Dimitrios N. Kiortsis

Increased plasma levels of visfatin/pre-B cell colony-enhancing factor in obese and overweight patients with metabolic syndrome.

Background: Visfatin [pre-B cell colony-enhancing factor (PBEF)] is a cytokine highly expressed in visceral fat that exhibits insulin-mimetic properties. However, its role in insulin-resistant states, such as in metabolic syndrome (MetS), remains largely unknown. Objective: To investigate the possible differences of plasma visfatin levels between obese and overweight subjects with and without MetS. Design and patients: Plasma visfatin concentrations were measured with enzyme-linked immunosorbent assay (ELISA) in 28 overweight and obese [body mass index (BMI)>28 kg/m2] subjects with Mets and 28 age- and sex-matched overweight and obese (BMI>28 kg/m2) individuals without MetS (control group). Results: Patients with MetS exhibited significantly elevated waist circumference (WCR) values, higher blood pressure readings, higher fasting glucose and triglyceride concentrations as well as lower levels of HDL cholesterol (HDL-C) compared with controls. Total and LDL cholesterol (LDL-C) concentrations did not differ significantly between the two groups. Plasma visfatin concentrations were significantly higher in subjects with MetS compared with controls [27 (16–65) ng/ml vs 19 (10–47) ng/ml, p<0.05]. The same results were observed even after adjustment for age, sex and BMI. Plasma visfatin levels were positively correlated with age (r=0.32, p<0.05), WCR (r=0.31, p<0.05), triglyceride (r=0.59, p<0.01) and glucose (r=0.33, p<0.05) levels and were negatively correlated with HDL-C levels (r=−0.38, p<0.05). Multiple linear regression analysis revealed similar results. Conclusion: Plasma visfatin levels are increased in overweight and obese subjects with MetS compared with those individuals who do not fulfil the criteria for the diagnosis of MetS.

A review of the metabolic effects of sibutramine.

ABSTRACT Background: Obesity is associated with an increased incidence of diabetes, hypertension, dyslipidaemia and coronary artery disease. Current management strategies of obesity include lifestyle interventions and pharmacotherapy. Sibutramine is a drug with established efficacy in weight reduction and maintenance of weight loss. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss. Objective: To review the metabolic effects associated with sibutramine use. Methods: Relevant articles were identified through a Medline search (up to December 2004). Results: Weight loss with sibutramine treatment is associated with improved insulin sensitivity and a fall in glycosylated haemoglobin levels in type 2 diabetic patients. In most trials sibutramine exerted favourable effects on lipids, especially on high density lipoprotein (HDL) cholesterol and triglycerides, as well as on the total:HDL cholesterol ratio. Sibutramine also lowers serum uric acid concentrations. Furthermore, this drug seems to favourably influence adipocytokines; it reduces serum leptin and resistin levels and increases adiponectin levels. Sibutramine also exerts a beneficial effect on hyperandrogenaemia in obese women with polycystic ovary syndrome. Preliminary findings also suggest that weight loss following treatment with sibutramine is useful in patients with non-alcoholic fatty liver disease (NAFLD). Conclusion: Weight loss following sibutramine administration is associated with several favourable metabolic effects.

Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study

ABSTRACT Background: Obesity is becoming increasingly common worldwide and is strongly associated with the metabolic syndrome (MetS). MetS is considered to be a cluster of risk factors that increase the risk of vascular events. Objective: In an open-label randomised study (the FenOrli study) we assessed the effect of orlistat and fenofibrate treatment, alone or in combination on reversing the diagnosis of the MetS (primary end-point) as well as on anthropometric and metabolic parameters (secondary end-points) in overweight and obese patients with MetS but no diabetes. Methods: Overweight and obese patients (N = 89, body mass index (BMI) > 28 kg/m2) with MetS [as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria] participated in the study. Patients were prescribed a low-calorie low-fat diet and were randomly allocated to receive orlistat 120 mg three times a day (tid) (O group), micronised fenofibrate 200 mg/day (F group), or orlistat 120 mg tid plus micronised fenofibrate 200 mg/day (OF group). Body weight, BMI, waist circumference, blood pressure, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL‐C), high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, triglyceride, creatinine (SCr) and uric acid (SUA) levels, as well as homeostasis model assessment (HOMA) index and liver enzyme activities were measured at baseline and after 3 months of treatment. Results: Of the 89 patients enrolled, three (one in each group) dropped out during the study due to side effects. After the 3‐month treatment period, 43.5% of patients in the O group, 47.6% in the F group and 50% in the OF group no longer met the MetS diagnostic criteria (primary end-point, p < 0.0001 vs. baseline in all treatment groups). No significant difference in the primary end-point was observed between the three treatment groups. Significant reductions in body weight, BMI, waist circumference, blood pressure, TC, LDL‐C, non-HDL‐C, triglyceride and SUA levels, as well as gamma-glutamyl transpeptidase activity and HOMA index were observed in all treatment groups. In the OF group a greater decrease in TC (–26%) and LDL‐C (–30%) was observed compared with that in the O and F groups ( p < 0.01) and a more pronounced reduction of triglycerides (–37%) compared with that in the O group ( p < 0.05). SUA levels and alkaline phosphatase activity decreased more in the F and OF groups compared with the O group ( p < 0.05). Moreover, SCr significantly increased and estimated creatinine clearance decreased in the F and OF groups but they were not significantly altered in the O group ( p < 0.01 for the comparison between O and either F or OF groups). Glucose (in groups O and OF), as well as insulin levels and HOMA index (in all groups), were significantly reduced after treatment ( p < 0.05 vs. baseline). Conclusion: The combination of orlistat and micronised fenofibrate appears to be safe and may further improve metabolic parameters in overweight and obese patients with MetS compared with each monotherapy.

