Nicholas Katsilambros

Leptin Concentrations in Relation to Body Mass Index and the Tumor Necrosis Factor-α System in Humans

The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF)alpha in rodents, but an association between the TNF alpha system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNF alpha system, we measured the levels of soluble TNF alpha-receptor (sTNF alpha-R55), which has been validated as a sensitive indicator of activation of the TNF alpha system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNF alpha-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNF alpha-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNF alpha-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNF alpha system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNF alpha system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.

Increased Heart Failure Risk in Normal-Weight People With Metabolic Syndrome Compared With Metabolically Healthy Obese Individuals

OBJECTIVES The purpose of this study was to assess whether the metabolically healthy obese phenotype is associated with lower heart failure (HF) risk compared with normal-weight individuals with metabolic syndrome (MetS). BACKGROUND Obesity and MetS often coexist and are associated with increased HF risk. It is controversial whether obese individuals with normal insulin sensitivity have decreased HF risk. METHODS A total of 550 individuals without diabetes or baseline macrovascular complications were studied during a median follow-up of 6 years. Participants were classified by presence (n = 271) or absence (n = 279) of MetS and by body mass index (body mass index: <25 kg/m(2) = normal weight, n = 177; 25 to 29.9 kg/m(2) = overweight, n = 234; ≥ 30 kg/m(2) = obese, n = 139). MetS was diagnosed with the National Cholesterol Education Program Adult Treatment Panel III criteria. Left ventricular functional capacity, myocardial structure, and performance were assessed echocardiographically. RESULTS Body mass index was not associated with increased HF risk. The presence of MetS conferred a 2.5-fold higher HF risk (hazard ratio [HR]: 2.5, 95% confidence interval [CI]: 1.68 to 3.40). Overweight and obese individuals without MetS had the lowest 6-year HF risk (HR: 1.12, 95% CI: 0.35 to 1.33 [corrected] and HR: 0.41, 95% CI: 0.10 to 1.31, respectively) compared with normal-weight individuals with MetS (HR: 2.33, 95% CI: 1.25 to 4.36, p < 0.001). From the individual components of MetS, impaired fasting glucose (HR: 1.09, 95% CI: 1.06 to 1.10), high BP (HR: 2.36, 95% CI: 1.03 to 5.43), low high-density lipoprotein cholesterol (HR: 1.88, 95% CI: 1.29 to -2.77), and central obesity (HR: 2.22, 95% CI: 1.02 to 1.05) were all associated with increased HF risk. Factors commonly associated with MetS such as insulin resistance and inflammation (high-sensitivity C-reactive protein and microalbuminuria) were also independently associated with HF incidence. CONCLUSIONS In contrast to normal weight insulin-resistant individuals, metabolically healthy obese individuals show decreased HF risk in a 6-year follow-up study.

Eating Slowly Increases the Postprandial Response of the Anorexigenic Gut Hormones, Peptide YY and Glucagon-Like Peptide-1

CONTEXT The rate at which people eat has been suggested to be positively associated with obesity, although appetite and related gut hormones have not been measured. The objective of the study was to determine whether eating the same meal at varying speeds elicits different postprandial gut peptide responses. DESIGN AND SETTING This was a crossover study at a clinical research facility. STUDY PARTICIPANTS Seventeen healthy adult male volunteers participated in the study. INTERVENTION A test meal consisting of 300 ml ice cream (675 kcal) was consumed in random order on two different sessions by each subject: meal duration took either 5 or 30 min. MAIN OUTCOME MEASURES The postprandial response of the orexigenic hormone ghrelin and the anorexigenic peptides peptide YY and glucagon-like peptide-1 over 210 min was assessed. Visual analog scales for the subjective feelings of hunger and fullness were completed throughout each session. RESULTS Peptide YY area under the curve (AUC) was higher after the 30-min meal than after the 5-min meal (mean +/- sem AUC 5 min meal: 4133 +/- 324, AUC 30 min meal: 5250 +/- 330 pmol/liter . min, P = 0.004), as was glucagon-like peptide-1 AUC (mean +/- sem AUC 5 min meal: 6219 +/- 256, AUC 30 min meal: 8794 +/- 656 pmol/liter . min, P = 0.001). There was a trend for higher visual analog scale fullness ratings immediately after the end of the 30-min meal compared with immediately after the 5-min meal. There were no differences in ghrelin response. CONCLUSIONS Eating at a physiologically moderate pace leads to a more pronounced anorexigenic gut peptide response than eating very fast.

