Combination Therapy of Endoscopic Gastric Remodeling with GLP-1RA for the Treatment of MASLD.

PURPOSE: The mainstay of treatment for metabolic dysfunction-associated steatotic liver disease (MASLD) is weight loss. Endoscopic gastric remodeling (EGR) and glucagon-like peptide-1 receptor agonist (GLP-1RA) are effective weight loss therapies. This study aims to assess the effect of combining EGR with GLP-1RA on liver-related outcomes and weight profile. MATERIALS AND METHODS: This is a retrospective study of a prospectively collected registry of patients with MASLD and compensated advanced chronic liver disease (cACLD) who underwent EGR. Patients were categorized as (1) monotherapy: EGR alone and (2) combination therapy: GLP-1RA prescribed within 6 months prior to or after EGR. Outcomes included changes in noninvasive tests of hepatic fibrosis, weight profile, and insulin resistance status at 12 months. RESULTS: Thirty patients (body mass index 40.7 ± 9.3 kg/m2) were included. Of these, 12 patients (40%) underwent EGR monotherapy, and 18 patients (60%) underwent EGR + GLP-1RA combination therapy. Combination therapy group experienced greater improvements in fibrosis compared to monotherapy group (alanine aminotransferase: reduction by 55 ± 23% vs 29 ± 22% (p = 0.008), NAFLD fibrosis score: reduction by 181 ± 182% vs 30 ± 83% (p = 0.04), liver stiffness measurement on transient elastography: reduction by 54 ± 12% vs 14 ± 45% (p = 0.05)). There were greater reductions in hemoglobin A1c and homeostatic model assessment for insulin resistance in combination therapy compared to monotherapy (p < 0.05). At 12 months, the combination therapy group experienced 18.2 ± 6.6% TWL, while monotherapy group experienced 9.6 ± 3.3% TWL (p = 0.004). CONCLUSIONS: In patients with MASLD and cACLD, combination of EGR with GLP-1RA is associated with greater improvements in hepatic fibrosis, weight profile, and insulin resistance compared to EGR alone.

Reduced tillage and crop diversification can improve productivity and profitability of rice-based rotations of the Eastern Gangetic Plains.

Intensive rice (Oryza sativa)-based cropping systems in south Asia provide much of the calorie and protein requirements of low to middle-income rural and urban populations. Intensive tillage practices demand more resources, damage soil quality, and reduce crop yields and profit margins. Crop diversification along with conservation agriculture (CA)-based management practices may reduce external input use, improve resource-use efficiency, and increase the productivity and profitability of intensive cropping systems. A field study was conducted on loamy soil in a sub-tropical climate in northern Bangladesh to evaluate the effects of three tillage options and six rice-based cropping sequences on grain, calorie, and protein yields and gross margins (GM) for different crops and cropping sequences. The three tillage options were: (1) conservation agriculture (CA) with all crops in sequences untilled, (2) alternating tillage (AT) with the monsoon season rice crop tilled but winter season crops untilled, and (3) conventional tillage (CT) with all crops in sequences tilled. The six cropping sequences were: rice-rice (R-R), rice-mung bean (Vigna radiata) (R-MB), rice-wheat (Triticum aestivum) (R-W), rice-maize (Zea mays) (R-M), rice-wheat-mung bean (R-W-MB), and rice-maize-mung bean (R-M-MB). Over three years of experimentation, the average monsoon rice yield was 8% lower for CA than CT, but the average winter crops yield was 13% higher for CA than CT. Systems rice equivalent yield (SREY) and systems calorie and protein yields were about 5%, 3% and 6%, respectively, higher under CA than CT; additionally, AT added approximately 1% more to these benefits. The systems productivity gain under CA and AT resulted in higher GM by 16% while reducing the labor and total production cost under CA than CT. The R-M rotation had higher SREY, calorie, protein yields, and GM by 24%, 26%, 66%, and 148%, respectively, than the predominantly practiced R-R rotation. The R-W-MB rotation had the highest SREY (30%) and second highest (118%) GM. Considering the combined effect of tillage and cropping system, CA with R-M rotation showed superior performance in terms of SREY, protein yield, and GM. The distribution of labor use and GM across rotations was grouped into four categories: R-W in low-low (low labor use and low GM), R-M in low-high (low labor use and high GM), R-W-MB and R-M-MB in high-high (high labor use and high GM) and R-R and R-MB in high-low (high labor use and low GM). In conclusion, CA performed better than CT in different winter crops and cropping systems but not in monsoon rice. Our results demonstrate the multiple benefits of partial and full CA-based tillage practices employed with appropriate crop diversification to achieve sustainable food security with greater calorie and protein intake while maximizing farm profitability of intensive rice-based rotational systems.

