti-endomysial antibodies underwent intestinal biopsy. Results. We found that the prevalence of coeliac disease was 5.7 % among the diabetic patients and 1.9 % among the relatives, values significantly higher than those found among the control subjects (p < 0.0001; p < 0.001). The prevalence of autoimmune disorders in diabetic patients with coeliac disease was significantly higher than in subjects with Type I diabetes alone (p < 0.0001). The prevalence of autoimmune disorders in the relatives with coeliac disease was significantly higher than in those who tested negative for anti-endomysial antibodies (p = 0.01). Conclusion/interpretation. This report provides further confirmation of the high prevalence of undiagnosed coeliac disease among diabetic patients and their relatives. This interesting new finding is the increased presence of other autoimmune diseases in these patients, as well as in their relatives with a delayed diagnosis for coeliac disease. Patients newly diagnosed with coeliac disease showed excellent compliance with the gluten-free diet. This should encourage policymakers to consider introducing an easy-to-use screening programme for diabetic patients and their relatives into everyday clinical practice, in order to prevent coeliac-associated symptoms and the onset of additional, more serious auto-immune disorders. [Diabetologia (2001) 44: 151–155]

Polymorphism of the Apolipoprotein E Gene and Early Carotid Atherosclerosis Defined by Ultrasonography in Asymptomatic Adults

Clinical and autoptical studies have suggested a predisposing role of the allele E4 of apolipoprotein E (apoE) in the development of atherosclerosis and cardiovascular disease. To investigate the possible contribution of apoE allele polymorphism to the carotid intima-media thickness (IMT) as assessed by ultrasound, we studied 260 asymptomatic nondiabetic subjects (121 men, 139 women; mean +/- SD age, 53 +/- 7 years), randomly selected from the population register of the inhabitants of Trieste, Italy. B-mode ultrasound was used to quantify the maximum IMT at 12 sites on the near and far wall of the common, bifurcation, and internal carotid arteries. ApoE genotypes were determined from amplified apoE sequences by restriction isotyping. The frequencies of E2, E3, and E4 alleles were 0.073, 0.827, and 0.100, respectively. As expected, subjects with E4 allele had the highest levels of total serum cholesterol and LDL cholesterol, subjects with E2 allele had the lowest levels, and those with E3 genotype had intermediate levels. The echographic measurements of carotid IMT showed increasing values from E2 to E4 carriers. After adjustment for total and LDL cholesterol serum levels, triglycerides, ratio of LDL to HDL cholesterol, age, sex, and body mass index, ANCOVA showed that the common carotid IMT was significantly greater (P = .029) in subjects with E4 allele compared with E3 carriers. Our data confirm the influence of apoE4 on cholesterol levels and clearly show that apoE genotype affects carotid atherosclerosis in its early stages in middle-aged asymptomatic subjects.

Functional Lecithin: Cholesterol Acyltransferase Is Not Required for Efficient Atheroprotection in Humans

Background— Mutations in the LCAT gene cause lecithin:cholesterol acyltransferase (LCAT) deficiency, a very rare metabolic disorder with 2 hypoalphalipoproteinemia syndromes: classic familial LCAT deficiency (Online Mendelian Inheritance in Man No. 245900), characterized by complete lack of enzyme activity, and fish-eye disease (Online Mendelian Inheritance in Man No. 136120), with a partially defective enzyme. Theoretically, hypoalphalipoproteinemia cases with LCAT deficiency should be at increased cardiovascular risk because of high-density lipoprotein deficiency and defective reverse cholesterol transport. Methods and Results— The extent of preclinical atherosclerosis was assessed in 40 carriers of LCAT gene mutations from 13 Italian families and 80 healthy controls by measuring carotid intima-media thickness (IMT). The average and maximum IMT values in the carriers were 0.07 and 0.21 mm smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose–dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT). Finally, no significant difference in carotid IMT was found between carriers of LCAT gene mutations that cause total or partial LCAT deficiency (ie, familial LCAT deficiency or fish-eye disease). Conclusions— Genetically determined low LCAT activity in Italian families is not associated with enhanced preclinical atherosclerosis despite low high-density lipoprotein cholesterol levels. This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk.

Ghrelin Enhances in Vivo Skeletal Muscle But Not Liver AKT Signaling in Rats

Objective: Ghrelin administration can induce fat weight gain and hyperglycemia (potentially through ghrelin‐induced hepatic glucose production), but plasma ghrelin is positively associated with whole‐body insulin sensitivity (mainly reflecting muscle insulin action) being increased in lean individuals or after diet‐induced weight loss and reduced in obesity or after diet‐induced weight gain. To investigate potential mechanisms, we measured in vivo effects of sustained ghrelin administration at a non‐orexigenic dose on skeletal muscle and liver insulin signaling at the AKT level and adipokine expression changes.

Factors associated with cognitive impairment among older Italian inpatients

OBJECTIVE: To examine the association of cognitive impairment with educational, demographic, and nutritional variables in older hospitalized people.