Perturbed Autonomic Nervous System Function in Metabolic Syndrome

The metabolic syndrome is characterized by the clustering of various common metabolic abnormalities in an individual and it is associated with increased risk for the development of type 2 diabetes and cardiovascular diseases. Its prevalence in the general population is approximately 25%. Central fat accumulation and insulin resistance are considered as the common denominators of the abnormalities of the metabolic syndrome. Subjects with metabolic syndrome have autonomic nervous system dysfunction characterized by predominance of the sympathetic nervous system in many organs, i.e. heart, kidneys, vasculature, adipose tissue, and muscles. Sympathetic nervous system activation in metabolic syndrome is detected as increased heart rate and blood pressure, diminished heart rate variability, baroreceptor dysfunction, enhanced lipolysis in visceral fat, increased muscle sympathetic nerve activity, and high urine or plasma catecholamine concentrations as well as turnover rates. The augmented sympathetic activity in individuals with metabolic syndrome worsens prognosis of this high-risk population. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not clearly understood. Whether sympathetic overactivity is involved in the development of the metabolic syndrome or is a consequence of it remains to be elucidated since data from prospective studies are missing. Intervention studies have demonstrated that the autonomic disturbances of the metabolic syndrome may be reversible.

Baroreflex Sensitivity in Obesity: Relationship With Cardiac Autonomic Nervous System Activity

Objective: The aim of this study was to test the hypothesis that baroreflex sensitivity (BRS), assessed by indirect measurement of aortic pressure, is blunted in obesity. Additionally, the potential effect of cardiac autonomic nervous system (ANS) activity, aortic compliance, and metabolic parameters on BRS of obese subjects was investigated.

Differential effects of high-fat and high-carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in lean and obese women.

Food ingestion can influence autonomic nervous system activity. This study compares the effects of 2 different isoenergetic meals on sympathetic nervous system (SNS) activity, assessed by heart rate variability (HRV) and plasma norepinephrine (NE) levels, in lean and obese women. Fifteen lean and 15 obese healthy women were examined on 2 occasions: after a carbohydrate (CHO)-rich and after a fat-rich test meal. Measurements of blood pressure, heart rate, resting energy expenditure, plasma glucose, lipids, insulin, leptin, and NE, as well as spectral analysis of the HRV, were performed at baseline and every 1 hour for 3 hours after meals. At baseline, obese women had higher SNS activity than lean controls (higher values of low-to-high frequency ratio [LF/HF], 1.52 +/- 0.31 v 0.78 +/- 0.13, P=.04; and plasma NE levels, 405.6 +/- 197.9 v 240.5 +/- 95.8 pg/mL, P<.0001). After the CHO-rich meal a greater increase in LF/HF and in plasma NE levels was observed in lean, compared to obese women (1.21 +/- 0.6 v 0.32 +/- 0.06, P=.04; and 102.9 +/- 35.4 v 38.7 +/- 12.3 pg/mL, P=.01, respectively), while no differences were observed after the fat-rich meal. Meal-induced thermogenesis was higher after the CHO-rich as compared to the fat-rich meal and was comparable between lean and obese women. Changes in HRV were not associated with the thermogenic response to the test meals. In conclusion, consumption of a CHO-rich meal causes greater cardiac SNS activation in lean than in obese women, while fat ingestion does not result in any appreciable change in either group. SNS activation does not appear to influence the thermic effect of the food in either lean or obese women.

Successful treatment of refractory adult-onset Still’s disease with infliximab. A prospective, non-comparative series of four patients

In this prospective, non-comparative case series, four patients with severe and highly active adult-onset Still’s disease (AOSD), refractory to high doses of corticosteroids (which had been combined with methotrexate in three of them) and methotrexate were treated with infliximab (initial dose 3–5 mg/kg, continuing at intervals depending on the patient’s individual disease activity). Resolution of their symptoms, which was evident within few days after the first infusion, and a parallel rapid improvement of the acute inflammatory response indices were observed in all. Concomitant corticosteroid treatment was reduced after the first courses of treatment with infliximab, which was well tolerated, and complete disease remission was sustained during a 5–18-month follow-up period. Although further studies to confirm long-term efficacy and safety in larger numbers of patients are needed, we suggest that administration of infliximab with observation for objective improvement is the treatment of choice in cases of AOSD refractory to conventional treatment.

The consumption of bread enriched with betaglucan reduces LDL-cholesterol and improves insulin resistance in patients with type 2 diabetes

AIM Previous studies have shown that the water-soluble dietary fibre betaglucan, a natural component of oats, reduces cholesterol and postprandial hyperglycaemia. The aim of the present study was to investigate the effect of betaglucan-enriched bread consumption on the lipid profile and glucose homoeostasis of patients with type 2 diabetes (T2D). METHODS We conducted a randomized, double-blind study in which 46 patients with T2D and LDL-C greater than 3.37 mmol/l (130 mg/dl) were randomized to incorporate into their diet, for 3 weeks, either bread enriched with betaglucan (providing 3g/day of betaglucan) or white bread without betaglucan. RESULTS The consumption of bread containing betaglucan led to significant reductions (vs the control group) in LDL-C of 0.66 mmol/l (15.79%) versus 0.11 mmol/l (2.71%) (P=0.009), in total cholesterol of 0.80 mmol/l (12.80%) versus 0.12 mmol/l (1.88%) (P=0.006), in Fasting plasma insulin (FPI) of 3.23 microU/ml versus an increase of 3.77 microU/ml (P=0.03) and in Homa-IR (Homoeostasis model assessment-insulin resistance) by 2.08 versus an increase of 1.33 (P=0.04). CONCLUSIONS Betaglucan enriched bread may contribute to the improvement of the lipid profile and insulin resistance in patients with T2D.

