Therapeutic application of GPR119 ligands in metabolic disorders.

GPR119 belongs to the G protein-coupled receptor family and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycaemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.

Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial.

Women with polycystic ovary syndrome (PCOS) were treated with the GLP-1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT) and the prevalence of nonalcoholic fatty liver disease (NAFLD). In a double-blind, placebo-controlled, randomized clinical trial 72 women with PCOS, with a BMI > 25 kg/m2 and/or insulin resistance, were treated with liraglutide or received placebo 1.8 mg/d (2:1) for 26 weeks. Liver fat content was assessed by 1 HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test. Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD by two-thirds (all P < .01). Sex-hormone-binding-globulin (SHBG) levels increased by 19% (P = .03), and free testosterone decreased by 19% (P = .054). HbA1c, fasting glucose and leptin were reduced (all: P < .05), whereas measures of insulin resistance, adiponectin and glucagon did not change. In conclusion, 26 weeks of liraglutide treatment in PCOS resulted in significant reductions in liver fat content, VAT and the prevalence of NAFLD.

A systematic review of Gymnema sylvestre in obesity and diabetes management.

The prevalence of obesity is associated with many health-related problems. Currently, more than 300 million people are considered to be obese. According to the World Health Organization (WHO), by 2030, 87 and 439 million people will be affected in India and the world, respectively. Today, herbal medicines are gaining interest in the treatment of obesity and diabetes, because of their minimal side effects. Gymnemic acid - an active component isolated from Gymnema sylvestre - has anti-obesity and antidiabetic properties, decreases body weight and also inhibits glucose absorption. Several components extracted from Gymnema prevent the accumulation of triglycerides in muscle and liver, and also decrease fatty acid accumulation in the circulation. In this paper, an attempt has been made to review the effects of various extracts from Gymnema sylvestre in the regulation of carbohydrate and lipid metabolism in both animal and clinical studies.

Antihyperglycemic, hypolipidemic, hepatoprotective and antioxidative effects of dietary clove (Szyzgium aromaticum) bud powder in a high-fat diet/streptozotocin-induced diabetes rat model.

BACKGROUND: Syzygium aromaticum (L.) Merr. & Perry (clove) bud is an important spice used in the preparation of several delicacies and in folklore for diabetes management. The present study was convened to assess the effects of dietary clove bud powder (CBP) on biochemical parameters in a type 2 diabetes rat model, induced by a combination of high-fat diet and low-dose streptozotocin (35 mg kg⁻¹) for 30 days. RESULTS: Diabetic rats were placed on dietary regimen containing 20-40 g kg⁻¹ clove bud powder. The results revealed that there was no significant (P > 0.05) difference in the average feed intake and weight changes between the rat groups. Furthermore, supplementation with CBP gradually reduced blood glucose level in diabetic rat compared to control diabetic rats without CBP supplementation (DBC). Moreover, reduced activity of α-glucosidase was observed in CBP and metformin-treated rat groups when compared to that of the DBC rat group. In addition, the DBC group had significantly (P < 0.05) higher lipid concentrations (except for high-density lipoprotein cholesterol) when compared to all other groups. Furthermore, CBP had significantly (P < 0.05) reduced activity of liver enzymes (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) and showed elevated levels of antioxidant status (glutathione, ascorbic acid, superoxide dismutase and catalase). CONCLUSION: The results suggest that the clove bud diet may attenuate hyperglycemia, hyperlipidemia, hepatotoxicity and oxidative stress in the type 2 diabetic condition.

Treatment of postoperative ileus with choline citrate--results of a prospective, randomised, placebo-controlled, double-blind multicentre trial.

