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Plasma Cytokeratin-18 Fragment Level Reflects the Metabolic Phenotype in Obesity

There is growing interest in the non-invasive identification and monitoring of the outcome of liver damage in obese patients. Plasma cytokeratin-18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis and have recently been proposed to independently predict the presence of non-alcoholic steatohepatitis (NASH). The aim of the study was to analyze the associations of CK-18 with obesity and related complications: insulin resistance, impaired lipid metabolism and the secretion of hepatokines, adipokines and pro-inflammatory cytokines. The study involved 151 overweight and obese patients (BMI 25–40), without diabetes, dyslipidemia or apparent liver disease. Liver function was assessed based on alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and the fatty liver index (FLI). CK-18 M30 plasma levels, FGF-21, FGF-19 and cytokines were determined by ELISA. CK-18 values >150 U/l were accompanied by high ALT, GGT and FLI, insulin resistance, postprandial hypertriglyceridemia, elevated FGF-21 and MCP-1 and decreased adiponectin. ALT activity was the strongest independent factor influencing high CK-18 plasma levels, even after an adjustment for age, sex and BMI [β coefficient (95%CI): 0.40 (0.19–0.61)]. In conclusion, the applied CK-18 cut-off point at 150 U/l allows to distinguish between two metabolic phenotypes in obesity

The effect of caloric restriction with and without n-3 PUFA supplementation on bone turnover markers in blood of subjects with abdominal obesity: A randomized placebo-controlled trial

Weight loss contributes to an increased risk of hip fracture, especially in postmenopausal women. Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation could diminish the adverse effect of weight loss on bone health. The aim of this randomized, placebo-controlled, double-blind parallel trial was to investigate the effect of caloric restriction and n-3 PUFA supplement intake on osteogenic markers (carboxylated osteocalcin (Gla-OC); procollagen I N-terminal propeptide (PINP)), as well as a bone resorption marker (C-terminal telopeptide of type I collagen (CTX-I)) in a serum of 64 middle aged individuals (BMI 25–40 kg/m2) with abdominal obesity. Bone remodeling, metabolic and inflammatory parameters and adipokines were determined before and after 3 months of an isocaloric diet (2300–2400 kcal/day) or a low-calorie diet (1200 kcal/day for women and 1500 kcal/day for men) along with n-3 PUFA (1.8 g/day) or placebo capsules. CTX-I and adiponectin concentrations were increased following 7% weight loss independently of supplement use. Changes in CTX-I were positively associated with changes in adiponectin level (rho = 0.25, p = 0.043). Thus, an increase in serum adiponectin caused by body weight loss could adversely affect bone health. N-3 PUFAs were without effect.<br/

Glucose-dependent insulinotropic polypeptide plasma level influences the effect of n-3 PUFA supplementation

Elevated glucose-dependent insulinotropic peptide (GIP) levels in obesity may predict the metabolic benefits of n-3 PUFA supplementation. This placebo-controlled trial aimed to analyze fasting and postprandial GIP response to 3-month n-3 PUFA supplementation (1.8 g/d; DHA:EPA, 5:1) along with caloric restriction (1200–1500 kcal/d) in obese subjects. Compliance was confirmed by the incorporation of DHA and EPA into red blood cells (RBCs). Blood analyses of glucose, insulin, non-esterified fatty acids (NEFAs), GIP and triglycerides were performed at fasting, and during an oral glucose tolerance test and a high fat mixed-meal tolerance test. Fatty acid composition of RBC was assessed by gas chromatography and total plasma fatty acid content and composition was measured by gas–liquid chromatography. The DHA and EPA content in RBCs significantly increased due to n-3 PUFA supplementation vs. placebo (77% vs. −3%, respectively). N-3 PUFA supplementation improved glucose tolerance and decreased circulating NEFA levels (0.750 vs. 0.615 mmol/L), as well as decreasing plasma saturated (1390 vs. 1001 µg/mL) and monounsaturated (1135 vs. 790 µg/mL) fatty acids in patients with relatively high GIP levels. The effects of n-3 PUFAs were associated with the normalization of fasting (47 vs. 36 pg/mL) and postprandial GIP levels. Obese patients with elevated endogenous GIP could be a target group for n-3 PUFA supplementation in order to achieve effects that obese patients without GIP disturbances can achieve with only caloric restriction<br/

