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Insulin-like growth factors (IGFs) are involved in regulating growth and metabolism and increase insulin sensitivity, improve glucose metabolism, and are potentially related to gestational diabetes mellitus (GDM) and its complications for mothers and fetuses.This study aimed to assess serum levels and cord blood levels of IGF system components in pregnant women with (39 participants) and without GDM (22 participants). Blood samples were obtained at 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. Cord blood samples were obtained during delivery. Results between both groups as well as between single visits were statistically compared.Both IGF1 and IGF2 maternal serum levels did not differ between the GDM and non-GDM groups. However, levels of IGF-binding proteins (IGFBPs) were different. IGFBP4 levels were decreased during pregnancy and after delivery in women with GDM, while IGFBP7 levels were increased during pregnancy in women with GDM. Cord blood IGFBP3 and IGFBP7 levels were increased (p lt; 0.001 for IGFBP3, p = 0.003 for IGFBP7), while IGFBP4 levels were decreased (p lt; 0.001) in the GDM group compared with the non-GDM group.Although IGF levels did not differ, changes in their function level could still persist possibly because of the effects of the binding proteins, especially their promoting or inhibitory effects on IGFs. These results should be considered in interpretation of IGF levels.

Context Gestational diabetes mellitus (GDM) is accompanied by subclinical inflammation; however, little is known about local inflammation in adipose tissue and placenta. Objective To analyze systemic and local subclinical inflammation and adipose tissue lymphocyte content and phenotype in pregnant women with and without GDM. Design Observational study. Settings Academic hospital. Patients Twenty-one pregnant women with GDM (GDM group), 16 pregnant women without GDM (non-GDM group) and 15 nonpregnant control women (N group). Interventions Serum samples taken at 28 to 32 (visit 1 [V1]) and 36 to 38 (V2) gestational weeks and 6 to 12 months after delivery (V3) in the GDM and non-GDM group and before elective gynecological surgery in the N group. Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained during cesarean delivery or surgery. Main Outcome Measures Serum levels and adipose tissue expression of proinflammatory cytokines, adipose tissue lymphocyte content and phenotype (for a subset of GDM and non-GDM subjects). Results Accented proinflammatory state in GDM was documented by increased circulating tumor necrosis factor-α (TNF-α) levels. In both groups of pregnant females total lymphocytes were higher in VAT compared to SAT. In GDM subjects B cells and NKT cells were higher in SAT compared to VAT and T helper cells were increased relative to SAT of non-GDM group, while no intercompartmental adipose tissue differences were seen in non-GDM women. Conclusions Pregnant females had higher total lymphocyte count in VAT relative to SAT regardless of GDM. In addition to increased systemic subclinical inflammation, GDM was associated with significant differences in lymphocyte composition between subcutaneous and visceral adipose tissue depots.

Myokines represent important regulators of muscle metabolism. Our study aimed to explore the effects of a cyclical ketogenic reduction diet (CKD) vs. a nutritionally balanced reduction diet (RD) combined with regular resistance/aerobic training in healthy young males on serum concentrations of myokines and their potential role in changes in physical fitness. Twenty-five subjects undergoing regular resistance/aerobic training were randomized to the CKD (n = 13) or RD (n = 12) groups. Anthropometric and spiroergometric parameters, muscle strength, biochemical parameters, and serum concentrations of myokines and cytokines were assessed at baseline and after 8 weeks of intervention. Both diets reduced body weight, body fat, and BMI. Muscle strength and endurance performance were improved only by RD. Increased musclin (32.9 pg/mL vs. 74.5 pg/mL, p = 0.028) and decreased osteonectin levels (562 pg/mL vs. 511 pg/mL, p = 0.023) were observed in RD but not in the CKD group. In contrast, decreased levels of FGF21 (181 pg/mL vs. 86.4 pg/mL, p = 0.003) were found in the CKD group only. Other tested myokines and cytokines were not significantly affected by the intervention. Our data suggest that changes in systemic osteonectin and musclin levels could contribute to improved muscle strength and endurance performance and partially explain the differential effects of CKD and RD on physical fitness.