OBJECTIVES: This was a prospective, randomised, placebo-controlled, double-blind multicentre trial to analyse the efficacy of choline citrate in patients with postoperative ileus (POI) after elective colorectal surgery. METHODS: From October 2005 until June 2008, 122 patients with POI were randomised to receive choline citrate or placebo. One hundred twenty patients were evaluable for tolerability and 107 patients were evaluable for efficacy. The treatment group, 47% (50/107), received 300.2 mg choline citrate intravenously, while the placebo group, 53% (57/107), received sodium chloride. Injections were performed every 12 h until defecation. RESULTS: Demographic data analysis did not show clinically differences between both groups. Operative procedures included 40% (43/107) hemicolectomy, 38% (41/107) sigmoid resection and 22% (23/107) other colorectal resections. Defecation occurred after an average of 91.8 ± 26.6 h postoperatively in the treatment group, vs. 96.7 ± 35.2 h in the placebo group (p = 0.805). After laparoscopy, defecation occurred after 78.7 ± 25.3 h, vs. 99.2 ± 31.6 h after laparotomy (p = 0.001). Serious adverse effects occurred in 2% (1/60) in the treatment group, vs. 3% (2/60) in the placebo group. None of the events have been assessed as related to the study medication. CONCLUSION: An efficacy of choline citrate in the treatment of POI after elective colorectal surgery could not be verified. The problem of POI requiring drug treatment seems to be less frequent than suggested by the literature. With technical advances in surgery, especially laparoscopic and fast track surgery, the frequency of POI will further decrease in the future.

Glucose homeostasis, insulin resistance and inflammatory biomarkers in patients with non-alcoholic fatty liver disease: Beneficial effects of supplementation with microalgae Chlorella vulgaris: A double-blind placebo-controlled randomized clinical trial.

BACKGROUND: Chlorella vulgaris (C. vulgaris) is reported to improve dyslipidemia and hypertension; however, its effect on inflammatory biomarkers and insulin resistance has not been noticed thus far. Non-alcoholic fatty liver disease (NAFLD) as a hepatic symptom of metabolic syndrome is strongly associated with insulin resistance and inflammation. AIM OF THE STUDY: In the current interventional trial, we aimed to study the effects of C. vulgaris supplementation on glucose homeostasis, insulin resistance and inflammatory biomarkers in patients with NAFLD. METHODS: Seventy NAFLD patients confirmed by ultra-sonographic findings were randomly assigned into intervention group (four 300 mg tablets of C. vulgaris) or placebo group (four 300 mg tablets of placebos) for 8 weeks. Anthropometric measurements, liver enzymes, fasting serum glucose (FSG), insulin, high sensitive C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-α) were assessed and homeostatic model assessment (HOMA) score for insulin resistance was estimated before and after the intervention. RESULTS: Anthropometric measurements decreased significantly in both group (p < 0.001). However, mean reduction in weight was significantly higher in C. vulgaris - treated group compared to placebo group. Serum concentrations of liver enzymes, FSG and hs-CRP also significantly decreased and serum insulin concentration and HOMA score increased significantly only in C. vulgaris-treated group (P < 0.001, P < 0.006 and P < 0.025, respectively). Mean change in serum glucose and TNF-α levels were significant between the groups even after adjusting for the serum insulin and baseline values of variables (P = 0.014, P = 0.005, P = 0.014, respectively); between-group differences were not significant for the other variables by the end of study. CONCLUSION: To our finding, C. vulgaris supplementation could be considered as an adjunctive therapy to decrease weight and improve glycemic status and reducing hs-CRP as well as improving liver function in patients with NAFLD. IRCT NUMBER: 201202233320N7.

Protective and therapeutic effects of Crataegus aronia in non-alcoholic fatty liver disease.

AIM: We evaluated the potential preventive and therapeutic effects of Crataegus aronia (C. aronia) in NAFLD induced by high-fat diet (HFD) in rat models. METHODS: Protective effect of Crataegus aronia or simvastatin was investigated in Wistar rats fed either low-fat diet (LFD) or HFD. RESULTS: Liver histopathological examinations confirmed the development of NAFLD in rats fed HFD. In both protective and therapeutic treatments, C. aronia significantly reduced liver index (3.85 ± 0.21% in HFD plus aronia group versus 6.22 ± 0.58% in HFD model group), increased the HDL-cholesterol and reduced the LDL-cholesterol in blood. The hawthorn plant also significantly ameliorated oxidative stress biomarker (p < 0.002) and liver enzymes (p < 0.0001) that indicate liver damage. CONCLUSION: C. aronia exhibits therapeutic and protective effects on NAFLD in an animal model possibly by its lipid lowering and antioxidant effects; thus, may offer therapeutic potential in humans.

Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet.