Tolerability and efficacy of combination therapy with simvastatin plus gemfibrozil in type IIb refractory familial combined hyperlipidemia

Abstract Type IIb hyperlipidemia due to familial combined hyperlipidemia (FCH) is a common lipid metabolism disorder associated with a high incidence of coronary heart disease. Simvastatin and gemfibrozil are two drugs commonly used to treat this lipid abnormality. However, monotherapy with these drugs often fails to reduce serum cholesterol and triglycerides to optimal levels. In this study the tolerability and efficacy of combined simvastatin plus gemfibrozil therapy was investigated over 18 months in 20 patients (15 men and five women, ages 42 to 71 years) at high risk for atherosclerosis affected by type IIb FCH. Patients were selected because they did not respond satisfactorily to monotherapy with simvastatin or gemfibrozil, taken for at least 6 months with no side effects, namely laboratory test alterations or subjective complaints. The administration protocol was designed as a three-phase open study. In the first phase (8 weeks) patients were assigned to take 10 mg/day simvastatin plus 600 mg/day gemfibrozil; in the second phase (4 months) variable doses of simvastatin [10 to 20 mg/day, depending on the decrease in low-density lipoprotein (LDL) cholesterol] and gemfibrozil (600 to 1200 mg/day, depending on serum triglyceride values) were prescribed. In the follow-up period (phase 3) optimum therapy was maintained. No patient dropped out of the study, and no side effects were recorded. Serum creatine phosphokinase remained within the normal range, as did other hematochemical tolerability parameters. At the end of the follow-up, total (TC) and LDL cholesterol dropped by 35% (from 334 ± 38 mg/dl to 218 ± 27 mg/dl, P P P P P

Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome.

AIMS The aim of the present study was to evaluate the high-density lipoprotein (HDL) structure and endothelial NO synthase (eNOS) activation capacity in ST-elevation myocardial infarction (STEMI) patients with different acute-phase inflammatory response (APR). METHODS AND RESULTS Forty-five STEMI patients were stratified in quartiles according to the delta CRP level, calculated by subtracting the CRP value at admission from the CRP peak value (APR peak). The HDL structure and HDL capacity to stimulate NO production were evaluated at admission and at APR peak. STEMI patients with a low APR had a completely preserved HDL structure and HDL ability to activate eNOS and promote NO production, which did not change during STEMI. On the contrary, HDL from STEMI patients developing a significant APR had compromised ability to stimulate eNOS and promote NO production, and underwent a significant particle remodelling during STEMI. The defective capacity to stimulate NO production of HDL isolated from STEMI patients with high APR was explained, at least in part, by the reduced PON-1 and S1P content. The HDL ability to promote cell cholesterol efflux through different pathways was preserved in ACS patients independently of the inflammatory response. CONCLUSION The present results extend previous studies reporting an impaired eNOS-activating capacity of HDL from ACS patients, showing that only a subset of patients undergoing STEMI, and in particular those developing an important inflammatory response, have circulating HDL defective in stimulating endothelial eNOS and NO production.

High-Fat Diet with Acyl-Ghrelin Treatment Leads to Weight Gain with Low Inflammation, High Oxidative Capacity and Normal Triglycerides in Rat Muscle

Obesity is associated with muscle lipid accumulation. Experimental models suggest that inflammatory cytokines, low mitochondrial oxidative capacity and paradoxically high insulin signaling activation favor this alteration. The gastric orexigenic hormone acylated ghrelin (A-Ghr) has antiinflammatory effects in vitro and it lowers muscle triglycerides while modulating mitochondrial oxidative capacity in lean rodents. We tested the hypothesis that A-Ghr treatment in high-fat feeding results in a model of weight gain characterized by low muscle inflammation and triglycerides with high muscle mitochondrial oxidative capacity. A-Ghr at a non-orexigenic dose (HFG: twice-daily 200-µg s.c.) or saline (HF) were administered for 4 days to rats fed a high-fat diet for one month. Compared to lean control (C) HF had higher body weight and plasma free fatty acids (FFA), and HFG partially prevented FFA elevation (P<0.05). HFG also had the lowest muscle inflammation (nuclear NFkB, tissue TNF-alpha) with mitochondrial enzyme activities higher than C (P<0.05 vs C, P = NS vs HF). Under these conditions HFG prevented the HF-associated muscle triglyceride accumulation (P<0.05). The above effects were independent of changes in redox state (total-oxidized glutathione, glutathione peroxidase activity) and were not associated with changes in phosphorylation of AKT and selected AKT targets. Ghrelin administration following high-fat feeding results in a novel model of weight gain with low inflammation, high mitochondrial enzyme activities and normalized triglycerides in skeletal muscle. These effects are independent of changes in tissue redox state and insulin signaling, and they suggest a potential positive metabolic impact of ghrelin in fat-induced obesity.

Prolonged Inactivity Up-Regulates Cholesteryl Ester Transfer Protein Independently of Body Fat Changes in Humans

CONTEXT Physical inactivity is associated with insulin resistance and decreased high-density lipoprotein (HDL) cholesterol. Cholesteryl ester transfer protein (CETP) is involved in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low- and low-density lipoproteins. OBJECTIVE We hypothesized that physical inactivity could decrease HDL cholesterol through changes in CETP availability. DESIGN AND PARTICIPANTS Twenty-four healthy, male volunteers (aged 23.1 +/- 0.5 yr) were investigated in eucaloric conditions before and at the end of 35 d of experimental bed rest. MEASURES Changes in body composition were monitored by bioimpedance throughout the study. Before and at the end of the experimental period, plasma insulin and glucose and plasma lipid pattern as well as CETP concentrations were determined. RESULTS Our results demonstrated that during bed rest, fat mass did not change significantly, whereas fat-free mass decreased by 3.9 +/- 0.4% (P < 0.01). The homeostatic model assessment index of insulin resistance significantly (P < 0.001) increased by 47 +/- 11% after bed rest. Bed rest decreased HDL cholesterol by 12 +/- 3% (P < 0.05), increased triglycerides by 51 +/- 10% (P < 0.05), whereas it did not change significantly low-density lipoprotein cholesterol. Plasma CETP concentration increased after bed rest by 27 +/- 9% (P < 0.01). Bed rest-induced changes in CETP concentrations inversely correlated with changes in the ratio between HDL and non-HDL cholesterol (n = 24; R = -0.43; P < 0.05). CONCLUSIONS Physical inactivity decreases HDL cholesterol, at least in part, through CETP up-regulation.