The insulin-like growth factor (IGF) is involved in the regulation of growth and metabolism. The aim of this study was to determine selected parameters of IGF system at systemic and local levels [subcutaneous (SAT) and visceral adipose tissue (VAT)] to assess its possible role in gestational diabetes mellitus (GDM). 37 pregnant women (21 with GDM and 16 without GDM) and 15 age-matched non-pregnant females were included in the study. Blood samples were taken in 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. SAT and VAT samples were obtained during delivery or surgery. Compared with non-pregnant women, serum IGF-1 and IGFBP-3 were increased in both groups of pregnant women. IGF-2 was elevated only in GDM women from 36 weeks of gestation culminating 6 months after delivery (p=0.003). Serum IGFBP-3 was increased and IGFBP-4 decreased in GDM women vs. pregnant women without GDM during the whole study (IGFBP-3: p˂0.001 for GDM vs. non-GDM; IGFBP-4: p=0.004 for GDM vs. non-GDM). Pregnant women with GDM had decreased mRNA expression of IGF-1, IGF-1R and IGF-2R and IGFBP-4 in VAT and IGF-1R in SAT compared to pregnant women without GDM. Changes in local activity of IGF are associated with the development of GDM.

The aim of our study was to assess the presence and degree of intestinal leakage in subjects suffering from short bowel syndrome (SBS) and its modification by parenteral nutrition. To this end we assessed circulating levels of selected makers of intestinal permeability including zonulin, fatty acid binding protein 2 (FABP-2), citrulline and glucagon-like peptide 2 (GLP-2). We also measured lipopolysaccharide binding protein (LBP) as a marker of circulating levels of lipopolysaccharide acting through the CD14 molecule. Eleven SBS and 10 age- and BMI-matched control subjects were included into the study. The effect of parenteral nutrition was assessed after 14 days, 6 and 12 months from its initiation, respectively. At baseline, SBS patients had increased gut permeability as measured by zonulin (47.24±2.14 vs. 39.48±1.20 ng/ml, p=0.006) and LBP (30.32±13.25 vs. 9.77±0.71 µg/ml, p

Purpose Cushing's syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications. Patients and methods We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing's syndrome and in 9 of them after successful treatment and 22 healthy control subjects. Results Patients with active Cushing's syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing's syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing's syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing's syndrome showed increased enzyme activity of complex I (NQR) in platelets. Conclusion Mitochondrial function in SCAT in patients with Cushing's syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing's syndrome.

(1) Background: The influence of ketogenic diet on physical fitness remains controversial. We performed a randomized controlled trial to compare the effect of cyclical ketogenic reduction diet (CKD) vs. nutritionally balanced reduction diet (RD) on body composition, muscle strength, and endurance performance. (2) Methods: 25 healthy young males undergoing regular resistance training combined with aerobic training were randomized to CKD (n = 13) or RD (n = 12). Body composition, muscle strength and spiroergometric parameters were measured at baseline and after eight weeks of intervention. (3) Results: Both CKD and RD decreased body weight, body fat, and BMI. Lean body mass and body water decreased in CKD and did not significantly change in RD group. Muscle strength parameters were not affected in CKD while in RD group lat pull-down and leg press values increased. Similarly, endurance performance was not changed in CKD group while in RD group peak workload and peak oxygen uptake increased. (4) Conclusions: Our data show that in healthy young males undergoing resistance and aerobic training comparable weight reduction were achieved by CKD and RD. In RD group, improved muscle strength and endurance performance was noted relative to neutral effect of CKD that also slightly reduced lean body mass.