Diet-induced thermogenesis and substrate oxidation are not different between lean and obese women after two different isocaloric meals, one rich in protein and one rich in fat.

Reduction in diet-induced thermogenesis (DIT) may promote weight gain and maintenance. Data on differences in DIT and macronutrient oxidation between lean and obese subjects are conflicting. In this study, we sought for differences in DIT and macronutrient oxidation between lean and obese women after consumption of 2 different isocaloric meals, one rich in protein and one rich in fat. Fifteen lean and 15 obese women were studied on 2 occasions, 1 week apart. In one visit, they consumed a protein-rich meal; in the other visit, a fat-rich meal. The 2 meals were isocaloric ( approximately 2026 kJ each), of equal volume, and given in random order. Resting energy expenditure and macronutrient oxidation rates were measured and calculated in the fasting state and every 1 hour for 3 hours after meal consumption. Diet-induced thermogenesis was not significantly different between lean and obese subjects after consumption of either the protein-rich (P = .59) or the fat-rich meal (P = .68). Diet-induced thermogenesis was significantly higher (by almost 3-fold) after consumption of the protein-rich meal in comparison with the fat-rich meal in both study groups. In addition, no significant differences in macronutrient oxidation rates were found between lean and obese women after the test meals. The results indicate that DIT is higher after protein intake than after fat intake in both lean and obese participants; however, DIT and macronutrient oxidation rate are not different between lean and obese subjects after consumption of either a protein-rich or a fat-rich meal. Over the long term, a low DIT after regular or frequent fat intake may contribute to the development and maintenance of obesity.

The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes

BACKGROUND Cardiac autonomic neuropathy (CAN) is a common diabetes complication associated with poor prognosis. This cross-sectional study aimed to examine for associations between CAN and metabolic and other parameters in patients with either type 1 (T1DM) or type 2 (T2DM) diabetes. PATIENTS AND METHODS A total of 600 patients (T1DM, n=200; T2DM, n=400) were recruited. Participants with overt nephropathy, macrovascular complications, and treated hypertension were excluded. CAN was diagnosed when two of the four classical autonomic function tests were abnormal. RESULTS CAN was diagnosed in 42.0% and in 44.3% of the participants with T1DM and T2DM, respectively. Multivariate logistic regression analysis demonstrated that, in T1DM, the odds [OR (95% confidence intervals)] of CAN increased with higher waist circumference [1.36 (1.01-2.02)], systolic blood pressure [1.16 (1.03-1.31)], hypertension [1.19 (1.03-2.67)], smoking [1.10 (1.12-1.40], fasting glucose [1.01 (1.00-1.01)], HbA(1c) [1.69 (1.07-2.76)], pubertal diabetes onset [1.08 (1.03-1.24)], LDL cholesterol [1.01(1.00-1.02)], triglycerides [1.58 (1.24-1.48)], retinopathy [1.13 (1.04-1.41)], peripheral neuropathy [2.53 (1.07-2.99)], glomerular filtration rate [0.93 (0.87-0.99)], and microalbuminuria [1.24 (1.12-1.36)]. The same analysis in T2DM demonstrated that the odds of CAN increased with higher waist circumference [1.08 (1.00-1.39)], systolic blood pressure [1.06 (1.02-1.12)], hypertension [1.50 (1.24-2.03)], smoking [1.22 (1.14-1.49)], diabetes duration [1.20 (1.09-1.34)], fasting glucose [1.21 (1.12-1.31)], HbA(1c) [1.25 (1.08-1.45)], LDL cholesterol [1.35 (1.04-1.75)], triglycerides [1.30 (1.00-1.68)], retinopathy [1.24 (1.16-1.35)], peripheral neuropathy [1.79 (1.07-2.01)], glomerular filtration rate [0.96 (0.95-0.97)], and microalbuminuria [1.20 (1.14-1.36)]. CONCLUSIONS CAN is common in diabetes and is associated with modifiable factors including central fat distribution, hypertension, dyslipidemia, worse diabetes control, and smoking, and with the other microvascular complications of diabetes. Our findings emphasize the need for a multifactorial intervention for the prevention of CAN.