Effect of caloric restriction with or without n-3 polyunsaturated fatty acids on insulin sensitivity in obese subjects: a randomized placebo controlled trial

BackgroundCaloric restriction and n-3 polyunsaturated fatty acid (PUFA) supplementation protect from some of the metabolic complications. The aim of this study was to assess the influence of a low calorie diet with or without n-3 PUFA supplementation on glucose dependent insulinotropic polypeptide (GIP) output and insulin sensitivity markers in obese subjects.MethodsObese, non-diabetic subjects (BMI 30–40 kg/m2 and aged 25–65 yr.) were put on low calorie diet (1200–1500 kcal/day) supplemented with either 1.8 g/day n-3 PUFA (DHA/EPA, 5:1) (n = 24) or placebo capsules (n = 24) for three months in a randomized placebo controlled trial. Insulin resistance markers and GIP levels were analysed from samples obtained at fasting and during an oral glucose tolerance test (OGTT).ResultsCaloric restriction with n-3 PUFA led to a decrease of insulin resistance index (HOMA-IR) and a significant reduction of insulin output as well as decreased GIP secretion during the OGTT. These effects were not seen with caloric restriction alone. Changes in GIP output were inversely associated with changes in red blood cell EPA content whereas fasting GIP level positively correlated with HOMA-IR index. Blood triglyceride level was lowered by caloric restriction with a greater effect when n-3 PUFA were included and correlated positively with fasting GIP level.ConclusionsThree months of caloric restriction with DHA + EPA supplementation exerts beneficial effects on insulin resistance, GIP and triglycerides.General significanceCombining caloric restriction and n-3 PUFA improves insulin sensitivity, which may be related to a decrease of GIP levels.AbbreviationsAUC, area under curve; BMI, body mass index; DHA, docosapentaenoic acid; EPA, eicosapentaenoic acid; GIP, glucose dependent insulinotropic polypeptide; IGI, insulinogenic index; NEFA, non esterified fatty acids; OGIS, oral glucose insulin sensitivity index; OGTT, oral glucose tolerance test; PC, phosphatidylcholine; PUFA, polyunsaturated fatty acid

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Relation of the protein glycation, oxidation and nitration to the osteocalcin level in obese subjects

Carboxylated osteocalcin (Gla-OC) contributes to the bone formation, whereas its undercarboxylated form (Glu-OC) takes part in the energy metabolism. In vitro studies had shown that treatment of osteoblast-like cells with advanced glycation end product-modified bovine serum resulted in reduced synthesis of collagen 1 and osteocalcin. The aim of this study was to find association between Gla-OC and markers of protein glycation, oxidation and nitration, as well as pro-inflammatory and antioxidant defense markers in obese subjects. Non-obese [(body mass index (BMI)<30 kg/m; n=34)] and obese subjects (30<BMI <40 kg/m2; n=98), both sexes, aged 25 to 65 years, were included in this study. Urinary glycation, oxidation and nitration free adduct concentrations were determined by stable isotopic dilution analysis liquid chromatography and mass spectrometry, and normalized to creatinine. Obese subjects had lower Gla-OC serum levels when compared to the non-obese controls. Obese subjects had increased serum concentrations of insulin, C reactive protein, interleukin 6, leptin and insulin resistance index (HOMA IR). Urinary early glycation and advanced glycation end product (AGE) free products, Nε-fructosyl-lysine and 3-deoxyglucosone-derived hydroimidazolone, respectively, and oxidative damage marker, N-formylkynurenine free adduct, were increased in the obese compared to the non-obese subjects. Serum Gla-OC was negatively correlated with urinary methylglyoxal-derived AGE, hydroimidazolone MG-H1, and N-formylkynurenine free adducts. The Gla-OC/Glu-OC index negatively correlated with the MG-H1 free adduct, and correlated positively with the antioxidant defense marker - the glutathione peroxidase activity. Our results suggest that increased AGEs and protein oxidative damage markers in the course of obesity may contribute to decreased Gla-OC level and, consequently, future risk of decreased bone formation