The situation following anti-obesity drug termination is rarely investigated, eventhough a decrease in body weight needs to be sustained. Therefore, this study examined the impact of twice-daily peripheral administration of 5 mg/kg [N-palm-γGlu-Lys11] prolactin-releasing peptide 31 (palm11-PrRP31) in mice with diet-induced obesity (DIO from consuming a high-fat diet) after 28 days of treatment (palm11-PrRP31 group) and after 14 days of peptide treatment followed by 14 days of discontinuation (palm11-PrRP31 + saline group). At the end of the treatment, cumulative food intake, body weight and subcutaneous fat weight/body weight ratio and leptin plasma level were reduced significantly in both the palm11-PrRP31 group and the palm11-PrRP31 + saline group compared to the saline control group. This reduction correlated with significantly increased FOSB, a marker of long-term neuronal potentiation, in the nucleus arcuatus and nucleus tractus solitarii, areas known to be affected by the anorexigenic effect of palm11-PrRP31. Moreover, activation of leptin-related hypothalamic signaling was registered through an increase in phosphoinositide-3-kinase, increased phosphorylation of protein kinase B (PKB, AKT) and enhanced extracellular signal-regulated kinase 1/2 phosphorylation. Besides, lowered apoptotic markers c-JUN N-terminal kinase and c-JUN phosphorylation were registered in the hypothalami of both palm11-PrRP31-treated groups. This study demonstrates that palm11-PrRP31 positively affects feeding and leptin-related hypothalamic signaling, not only after 28 days of treatment but even 14 days after the termination of a 14-day long treatment without the yo-yo effect.

Context Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied. Objective To compare changes in pancreatic endocrine function and gut hormones’ production during a liquid meal test before and 1 year after adrenalectomy. Methods In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins. Results During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC Conclusions Our study shows suppression of pancreatic α and β cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.

Purpose Cushing’s syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications. Patients and methods We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing’s syndrome and in 9 of them after successful treatment and 22 healthy control subjects. Results Patients with active Cushing’s syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing’s syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing’s syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing’s syndrome showed increased enzyme activity of complex I (NQR) in platelets. Conclusion Mitochondrial function in SCAT in patients with Cushing’s syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing’s syndrome.

Immunocompetent cells including lymphocytes play a key role in the development of adipose tissue inflammation and obesity-related cardiovascular complications. The aim of the study was to explore the relationship between epicardial adipose tissue lymphocytes and coronary artery disease (CAD). To this end, we studied the content and phenotype of lymphocytes in peripheral blood, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT) in subjects with and without CAD undergoing elective cardiac surgery. Eleven subjects without CAD (non-CAD group) and 22 age-, BMI-, and HbA1C-matched individuals with CAD were included into the study. Blood, SAT, and EAT samples were obtained at the beginning of surgery. Lymphocyte populations were quantified as % of CD45+ cells using flow cytometry. Subjects with CAD had a higher total lymphocyte amount in EAT compared with SAT (32.24±7.45 vs. 11.22±1.34%, p=0.025) with a similar trend observed in non-CAD subjects (29.68±7.61 vs. 10.13±2.01%, p=0.067). T (CD3+) cells were increased (75.33±2.18 vs. 65.24±4.49%, p=0.032) and CD3- cells decreased (21.17±2.26 vs. 31.64±4.40%, p=0.028) in EAT of CAD relative to the non-CAD group. In both groups, EAT showed an elevated percentage of B cells (5.22±2.43 vs. 0.96±0.21%, p=0.039 for CAD and 12.49±5.83 vs. 1.16±0.19%, p=0.016 for non-CAD) and reduced natural killer (NK) cells (5.96±1.32 vs. 13.22±2.10%, p=0.012 for CAD and 5.32±1.97 vs. 13.81±2.72%, p=0.022 for non-CAD) relative to SAT. In conclusion, epicardial adipose tissue in subjects with CAD shows an increased amount of T lymphocytes relative to non-CAD individuals as well as a higher number of total and B lymphocytes and reduced NK cells as compared with corresponding SAT. These changes could contribute to the development of local inflammation and coronary atherosclerosis.