Consider your origins: Parental social class and preferences for redistribution in the United States from 1977 to 2018.

Capitalizing on the newly available and consistent coding of detailed occupations for the General Social Surveys (GSS), this article examines the link between class origins and public support for redistribution in the United States from 1977 through 2018. The findings reveal significant net associations between class origins and preferences for redistribution. Individuals with farming-class or working-class origins are more supportive of government action to reduce inequality than individuals with salariat-class origins. These class-origin differences are associated with individuals' current socioeconomic characteristics but are not fully accounted for by these factors. In addition, individuals in more privileged class positions have increased their support for redistribution over time. Attitudes toward federal income taxes are also analyzed as an additional measure of redistribution preferences. Overall, the findings suggest a continuing role of class origin in determining support for redistribution.

In vitro Scolicidal Efficacy of 5-Fluorouracil and Radiation Against Protoscoleces of Echinococcus granulosus Sensu Lato.

PURPOSE: Cystic echinococcosis (CE) caused by Echinococcus granulosus sensu lato (s.l.) is a globally distributed zoonosis. CE treatment is difficult, but radiation and 5-fluorouracil (5-FU) can be effective. However, the combination of radiation and 5-FU has not been reported. This study evaluated the effect of combination of 5-FU and radiation on E. granulosus s.l. protoscoleces (PSCs). MATERIAL AND METHODS: In this study, PSCs were collected from the liver of diseased sheep, and some were exposed to a single dose of 20 Gy 6-MV X-ray combined with (5 µg/mL or 10 µg/mL) 5-FU in vitro. Methylene blue staining was used to detect the viability of the PSCs. Transcription of EgHSP70 and Egp38 was measured by quantitative real-time PCR (qRT- PCR). RESULTS: A single dose of radiation killed 18% of the PSCs, and 5-FU showed weak parasiticidal efficacy on the first day of treatment. After 14 d, 5 µg and 10 µg/mL of 5-FU killed 40.20% and 50.02% of the PSCs, whereas 20 Gy of radiation killed 31.44%. The combination of 5-FU (10 µg/mL) with 20 Gy of radiation showed 77.55% killing efficacy. qRT-PCR showed that 5-FU inhibited Egp38 expression, whereas radiation increased its expression. EgHSP70 was highly expressed 14 days after radiation treatment. The data indicate that 5-FU has parasiticidal efficacy against the PSCs of E. granulosus s.l. CONCLUSION: The lethal efficacy of PSCs caused by a single dose of radiation exposure is related to the upregulated expression level of Egp38 and EgHSP70. The killing effect of 5-FU (10 µg/mL) with 20Gy of radiation was significantly better than that of single treatment group. This study provided a basis for the potential role of 5-FU combined with radiation in the treatment of CE.

Estimating Enhanced Endogenous Glucose Production in Intensive Care Unit Patients with Severe Insulin Resistance.

BACKGROUND: Critically ill ICU patients frequently experience acute insulin resistance and increased endogenous glucose production, manifesting as stress-induced hyperglycemia and hyperinsulinemia. STAR (Stochastic TARgeted) is a glycemic control protocol, which directly manages inter- and intra- patient variability using model-based insulin sensitivity (SI). The model behind STAR assumes a population constant for endogenous glucose production (EGP), which is not otherwise identifiable. OBJECTIVE: This study analyses the effect of estimating EGP for ICU patients with very low SI (severe insulin resistance) and its impact on identified, model-based insulin sensitivity identification, modeling accuracy, and model-based glycemic clinical control. METHODS: Using clinical data from 717 STAR patients in 3 independent cohorts (Hungary, New Zealand, and Malaysia), insulin sensitivity, time of insulin resistance, and EGP values are analyzed. A method is presented to estimate EGP in the presence of non-physiologically low SI. Performance is assessed via model accuracy. RESULTS: Results show 22%-62% of patients experience 1+ episodes of severe insulin resistance, representing 0.87%-9.00% of hours. Episodes primarily occur in the first 24 h, matching clinical expectations. The Malaysian cohort is most affected. In this subset of hours, constant model-based EGP values can bias identified SI and increase blood glucose (BG) fitting error. Using the EGP estimation method presented in these constrained hours significantly reduced BG fitting errors. CONCLUSIONS: Patients early in ICU stay may have significantly increased EGP. Increasing modeled EGP in model-based glycemic control can improve control accuracy in these hours. The results provide new insight into the frequency and level of significantly increased EGP in critical illness.