Recent studies have shown that dietary creatine supplementation can prevent lipid accumulation in the liver. Creatine is a small molecule that plays a large role in energy metabolism, but since the enzyme creatine kinase is not present in the liver, the classical role in energy metabolism does not hold in this tissue. Fat accumulation in the liver can lead to the development of nonalcoholic fatty liver disease (NAFLD), a progressive disease that is prevalent in humans. We have previously reported that creatine can directly influence lipid metabolism in cell culture to promote lipid secretion and oxidation. Our goal in the current study was to determine whether similar mechanisms that occur in cell culture were present in vivo. We also sought to determine whether dietary creatine supplementation could be effective in reversing steatosis. Sprague-Dawley rats were fed a high-fat diet or a high-fat diet supplemented with creatine for 5 weeks. We found that rats supplemented with creatine had significantly improved rates of lipoprotein secretion and alterations in mitochondrial function that were consistent with greater oxidative capacity. We also find that introducing creatine into a high-fat diet halted hepatic lipid accumulation in rats with fatty liver. Our results support our previous report that liver cells in culture with creatine secrete and oxidize more oleic acid, demonstrating that dietary creatine can effectively change hepatic lipid metabolism by increasing lipoprotein secretion and oxidation in vivo. Our data suggest that creatine might be an effective therapy for NAFLD.

Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase.

Non-alcoholic fatty liver disease is associated with inhibited AMP-activated kinase (AMPK) and activation of sterol regulatory element binding protein 1 (SREBP-1). AMPK phosphorylation inhibits SREBP-1, a major transcription factor of de novo lipogenesis, by inhibiting the liver X receptor (LXR) or by direct phosphorylation. Resveratrol, a polyphenol, has regulatory effects on hepatic lipid metabolism as a potent AMPK activator. In this study, we evaluated the anti-steatogenic effects of resveratrol and its derivatives and identified the molecular mechanism in vitro and in vivo. Resveratrol and its derivatives decreased lipid accumulation by free fatty acids (FFA mixture; 0.5 mM, oleic acid:palmitic acid = 2: 1) in H4IIEC3 cells. Synthesized derivatives of resveratrol had lower cytotoxicity than the parental molecule with similar potency. SY-102 suppressed SREBP-1 maturation by T0901317, an LXR agonist, and decreased SRE luciferase activity and the mRNA levels of lipogenic genes. Inhibition of AMPK by pre-treatment with compound C completely blocked the effects of SY-102. To evaluate their efficacy in vivo, mice were fed a high-fat diet for 5 days, and resveratrol or SY-102 was administered orally for the last 2 days. Oral administration of the SY-102 increased AMPK phosphorylation, followed by reduced hepatic triglyceride accumulation to a similar extent as resveratrol. These data demonstrate that SY-102, a synthesized derivative of resveratrol, might provide a promising therapeutic effect against fatty liver disease.

Fibroblast growth factor 21 and thyroid hormone show mutual regulatory dependency but have independent actions in vivo.

Thyroid hormone (TH) regulates fibroblast growth factor 21 (FGF21) levels in the liver and in the adipose tissue. In contrast, peripheral FGF21 administration leads to decreased circulating levels of TH. These data suggest that FGF21 and TH could interact to regulate metabolism. In the present study, we confirmed that TH regulates adipose and hepatic FGF21 expression and serum levels in mice. We next investigated the influence of TH administration on key serum metabolites, gene expression in the liver and brown adipose tissue, and energy expenditure in FGF21 knockout mice. Surprisingly, we did not observe any significant differences in the effects of TH on FGF21 knockout mice compared with those in wild-type animals, indicating that TH acts independently of FGF21 for the specific outcomes studied. Furthermore, exogenous FGF21 administration to hypothyroid mice led to similar changes in serum and liver lipid metabolites and gene expression in both hypothyroid and euthyroid mice. Thus, it appears that FGF21 and TH have similar actions to decrease serum and liver lipids despite having some divergent regulatory effects. Whereas TH leads to up-regulation in the liver and down-regulation in brown adipose tissue of genes involved in the lipid synthesis pathway (eg, fatty acid synthase (FASN) and SPOT14), FGF21 leads to the opposite changes in expression of these genes. In conclusion, TH and FGF21 act independently on the outcomes studied, despite their ability to regulate each other's circulating levels. Thus, TH and FGF21 may modulate the availability of each other in critical metabolic states.

Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study.

In a prospective, randomized, double-blind therapeutic trial, 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d. orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate (Ietepar) (96 patients) or with undistinguishable placebo capsules (95 patients). The verum treatment effectively reduced by 25% hepatic steatosis (p < 0.01) and by 6% hepatomegaly (p < 0.05), while placebo did not significantly reduce the disorders. Verum was also more effective than placebo on discomfort in abdominal upper right quadrant. The global efficacy of treatment was rated by the doctor "very good" or "good" in 48% of verum treated patients and only in 17% after placcbo (P of difference = 9 x 10(-6)). 52% of patients self-rated efficacy as "very good" or "good" after verum and only 34% after placebo (P of difference = 0.017). The verum treatment provoked a significant reduction of the increased liver transaminases (ALT, AST and gamma-GT) while placebo was ineffective. Adverse events were recorded in 10% of verum-treated patients and in 7% under placebo (no significant difference). In both groups the adverse events were mild and transient, did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders. In conclusion, the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis, a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective.

Alergia de contacto a 3-dimetilaminopopilamina y cocamidopropil betaína / Contact allergy to 3-dimethylaminopropylamine and cocamidopropyl betaine

Se ha descubierto que todos los individuos con alergia a la cocamidopropil betaína (CAPB) se encuentran sensibilizados a la 3-dimetilaminopropilamina (DMAPA) y a la amidoamina, moléculas que son intermediarias en la síntesis de CAPB, y que persisten como impurezas en el material comercializado, en cantidades variables dependiendo de la calidad de la CAPB en el producto final. Se presentan 3 casos de dermatitis de contacto alérgica a DMAPA. En los tres las pruebas epicutáneas para DMAPA fueron positivas, mientras que no hubo reacción a la CAPB. La relevancia actual de estas pruebas fue confirmada por la reexposición de los pacientes a los productos propios sospechados, que contenían CAPB. La alergia de contacto a la CAPB es ahora poco frecuente, en parte por el creciente uso de nuevos agentes tensoactivos no irritantes introducidos en el mercado en la última década. Sin embargo, siguen dándose a conocer casos de pacientes alérgicos a la CAPB comercial que sólo reaccionan a la DMAPA ­y no a la CAPB­ cuando son parcheados. La propia DMAPA u otras moléculas como la amidoamina serían los alérgenos verdaderos y, por tanto, algunos casos de alergia a la CAPB se estarían pasando por alto debido a que la DMAPA no siempre está incluida en la serie de cosméticos. La CAPB podría no ser ya necesaria en las pruebas del parche, puesto que la DMAPA parece ser la principal fracción alergénica en este agente tensoactivo, y también porque los fabricantes de alérgenos epicutáneos elaboran unos extractos de CAPB tan puros que no son ya una buena herramienta de cribado de la alergia de contacto a la CAPB comercial

It has been discovered that all individuals who are allergic to cocamidopropyl betaine (CAPB) are sensitized to 3-dimethylaminopropylamine (DMAPA) and to amidoamine, molecules which are intermediaries in CAPB synthesis, and which persist as impurities in the material that is sold; the amounts vary, depending on the quality of the CAPB in the end product. We present three cases of allergic contact dermatitis to DMAPA. In all three cases, the skin tests for DMAPA were positive, while there was no reaction to CAPB. The current relevance of these tests was confirmed by the patients' re-exposure to the suspect products themselves, which contained CAPB. Contact allergy to CAPB is now infrequent, partly because of the increasing use of new non-irritating surfactants that have been introduced on the market in the last decade. However, cases of patients allergic to commercial CAPB who only react to DMAPA ­and not to CAPB­ when they are patch tested are still being reported. DMAPA itself, and other molecules like amidoamine, would be the true allergens, and some cases of CAPB allergy are therefore being overlooked because DMAPA is not always included in the cosmetics series. CAPB may no longer be necessary in patch tests, as DMAPA seems to be the principal allergenic fraction in this surfactant, and also because manufacturers of skin allergens currently prepare CAPB extracts that are so pure that they are no longer a good screening tool for contact allergy to commercial CAPB