Dendritic cells (DCs) are professional antigen-presenting cells contributing to regulation of lymphocyte immune response. DCs are divided into two subtypes: CD11c-positive conventional or myeloid (cDCs) and CD123-positive plasmacytoid (pDCs) DCs. The aim of the study was to assess DCs (HLA-DR+ lineage-) and their subtypes by flow cytometry in peripheral blood and subcutaneous (SAT) and epicardial (EAT) adipose tissue in subjects with (T2DM, n=12) and without (non-T2DM, n=17) type 2 diabetes mellitus undergoing elective cardiac surgery. Subjects with T2DM had higher fasting glycemia (8.6±0.7 vs. 5.8±0.2 mmol/l, p<0.001) and glycated hemoglobin (52.0±3.4 vs. 36.9±1.0 mmol/mol, p<0.001) and tended to have more pronounced inflammation (hsCRP: 9.8±3.1 vs. 5.1±1.9 mg/ml, p=0.177) compared with subjects without T2DM. T2DM was associated with reduced total DCs in SAT (1.57±0.65 vs. 4.45±1.56% for T2DM vs. non-T2DM, p=0.041) with a similar, albeit insignificant, trend in EAT (0.996±0.33 vs. 2.46±0.78% for T2DM vs. non-T2DM, p=0.171). When analyzing DC subsets, no difference in cDCs was seen between any of the studied groups or adipose tissue pools. In contrast, pDCs were increased in both SAT (13.5±2.0 vs. 4.6±1.9% of DC cells, p=0.005) and EAT (29.1±8.7 vs. 8.4±2.4% of DC, p=0.045) of T2DM relative to non-T2DM subjects as well as in EAT of the T2DM group compared with corresponding SAT (29.1±8.7 vs. 13.5±2.0% of DC, p=0.020). Neither obesity nor coronary artery disease (CAD) significantly influenced the number of total, cDC, or pDC in SAT or EAT according to multiple regression analysis. In summary, T2DM decreased the amount of total dendritic cells in subcutaneous adipose tissue and increased plasmacytoid dendritic cells in subcutaneous and even more in epicardial adipose tissue. These findings suggest a potential role of pDCs in the development of T2DM-associated adipose tissue low-grade inflammation.

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery, mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.

Duodenal–jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects.

Background Angiopoietin-like proteins (ANGPTLs) 3 and 4 are circulating factors that participate in the regulation of lipid and glucose metabolism. Subjects and methods We measured serum ANGPTL3 and 4 levels in 23 patients with obesity, 40 patients with obesity and type 2 diabetes mellitus (T2DM), 22 patients with anorexia nervosa (AN), 15 subjects undergoing 72-h fasting, and 12 patients with short bowel syndrome (SBS), and their changes after very-low-calorie diet (VLCD), bariatric surgery, partial realimentation, acute fasting, and parenteral nutrition in order to assess their possible role in metabolic regulations. Results Serum ANGPTL4 levels were higher in obese subjects without/with T2DM (94.50 ± 9.51 and 134.19 ± 7.69 vs. 50.34 ± 4.22 ng/ml, p p = 0.002), while serum ANGPTL3 levels demonstrated inverse tendency. Nutritional status had no effect on ANGPTL3 and 4 mRNA expression in adipose tissue. Fasting decreased ANGPTL3 and increased ANGPTL4 levels, while VLCD reduced only ANGPTL3. Bariatric surgery and realimentation of AN or SBS patients had no effect on either ANGPTL. Multiple regression analysis identified BMI as an independent predictor of ANGPTL3; and BMI and HbA1c as independent predictors of ANGPTL4, respectively. Conclusions Taken together, our data suggest that serum ANGPTL3 and 4 levels are influenced by nutritional status and fasting and could be involved in the metabolic disturbances present in obesity and AN.

Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM.