Effects of endoscopic gastric plication on portal pressure gradient in a patient with nonalcoholic steatohepatitis cirrhosis.

Video 1Endoscopic gastric plication (EGP) to treat obesity and nonalcoholic steatohepatitis (NASH) in a patient with compensated cirrhosis, as well as the application of EUS-guided portal pressure gradient (EUS-PPG) measurement to monitor changes in PPG after EGP.

Estimating Increased EGP During Stress Response in Critically Ill Patients.

BACKGROUND: Stress-induced hyperglycemia is frequently experienced by critically ill patients and the use of glycemic control (GC) has been shown to improve patient outcomes. For model-based approaches to GC, it is important to understand and quantify model parameter assumptions. This study explores endogenous glucose production (EGP) and the use of a population-based parameter value in the intensive care unit context. METHOD: Hourly insulin sensitivity (SI) was fit to clinical data from 145 patients on the Specialized Relative Insulin and Nutrition Titration GC protocol for at least 24 hours. Constraint of SI at a lower bound was used to explore likely EGP variability due to stress response. Minimum EGP was estimated during times when the model SI was constrained, and time and duration of events were examined. RESULTS: Constrained events occur for 1.6% of patient hours. About 70% of constrained events occur in the first 12 hours and most events (~80%) occur when there is no exogenous nutrition given. Enhanced EGP values ranged from 1.16 mmol/min (current population value) to 2.75 mmol/min, with most being below 1.5 mmol/min (21% increase). CONCLUSION: The frequency of constrained events is low and the current population value of 1.16 mmol/min is sufficient for more than 98% of patient hours, however, some patients experience significantly raised EGP probably due to an extreme stress response early in patient stay.

Counter-regulatory responses to Telfairia occidentalis-induced hypoglycaemia.

BACKGROUND: Telfairia occidentalis (TO) has many biological activities including blood glucose regulation. Thus, it is being used in the treatment of diabetes mellitus. TO has been shown to cause insulin-mediated hypoglycaemia, which leads to post-hypoglycaemic hyperglycaemia. However, the mechanism involved in the post-hypoglycaemic hyperglycaemia is still poorly understood. OBJECTIVE: This research was designed to determine the response of glucoregulatory hormones and enzymes to TO treatment. METHODS: Thirty-five male Wistar rats were divided into seven oral treatment groups (n = 5/group), which received either of 100 mg/kg or 200 mg/kg TO for 7-, 10- or 14 days. RESULTS: The 7-day treatment with TO significantly increased the levels of insulin, glucagon, and glucose-6-phosphatase (G6Pase) activity but decreased the levels of glucose, adrenaline, and glucokinase (GCK) activity. The 10-day treatment with 100 mg/kg TO increased glucose and decreased GCK activity while 200 mg/kg for the same duration increased glucose, insulin, GCK and G6Pase activities but reduced glucagon. The 14-day treatment with 100 mg/kg TO decreased glucose and glucagon but increased cortisol, while 200 mg/kg TO for same duration increased insulin, but reduced glucagon and GCK activity. CONCLUSION: The TO's post-hypoglycaemic hyperglycaemia results from increased glucagon and G6Pase activity, and reduced GCK activity. Moreover, the glucagon response mainly depends on glucose rather than insulin.

Cartilage -specific knockout of Sirt1 significantly reduces bone quality and catch-up growth efficiency.

