A randomized controlled trial: the effect of inulin on weight management and ectopic fat in subjects with prediabetes.

BACKGROUND: Fat infiltration of the liver, muscle and pancreas is associated with insulin resistance and risk of diabetes. Weight loss reduces ectopic fat deposition and risk of diabetes, but is difficult to sustain to due to compensatory increases in appetite. Fermentable carbohydrates have been shown to decrease appetite and food intake, and promote weight loss in overweight subjects. In animal studies, fermentable carbohydrate reduces ectopic fat independent of weight loss. We aimed to investigate the effect of the fermentable carbohydrate inulin on weight maintenance, appetite and ectopic fat in subjects with prediabetes. METHODS: Forty-four subjects with prediabetes were randomized to 18 weeks' inulin or cellulose supplementation. During weeks 1-9 (weight loss phase) all subjects had four visits with a dietitian to guide them towards a 5 % weight loss. During weeks 10-18 (weight maintenance phase) subjects continued taking their assigned supplementation and were asked to maintain the weight they had lost but were offered no further support. All subjects attended study sessions at baseline, 9 and 18 weeks for measurement of weight; assessment of adipose tissue and ectopic fat content by magnetic resonance imaging and magnetic resonance spectroscopy; glucose, insulin and GLP-1 levels following a meal tolerance test; and appetite by ad libitum meal test and visual analogue scales. RESULTS: Both groups lost approximately 5 % of their body weight by week nine (-5.3 ± 0.1 % vs -4.3 ± 0.4 %, p = 0.13, but the inulin group lost significantly more weight between 9 and 18 weeks (-2.3 ± 0.5 % vs -0.6 ± 0.4 %, p = 0.012). Subjects taking inulin had lower hepatic (p = 0.02) and soleus muscle (p < 0.05) fat content at 18 weeks compared to control even after controlling for weight loss and consumed less at the ad libitum meal test (p = 0.027). Fasting glucose significantly decreased at week nine only (p = 0.005), insulin concentrations did not change, and there was a significant increase in GLP-1 in the cellulose group at 9 and 18 weeks (p < 0.03, p < 0.00001). CONCLUSION: Inulin may have a two-pronged effect on the risk of diabetes by 1) promoting weight loss 2) reducing intrahepatocellular and intramyocellular lipid in people with prediabetes independent of weight loss

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53-/-. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo

Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets.

Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n=11) and low liver fat 'controls' (n= 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling. There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high ( P <0.02) and low sugar ( P <0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet ( P <0.01), and a higher VLDL1-TAG production rate after the low sugar diet ( P <0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG ( P <0.02) in the controls, but in contrast, a higher production of VLDL2-TAG ( P <0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. This study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars.The work was supported by a UK government grant from the Biological Biotechnology Scientific Research Council (Grant no. BB/G009899/1); University of Surrey PhD scholarship for AM; Medical Research Council (body composition measurements) and infrastructure support from the National Institute of Health Research at the Cambridge Biomedical Research Centre

Circulating pancreatic polypeptide concentrations predict visceral and liver fat content

CONTEXT AND OBJECTIVE: No current biomarker can reliably predict visceral and liver fat content, both of which are risk factors for cardiovascular disease. Vagal tone has been suggested to influence regional fat deposition. Pancreatic polypeptide (PP) is secreted from the endocrine pancreas under vagal control. We investigated the utility of PP in predicting visceral and liver fat. PATIENTS AND METHODS: Fasting plasma PP concentrations were measured in 104 overweight and obese subjects (46 men and 58 women). In the same subjects, total and regional adipose tissue, including total visceral adipose tissue (VAT) and total subcutaneous adipose tissue (TSAT), were measured using whole-body magnetic resonance imaging. Intrahepatocellular lipid content (IHCL) was quantified by proton magnetic resonance spectroscopy. RESULTS: Fasting plasma PP concentrations positively and significantly correlated with both VAT (r = 0.57, P < .001) and IHCL (r = 0.51, P < .001), but not with TSAT (r = 0.02, P = .88). Fasting PP concentrations independently predicted VAT after controlling for age and sex. Fasting PP concentrations independently predicted IHCL after controlling for age, sex, body mass index (BMI), waist-to-hip ratio, homeostatic model assessment 2-insulin resistance, (HOMA2-IR) and serum concentrations of triglyceride (TG), total cholesterol (TC), and alanine aminotransferase (ALT). Fasting PP concentrations were associated with serum ALT, TG, TC, low- and high-density lipoprotein cholesterol, and blood pressure (P < .05). These associations were mediated by IHCL and/or VAT. Fasting PP and HOMA2-IR were independently significantly associated with hepatic steatosis (P < .01). CONCLUSIONS: Pancreatic polypeptide is a novel predictor of visceral and liver fat content, and thus a potential biomarker for cardiovascular risk stratification and targeted treatment of patients with ectopic fat deposition

Genetic predisposition influences plasma lipids of participants on habitual diet, but not the response to reductions in dietary intake of saturated fatty acids