Patients with obesity and type 2 diabetes often display high levels of the anti-diabetic factor fibroblast growth factor-21 (FGF21), suggesting that the overproduction of FGF21 may result from increased adiposity in an attempt by white adipose tissue (WAT) to counteract insulin resistance. However, the production of FGF21 diabetes in the absence of WAT has not been examined. In this study, we investigated the effects of lipodystrophy in A-ZIP F-1 mice on FGF21 production in relation to diabetes. A-ZIP F-1 mice displayed high FGF21 plasma levels resulting from enhanced FGF21 mRNA expression in the liver. Concomitant enhancement of FGF21 receptor (FGFR1) and glucose transporter 1 (GLUT-1) mRNA expression was observed in the muscles of A-ZIP F-1 mice. Furthermore, the activation of hypothalamic NPY and AgRP mRNA expression positively correlated with plasma levels of FGF21 but not active ghrelin. Our study demonstrates that an increased FGF21 plasma level in lipodystrophic A-ZIP F-1 mice results mainly from up-regulated liver production but does not suffice to overcome the lipodystrophy-induced severe type 2-diabetes and insulin resistance in the liver linked to the augmented liver fat deposition.

Salivary cortisol reflects the free fraction of serum cortisol. Monitoring salivary cortisol may be a promising alternative method for assessing serum cortisol in some clinical situations. We aimed to compare the reliability of salivary vs. serum cortisol during ACTH test. 84 subjects (mean age 63.2; 24-89 years; n=66 males) suspected for adrenocortical insufficiency underwent an ACTH test. Patients were divided based on peak serum cortisol into hypocortical group with cortisol 500 nmol/l. Median serum cortisol levels in reference group were 445, 766, and 902 nmol/l at 0, 30, and 60 minutes, respectively, and in hypocortical group were 256, 394, and 453 nmol/l. Median salivary cortisol levels were 19.02, 40.02, and 62.1 nmol/l in reference group, and 9.60, 14.08, and 13.28 nmol/l in hypocortical group. Obtained values showed good correlation between serum and salivary cortisol (p

Objective Fibroblast growth factor (FGF)-19 and FGF-21 are novel metabolic regulators that improve insulin resistance and obesity in rodents. The aim of the study was to assess the effects of laparoscopic sleeve gastrectomy (LSG) on serum concentrations of FGF-19 and FGF-21 along with circulating bile acids and other relevant hormonal and biochemical parameters. Design and Methods Seventeen females with obesity undergoing LSG and 15 lean healthy females were included into the study. Anthropometric and biochemical parameters, serum concentrations of FGF-19 and -21, insulin, adiponectin, leptin, C-reactive protein, resistin, amylin (total), ghrelin (active), glucagon-like peptide 1 (GLP-1, active), glucose-dependent insulinotropic peptide (GIP, total), peptide YY (PYY, total), pancreatic polypeptide (PP), and bile acids, and mRNA expression of selected adipokines and inflammatory markers in bioptic samples of subcutaneous fat were assessed at baseline and 6, 12, and 24 months after LSG. Results LSG markedly decreased body weight, BMI, waist circumference, and insulin levels and improved systemic inflammation and lipid levels. FGF-19 concentrations increased and FGF-21 concentrations decreased after LSG along with increased adiponectin and decreased leptin, amylin, and ghrelin levels. GLP-1, GIP, PP, and circulating bile acids were not affected by LSG. PYY decreased significantly 24 months after surgery only. mRNA expression analysis in subcutaneous fat showed markedly reduced proinflammatory state. Conclusions Our results indicate that increased FGF-19 and decreased ghrelin concentrations could have partially contributed to the improvement of systemic inflammation and some metabolic parameters after LSG, while changes of FGF-21 are rather secondary because of weight loss.

Nowadays, there is increasing evidence showing that the development of the metabolic syndrome combining obesity, type 2 diabetes mellitus, arterial hypertension and dyslipidemia involves except of traditional risk factors (overnutrition, lack of physical activity, genetic predisposition) also the effect of environmental organic substances called organic pollutants or endocrine disruptors. These chemicals can be found in plastic covers, paints, flame retardants, exhaust gases, fertilizers as well as diverse daily utensils. Phthalates, used primarily as plasticizers, and bisphenol A, are among the most wide-spread members of this group.The aim of this article is to provide a basic overview of the relationship between phthalates and bisphenol A and the etiopathogenesis of the metabolic syndrome and to highlight their potential sources. According to the analysis of materials used for parenteral nutrition and urinary excretion of phthalate metabolites and bisphenol A in subjects on long-term parenteral nutrition we suppose that currently used medical materials are safe with respect to the exposure to both phthalates and bisphenol A and that home environment, especially cosmetic products, might constitute a more probable source of these substances.