BACKGROUND: Spontaneous catch-up (CU) growth occurs when a growth-restricting factor is resolved. However, its efficiency is sometimes inadequate and growth deficits remain permanent. The therapeutic toolbox for short stature is currently very limited, thus, finding new regulatory pathways is important for the development of novel means of treatment. Our previous studies using a nutrition-induced CU growth model showed that the level of sirtuin-1 (Sirt1) was significantly increased in food-restricted animals and decreased during CU growth. AIM: This study sought to investigate the role of Sirt1 in modulating the response of the epiphyseal growth plate (EGP) to nutritional manipulation. METHOD: Collagen type II-specific Sirt1 knockout (CKO) mice were tested for response to our CU growth model consisting of a period of food restriction followed by re-feeding. RESULTS: The transgenic CKO mice weighed more than the control (CTL) mice, their EGP was higher and less organized, specifically at the resting and proliferative zones, leading to shorter bones. Ablation of Sirt1 in the chondrocytes was found to have a dramatic effect on bone mineralization on micro-CT analysis. The CKO mice were less responsive to the nutritional manipulation, and their CU growth was less efficient. They remained shorter than the CTL mice who corrected the food restriction-induced growth deficit during the re-feeding period. CONCLUSIONS: Sirt1 appears to be important for normal regulation of the EGP. In its absence, the EGP is less organized and CU growth is less efficient. These results suggest that SIRT1 may serve as a novel therapeutic target for short stature.

More than self-interest: Why different classes have different attitudes to income inequality.

The connection between social class and political preferences is among the most well established in the social sciences. This association is typically taken as prima facie evidence of economic self-interest: Classes hold different attitudes, values, and party preferences because they have different economic interests. However, this assumption has rarely been tested empirically. In this article, we use survey data from 18 West European countries to examine why classes differ on a central aspect of political preferences, namely their views on the desirability of income inequality. We find that only a moderate proportion of differences between employee classes in support for redistribution can be accounted for by contemporary differences in resources and risks; differences in economic interests to some degree account for the anti-redistributive preferences of the professional middle classes compared with the working class. However, the preferences of the self-employed have a different explanation; autonomy is a better explanation of the right-wing preferences of the self-employed compared with the working class.

Ophthalmic Drug Delivery Using Iontophoresis: Recent Clinical Applications.

Background: Iontophoresis is a noninvasive delivery system designed to overcome barriers to ocular penetration of topical ophthalmic medications by employing a low-amplitude electrical current to promote the migration of a charged drug substance across biological membranes. Trans-scleral iontophoresis of dexamethasone phosphate has demonstrated dramatically increased intraocular concentrations of dexamethasone in rabbit ocular tissues compared with topical instillation, including 50- to 100-fold greater aqueous humor concentrations. Methods: This article reviews available data on recent clinical applications of iontophoretic ophthalmic drug delivery. Results: The EyeGate II delivery system (EGDS) is a trans-scleral iontophoresis system that has been used in conjunction with EGP-437, a proprietary-charged formulation of dexamethasone phosphate for iontophoretic delivery. In patients with noninfectious anterior uveitis, EGP-437, delivered through 2 iontophoretic treatments using the EGDS, demonstrated similar efficacy to topical prednisolone acetate 1% eye drops instilled 8 times daily over 28 days, suggesting the potential to decrease or eliminate the need for daily dosing of topical steroids in this patient population. Other applications for EGP-437 delivered through the EGDS that have been explored in clinical trials include treatment of dry eye, postsurgical inflammation and pain, and scleritis. In addition, transcorneal iontophoresis has been used outside of the United States to enhance riboflavin penetration in patients undergoing corneal cross-linking as therapy for progressive keratoconus. Conclusions: The reviewed studies demonstrate the feasibility of using iontophoresis to enhance drug delivery to ocular tissues and support the potential of this noninvasive technique across a range of ophthalmic indications.

Expression of epithelial glycoprotein (EGP40) in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC).