Objective: SNPs identified from genome wide association studies associate with lipid risk markers of cardiovascular disease. This study investigated whether these SNPs altered the plasma lipid response to diet in the ‘RISCK’ study cohort. Methods: Participants (n = 490) from a dietary intervention to lower saturated fat by replacement with carbohydrate or monounsaturated fat, were genotyped for 39 lipid-associated SNPs. The association of each individual SNP, and of the SNPs combined (using genetic predisposition scores), with plasma lipid concentrations was assessed at baseline, and on change in response to 24 weeks on diets. Results: The associations between SNPs and lipid concentrations were directionally consistent with previous findings. The genetic predisposition scores were associated with higher baseline concentrations of plasma total(P = 0.02) and LDL (P = 0.002) cholesterol, triglycerides (P = 0.001) and apolipoprotein B (P = 0.004), and with lower baseline concentrations of HDL cholesterol (P < 0.001) and apolipoprotein A-I (P < 0.001). None of the SNPs showed significant association with the reduction of plasma lipids in response to the dietary interventions and there was no evidence of diet-gene interactions. Conclusion: Results from this exploratory study have shown that increased genetic predisposition was associated with an unfavourable plasma lipid profile at baseline, but did not influence the improvement in lipid profiles by the low-saturated-fat diets

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium

Aims/hypothesis The DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT. Methods Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size similar to 1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires. Conclusinos/interpretation DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes

Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk: An IMI Direct study

Background: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. Methods: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 n=403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 n=458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariate regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. Findings: A higher Tpred was associated with healthier diets high in wholegrain (β=0.004 g, p=0.02 and β=0.003 g, p=0.03) and lower energy intake (β=-0.0002 kcal, p=0.04 and β=-0.0002 kcal, p=0.003), and saturated fat (β=-0.03 g, p<.0001 and β=-0.03 g, p<.0001), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and improved lipid profiles HDL-cholesterol (β=0.07 mmol/L, p<.0001), (β=0.08 mmol/L, p=0.0002), and triglycerides (β=-0.1 mmol/L, p=0.003), (β=-0.2 mmol/L, p=0.0002), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat content (β=-0.74 %, p<.0001), and lower fasting concentrations of HbA1c (β=-0.9mmol/mol, p=0.02), glucose (β=-0.2 mmol/L, p=0.01) and insulin (β=-11.0 pmol/mol, p=0.01). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (β=-0.2 mmol/L, p=0.03) and insulin (β=-9.2 pmol/mol, p=0.04) concentrations in cohort 2. Interpretation: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health

Modeling infectious disease dynamics in the complex landscape of global health.

Despite some notable successes in the control of infectious diseases, transmissible pathogens still pose an enormous threat to human and animal health. The ecological and evolutionary dynamics of infections play out on a wide range of interconnected temporal, organizational, and spatial scales, which span hours to months, cells to ecosystems, and local to global spread. Moreover, some pathogens are directly transmitted between individuals of a single species, whereas others circulate among multiple hosts, need arthropod vectors, or can survive in environmental reservoirs. Many factors, including increasing antimicrobial resistance, increased human connectivity and changeable human behavior, elevate prevention and control from matters of national policy to international challenge. In the face of this complexity, mathematical models offer valuable tools for synthesizing information to understand epidemiological patterns, and for developing quantitative evidence for decision-making in global health

Algunes reflexions entorn de la conceptualització de la infància i adolescència en risc social a l'Estat espanyol

L'article realitza una aproximació a les interpretacions del concepte de risc social de la infancia per part de diversos autors d'àmbit estatal, tenint també en compte els marcs legals català i espanyol. Pretén aclarir quins són els criteris valoratius emprats, tant des de l'àmbit acadèmic com del professional, per interpretar les categoritzacions de la infància i l'adolescència en processos de dificultat i precarietat social. Des d'aquesta perspectiva, s'hi analitza l'estreta relació entre factors de risc, desemparament i marginació. S'hi rebutgen les interpretacions que responsabilitzen el propi menor de la desadaptació, i s'hi defensa la hipótesi de la necessitat d'una intervenció socioeducativa que treballi per una disminució dels factors de risc en el propi medi, mantenint el seu protagonisme en aquest procés.This article is an approach to the different acceptances of the concept social risk as well as the terms neglect and maladjustment, based on the reflections made by different authors and both statal and autonomous legal framework. It intends to clarify which are the criteria of values used in academic and professional ambits in order to understand the categoriesfound in the fields of childhood and adolescence in difficult and precarious conditions. The strong relation between risk factors, neglect and margination has been analysed from this point of view. In the same way the interpretations that hold the minor himself responsible for his maladjustment are rejected and the author defends the necessity of a socio-educational intervention, which reduces the risk factors in the child's environment, and the need of paying close attention to the child's main role in this process.El artículo realiza una aproximación a las interpretaciones del concepto de riesgo social de la infancia por parte de diversos autores de ámbito estatal, teniendo también en cuenta los marcos legales catalán y español. Pretende aclarar cuáles son los criterios valorativos utilizados, tanto desde el ámbito academico como profesional, para interpretar las categorizaciones de la infancia en procesos de dificultad y precariedad. Desde esta perspectiva, se analiza la estrecha relación entre factores de riesgo, desamparamiento y marginación. Se rechazan las interpretaciones que responsabilizan al propio menor de la desadaptación y se defiende la hipótesis de la necesidad de una intervención socioeducativa que trabaje para una disminución de los factores de riesgo en el propio medio, manteniendo su protagonismo en este proceso