We studied the effect of peroxisome proliferator-activated receptor-α (PPAR-α) activation on serum concentrations and tissue expression of resistin, adiponectin, and adiponectin receptor-1 and -2 (AdipoR1 and AdipoR2) mRNA in normal mice and mice with insulin resistance induced by lipogenic, simple-carbohydrate diet (LD). Sixteen weeks of LD feeding induced obesity with liver steatosis and increased insulin levels but did not significantly affect circulating adiponectin or resistin. Treatment with PPAR-α agonist fenofibrate decreased body weight and fat pad weight and ameliorated liver steatosis in LD-fed mice with concomitant reduction in blood glucose, free fatty acid, triglyceride, serum insulin levels, and homeostasis model assessment index values. Euglycemic-hyperinsulinemic clamp demonstrated the development of whole-body and liver insulin resistance in LD-fed mice, which were both normalized by fenofibrate. Fenofibrate treatment markedly increased circulating resistin levels on both diets and adiponectin levels in chow-fed mice only. Fat adiponectin mRNA expression was not affected by fenofibrate treatment. Resistin mRNA expression increased in subcutaneous but not gonadal fat after fenofibrate treatment. In addition to fat, a significant amount of adiponectin mRNA was also expressed in the muscle. This expression markedly increased after fenofibrate treatment in chow- but not in LD-fed mice. Adipose tissue expression of AdipoR1 mRNA was significantly reduced in LD-fed mice and increased after fenofibrate treatment. In conclusion, PPAR-α activation ameliorated the development of insulin resistance in LD-fed mice despite a major increase in serum resistin levels. This effect could be partially explained by increased AdipoR1 expression in adipose tissue after fenofibrate treatment.

Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight and improved metabolic parameters, and attenuated lipogenesis in mice with diet-induced obesity. Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.

The objective was to study the effect of recombinant human growth hormone (rhGH) administration to patients with chronic malnutrition maintained on total parenteral nutrition (TPN) on the levels of insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBPs) during a double-blind trial. After 1 week of TPN the patients were randomized into group I (placebo) or group II (rhGH). Samples were collected on the first day (start of the TPN) to measure basal values, the seventh day to study the effect of TPN and the 10th, 14th and 21st days to evaluate the rhGH effect. Basal laboratory evaluation, nutritional status and glucose tolerance were assessed using standard laboratory techniques. Radioimmunoassays were used to analyse IGF-I, free IGF-I (fIGF-I) and IGFBP1-3. Electrophoresis with Western ligand blotting and Western immunoblotting was applied to find the pattern of IGFBPs. TPN had no effect on the circulating IGF-I concentration and the pattern of IGFBPs present in the studied groups of patients. The rhGH administration led to significant increases of IGF-I, total IGFBP-3, glycosylated IGFBP-3 (39, 42 kDa) and the 29 kDa fragment of IGFBP-3 and the decrease of IGFBP-2 during the trial (P

Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance. Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively. In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P

It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet. Ghrelin receptor antagonist [D-Lys(3)]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased β-hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair-feeding revealed that effect of [D-Lys(3)]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys(3)]GHRP-6. OVX [D-Lys(3)]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21. Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency.