Increased plasma visfatin levels in subjects with the metabolic syndrome

Editor – The presence of the metabolic syndrome (MetS) increases the risk for cardiovascular disease (CVD) and type 2 diabetes mellitus [1]. A ‘new’ adipocytokine named ‘visfatin’ (pre-B cell colony-enhancing factor) is a cytokine highly expressed in visceral fat that exhibits insulin-mimetic properties [2]. We investigated the possible differences in plasma visfatin levels between subjects with and without MetS. Consecutive patients (n = 186, 81 men/105 women) without known CVD or diabetes mellitus attending the Outpatient Lipid Clinic of the University Hospital of Ioannina participated in the present study. Ninety of them fulfilled the National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III) criteria for the diagnosis of MetS [3] and the remaining 96 subjects served as a control group (non-MetS). Plasma visfatin concentrations were measured using an enzyme-linked immunoabsorbent assay (EIA) kit (Phoenix Pharmaceuticals, Belmont, California, USA). Plasma visfatin concentrations were higher in MetS subjects compared with non-MetS individuals [24·6 (9·1–56·6) ng mL vs. 16·1 (6·7–48·7) ng mL, P < 0·01], even after adjustment for age, sex and body mass index. Visfatin levels increased proportionally to the number of MetS components (P for trend < 0·01) (Fig. 1). Plasma visfatin concentrations were correlated with waist circumference (rho = 0·3, P < 0·001), triglycerides (rho = 0·35, P < 0·001), systolic (rho = 0·28, P < 0·001) and diastolic (rho = 0·27, P < 0·001) blood pressure but not with high-density lipoprotein cholesterol levels. Plasma visfatin levels were marginally correlated with fasting glucose (rho = 0·144, P = 0·055) and insulin levels (rho 0·165, P = 0·035), as well as with the homeostasis model assessment (HOMA) index (rho = 0·16, P = 0·041). In conclusion, plasma visfatin levels are increased in patients with MetS compared with individuals that do not fulfil the criteria for this syndrome. Visfatin concentrations elevate in parallel with the number of MetS components. Gene expression of visfatin was recently found to be enhanced in macrophages of human unstable carotid and coronary atherosclerotic lesions; this finding suggests a potential role for visfatin as an inflammatory mediator and in plaque destabilisation process [4]. Larger clinical studies are needed in order to assess if the observed increase in visfatin levels in MetS subjects is a consequence of the involvement of the molecule in the pathogenesis of this syndrome, or it is just an epiphenomenon that might be a useful marker of abdominal fat deposition and cardiovascular risk.

The effects of orlistat on metabolic parameters and other cardiovascular risk factors

Orlistat is an antiobesity drug with a well documented efficacy in weight reduction and weight maintenance. Weight reduction with orlistat has been associated with a favourable effect on obesity-related cardiovascular risk factors. Orlistat treatment is associated with a reduction in serum insulin levels. Moreover, orlistat reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance and lowers the required dose of metformin, sulfonylureas and insulin in patients with type 2 diabetes. Furthermore, orlistat can reduce total and low density lipoprotein (LDL) cholesterol levels and improve postprandial triglyceridemia, as well as the low density lipoprotein cholesterol/high density lipoprotein cholesterol ratio (LDL/HDL ratio). Moreover, orlistat appears to have a favourable effect on some inflammatory markers, such as TNF-alpha and interleukin-6 and has a time-depended effect on some haemostatic factors.

Pathogenesis, detection and treatment of Achilles tendon xanthomas

Tendon xanthomatosis often accompanies familial hypercholesterolaemia, but it can also occur in other pathologic states. Achilles tendons are the most common sites of tendon xanthomas. Low‐density lipoprotein (LDL) derived from the circulation accumulates into tendons. The next steps leading to the formation of Achilles tendon xanthomas (ATX) are the transformation of LDL into oxidized LDL (oxLDL) and the active uptake of oxLDL by macrophages within the tendons. Although physical examination may reveal Achilles tendon xanthomas (ATX), there are several imaging methods for their detection. It is worth mentioning that ultrasonography is the method of choice in everyday clinical practice. Although several treatments for Achilles tendon xanthomas (ATX) have been proposed (LDL apheresis, statins, etc.), they target mostly in the treatment of the basic metabolic disorder of lipid metabolism, which is the main cause of these lesions. In this review we describe the formation, detection, differential diagnosis and treatment of ATX as well as the relationship between tendon xanthomas and atheroma.