Summary Objective Fibroblast growth factor-21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions. Design We measured biochemical parameters, serum FGF21, adiponectin, leptin and insulin levels by commercial ELISA and RIA kits, and mRNA expression in the liver, subcutaneous and visceral fat by RT PCR in 26 obese patients, 11 T2DM patients and 32 control subjects. The interventions were acute hyperinsulinaemia during isoglycaemic–hyperinsulinaemic clamp, very low calorie diet (VLCD) and 3 months treatment with PPAR-α agonist fenofibrate. Results Baseline serum FGF21 levels were significantly higher in both obese and T2DM patients relative to healthy controls. FGF21 levels in obesity did not significantly differ from T2DM group. Both 3 weeks of VLCD and 3 months of fenofibrate treatment significantly increased FGF21 levels. FGF21 mRNA expression in visceral fat was twofold higher in obesity relative to C group, while it did not differ in subcutaneous fat. VLCD significantly increased FGF21 mRNA expression in subcutaneous fat of obesity. 3-h hyperinsulinaemia during the clamp increased FGF21 levels in T2DM but not in C group. Conclusion An increase in FGF21 levels after VLCD and fenofibrate treatment may contribute to positive metabolic effect of these interventions and suggests the possibility of direct positive metabolic effects of FGF21 in humans.

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors alpha and beta were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-alpha, CD68, IL-6, IL-8, ER alpha, ER beta) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Ghrelin was originally isolated from the rat stomach and significant amounts were found also in the kidney. Present study was designed to examine changes in ghrelin levels in renal failure and their relationship to the GH/IGF-I axis. Fourty patients with mild-to-severe CRF (19 men, 21 women, aged 62.5 +/- 2.2 years, BMI 27.57 +/- 0.73 kg/m(2)) and 34 healthy control subjects (17 men, 17 women, aged 60 +/- 2.6 years, BMI 27.55 +/- 0.79 kg/m(2)) were included in the study. Total ghrelin levels were significantly increased in patients with chronic renal failure (CRF) (p < 0.0001). Total ghrelin in CRF correlated positively with active ghrelin (p < 0.001), GH (p < 0.05), IGF-I (p < 0.05), free IGF-I (p = 0.0001), IGFBP-3 (p < 0.01), IGFBP-2 and -6 (p < 0.05). Active ghrelin in CRF correlated positively with IGF-I (p < 0.001), free-IGF-I (p < 0.005), IGFBP-2 (p < 0.05) and IGFBP-3 (p < 0.05). However, most of the correlation were markedly reduced and the significance disappeared after adjustment for different creatinine levels. Hemodialysis in patients with end stage renal disease (ESRD) resulted in a significant reduction of plasma total and active ghrelin (p < 0.01 and p < 0.001 respectively). In conclusion we demonstrated elevated plasma levels of total ghrelin in CRF, and a reduction of total and active ghrelin after a single course of hemodialysis in ESRD. The elevation of ghrelin levels could be caused by impaired clearance and/or metabolism of ghrelin in the kidney. We did not prove clearly significant relationship between ghrelin serum levels and parameters of GH/IGF-I axis in study subjects.

Ghrelin is a peptide hormone that is involved in regulating growth hormone secretion as well as food intake and energy homeostasis. The aim of this study was to compare changes in plasma ghrelin levels in patients with malnutrition due to anorexia nervosa (AN) or short bowel syndrome (SBS). Blood samples for laboratory analyses were taken from 16 AN patients (plus 13 comparable healthy controls) and 27 SBS patients (plus 13 comparable healthy controls) after an overnight fast. In comparison with their respective control groups, plasma ghrelin levels were increased in the AN patients (p

Over the past decade we have seen a gradual increase in reports giving more support to the hypothesis that mildly or moderately increased values of serum prolactin have a role in the pathogenesis and clinical activity of systemic lupus erythematosus (SLE). Jara et al summed up this information in an article published in a special edition of the international journal Lupus .1 “Idiopathic hyperprolactinaemia” (hyperprolactin) has been confirmed under a variety of conditions by several authors, including us,2 in 20–30% of patients with SLE investigated; nevertheless, opinion continues to vary about its connection with greatly increased clinical activity of the disease.3,4 Prolactin is a hormone with a very wide range of action, and its effect on the immune response has been proved in both animal experiments5 and in humans.6 It is also one of the stress hormones, and the physiological 24 hour curve of its serum concentrations is similar to that of the growth hormone, a near relation, but not to those of the hormones along the line connecting the hypothalamus-pituitary-adrenocortex. In our first experiments designed to reproduce the study of hyperprolactin in patients with SLE or even rheumatoid arthritis (RA), we took account of the fact, emphasised by endocrinologists, that prolactin as a stress hormone is released in repeated pulses rather than continually; this is true at least, for the prolactin of pituitary origin, though not prolactin secreted in lymphoid paracrine tissue.7 The secretion of prolactin in the adenohypophysis …

The system of insulin-like growth factor-I (IGF-I) and its binding proteins is thought to be involved in the pathogenesis of vascular damage under different pathological circumstances. The results of various studies are rather controversial. This study considers the relationship between the activity of this system and the function of microcirculation in acromegalic patients. Thirteen patients with hormonally active acromegaly and 15 healthy controls were included in the study. The growth hormone, free IGF-I, IGF-I, IGF binding protein (IGFBP) -1, -2, -3 and -6 serum levels and parameters of lipid metabolism were determined. The function of microcirculation was determined by laser Doppler fluxmetry and the intima media thickness of the common carotid artery was measured by ultrasound. We noted significant reduction in postocclusive reactive hyperaemia (PORHmax) (P ≤ 0.01), in thermal hyperaemia (THmax) (P ≤ 0.05) and in the velocity of reaction in both tests in the group of acromegalic patients. A significant negative correlation between free IGF-I serum levels and maximal perfusion during thermal hyperaemia THmax (P ≤ 0.02) was found in the control group. Statistically significant positive correlation between free IGF-I serum levels and the time to maximal perfusion in postocclusive reactive hyperaemia PORHtmax (P ≤ 0.05) was found in the group with hormonally active acromegaly. Moreover, a positive relationship between IGFBP-1 serum levels and serum levels of total (P ≤ 0.01) and low density lipoprotein (LDL) (P ≤ 0.05) cholesterol was found in the group of patients with acromegaly. We conclude that the function of microcirculation is impaired in patients with acromegaly and that free IGF-I serum levels may affect the microvascular function as measured by laser Doppler fluxmetry. In addition, we found a significant relationship between the serum levels of IGFBP-1 and those of total and LDL cholesterol in the group of patients with hormonally active acromegaly.

Background Prolactin (PRL) is an anterior pituitary hormone which is known to stimulate humoral and cell mediated immune responses, and may have a role in the pathogenesis of systemic lupus erythematosus (SLE). Objectives To determine whether elevated serum prolactin associates the SLEDAI activity and/or specific organ involvement in SLE when recent reports have been till now discrepant. Methods Basal serum PRL levels were determined in 55 consecutive SLE patients (pts) (49 females, 6 males) and in 41 healthy controls (31 females, 10 males) by RIA method. The estimated normal values of serum PRL were 200 mUI/l for males and 450 mUI/l for females. Results The idiopathic hyperprolactinemia (hyper-PRL) was found in 7 SLE females (14,29%; 828,682 ± 391,410 mUI/l) and in 3 males (50,00%; 305,469 ± 65,751 mUI/l); and in one male in healthy controls (10,00%; 348,352 mUI/l) only. In remaining 42 SLE females and in 3 males PRL serum level was normal (365,783 ± 282,796 mUI/l; 142,854 ± 84,512 mUI/l). After 6 months repeatedly determined serum PRL in 2 females and 2 males with initial hyper-PRL, has shown normalisation in 1 female and 1 male. As to the proposed association between hyper-PRL and disease activity and specific organ involvement and presence of anti-ds-DNA there are some data on the Table 1. Conclusion There was significantly higher frequency of hyper-PRL in 55 SLE pts compared to 41 healthy controls (p References Walker SE, et al. Effect of prolactin in stimulating disease activity in SLE. Proc NY Acad Sci 1998;840:762–72 Neidhart M. Prolactin in autoimmune diseases. Proc Soc Exp Bio Med. 1998;217:408–79