The effect of orlistat and ezetimibe, alone or in combination, on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia

ABSTRACT Background: Increased concentrations of low density lipoprotein cholesterol (LDL-C), as well as of small dense LDL-C (sdLDL-C), are considered as cardiovascular risk factors. Objective: An assessment of the effects of ezetimibe and orlistat administration, alone or in combination, on LDL-C and sdLDL-C levels (primary endpoint), as well as on anthropometric variables and metabolic parameters (secondary endpoints) in overweight and obese patients [body mass index (BMI) > 28 kg/m2] with hypercholesterolaemia [total cholesterol > 200 mg/dL (5.2 mmol/L)]. Methods: Eighty six subjects were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, 3 times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. Results: Significant reductions in LDL-C (−19%, −21%, −32% in groups O, E and OE, respectively, all p < 0.01 vs. baseline) and sdLDL-C levels (−45%, −48%, −76% in groups O, E, OE, respectively, all p < 0.01 vs. baseline) were observed. Group OE experienced a significantly greater reduction in LDL-C and sdLDL-C levels compared with groups O and E (p < 0.05). Furthermore, significant reductions of BMI, homeostasis model assessment (HOMA) index, serum uric acid, transaminase activities and plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were observed in the O and OE groups. Gamma-glutamyl transpeptidase activity and Lp-PLA2 activity improved significantly more with the combination treatment compared with either orlistat or ezetimibe monotherapy. Conclusions: Orlistat and ezetimibe combination had a more favourable effect on LDL-C and sdLDL-C levels in overweight and obese hypercholesterolaemic patients than either drug alone. Furthermore, orlistat, alone or in combination with ezetimibe, additionally improved several anthropometric and metabolic variables.

The Metabolic Role of Retinol Binding Protein 4: An Update

Retinol binding protein 4 (RBP(4)) is regarded as a novel cardiometabolic risk factor, which is secreted mainly by the hepatocytes and also by the adipose tissue. RBP(4) has been shown to induce insulin resistance, and plasma RBP(4) values are increased in type 2 diabetes mellitus, obesity, metabolic syndrome, and cardiovascular disease. Moreover, it has been found that circulating RBP(4) decreases during medical interventions that result in amelioration of the metabolic profile, such as diet, exercise, oral antidiabetic drugs, and hypolipidemic agents. However, only few of the RBP(4)-related studies have investigated whether RBP(4) constitutes a causal factor of the above-mentioned metabolic conditions. Importantly, circulating RBP(4) is influenced by some nonmetabolic conditions, such as renal failure, acute illness, injury, and liver failure. Thus, further studies investigating the metabolic roles of RBP(4) should be carefully planned, taking into account the effects of nonmetabolic conditions on circulating RBP(4).

The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome.

Objective:  We assessed the effect of orlistat and fenofibrate, alone or in combination, on plasma high‐density lipoprotein (HDL) subfractions and plasma pre‐beta1‐HDL levels in overweight and obese subjects with metabolic syndrome (MetS).

The role of adiponectin in renal physiology and development of albuminuria

Adiponectin is secreted by the adipose tissue and is downregulated in states of obesity and insulin resistance. There is a growing body of evidence indicating that adiponectin has renoprotective effects and protects against the development of albuminuria in rodent experiments. Adiponectin crossing the glomerular filtration barrier possibly inhibits inflammation, fibrosis and oxidative stress in kidneys through activation of AMP-activated protein kinase. Moreover, microalbuminuria is a well established early sign of progressive cardiovascular and renal disease, even in subjects with preserved glomerular filtration rate. Studies investigating the relationship between serum adiponectin levels and urinary albumin excretion rate (UAE) have yielded conflicting data and the mechanisms underlying the interplay between adiponectin and albuminuria remain to be elucidated. This article constitutes a critical review attempting to clarify any remaining confusion about this matter. Furthermore, this article examines the clinical significance of adiponectin-albuminuria interplay, suggesting that adiponectin is possibly involved in the development of albuminuria that is associated with obesity, diabetes and cardiovascular disease and may mediate, at least in part, the actions of medical treatments that influence UAE, such as angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, thiazolidinediones, fenofibrate and diet. Further studies to investigate more thoroughly the renoprotective role of adiponectin in the human setting should be carefully planned, focusing on causality and the possible influence of adiponectin on the development of albuminuria in specific clinical settings.