AIM: To study the expression of Epithelial Glycoprotein (EGP40) in various grades of Oral Epithelial Dysplasia namely mild, moderate and severe epithelial dysplasia and in various grades of Oral Squamous Cell Carcinoma (OSCC) namely well, moderate & in poorly differentiated squamous cell carcinoma. MATERIAL AND METHODS: This laboratory study comprised of 47 samples in which 27 samples were of three different grades of OSCC, Well (n=10), Moderate (n=10) and Poorly differentiated (n=7) and remaining 20 samples were of three different grades of dysplasia [Mild (n=7), Moderate (n=8), Severe dysplasia (n=5)]. All the 47 cases were subjected to immunohistochemical staining to evaluate the expression of EGP40. Chi square was used to analyze the significance of differences in different grades of oral epithelial dysplasia & in different grades of OSCC. RESULTS: The percentage of EGP40 immuno positivity was increased from mild to severe dysplasia and the percentage of EGP40 immuno positivity was increased from well to poorly differentiated carcinoma No statistical significance was observed in the immunoreactivity and in the intensity of expression between various grades of oral epithelial dysplasia and oral squamous cell carcinoma. CONCLUSION: The epithelial cell adhesion molecule can be considered as an early marker for predicting malignant transformation of dysplastic epithelial lesions and used as a marker in predicting the OSCC prognosis.

A Novel Bacterium-Like Particle-Based Vaccine Displaying the SUDV Glycoprotein Induces Potent Humoral and Cellular Immune Responses in Mice.

Sudan virus (SUDV) causes severe lethal hemorrhagic fever in humans and nonhuman primates. The most effective and economical way to protect against Sudan ebolavirus disease is prophylactic vaccination. However, there are no licensed vaccines to prevent SUDV infections. In this study, a bacterium-like particle (BLP)-based vaccine displaying the extracellular domain of the SUDV glycoprotein (eGP) was developed based on a gram-positive enhancer matrix-protein anchor (GEM-PA) surface display system. Expression of the recombinant GEM-displayed eGP (eGP-PA-GEM) was verified by Western blotting and immunofluorescence assays. The SUDV BLPs (SBLPs), which were mixed with Montanide ISA 201VG plus Poly (I:C) combined adjuvant, could induce high SUDV GP-specific IgG titers of up to 1:40,960 and robust virus-neutralizing antibody titers reached 1:460. The SBLP also elicited T-helper 1 (Th1) and T-helper 2 (Th2) cell-mediated immunity. These data indicate that the SBLP subunit vaccine has the potential to be developed into a promising candidate vaccine against SUDV infections.

Determination of physiological parameters for endogenous glucose production in individuals using diurnal data.

BACKGROUND: Triple tracer meal experiments used to investigate organ glucose-insulin dynamics, such as endogenous glucose production (EGP) of the liver are labor intensive and expensive. A procedure was developed to obtain individual liver related parameters to describe EGP dynamics without the need for tracers. RESULTS: The development used an existing formula describing the EGP dynamics comprising 4 parameters defined from glucose, insulin and C-peptide dynamics arising from triple meal studies. The method employs a set of partial differential equations in order to estimate the parameters for EGP dynamics. Tracer-derived and simulated data sets were used to develop and test the procedure. The predicted EGP dynamics showed an overall mean R 2 of 0.91. CONCLUSIONS: In summary, a method was developed for predicting the hepatic EGP dynamics for healthy, pre-diabetic, and type 2 diabetic individuals without applying tracer experiments.

Autologous versus synthetic slings in female stress urinary incontinence: A retrospective study.

OBJECTIVE: To evaluate and compare the clinical (patient's morbidity, quality of life [QoL]) and economic impact of autologous vs synthetic slings in female stress urinary incontinence (SUI), as over the last decade, the introduction of synthetic vaginal tapes for managing SUI has gained wide acceptance being quicker with low morbidity. Synthetic vaginal tapes have been progressively replacing the use of autologous rectus fascia. However, the high cost of these synthetic tapes is almost always an obstacle for most patients of limited socio-economic resources in the Egyptian community. PATIENTS AND METHODS: This retrospective study included 126 women with SUI. Data for patients that matched the study inclusion criteria were collected from the Urology Department of Ain-Shams University Hospitals from March 2011 to May 2013. Patients were categorised into two groups: Group I included 62 patients who underwent an autologous sling procedure using rectus sheath; and Group II included 64 patients that had a synthetic sling, using transobturator tape (TOT). The following variables were compared: operative time, postoperative pain scores, duration of indwelling urethral catheter, hospital stay, cost including the price of the synthetic tape when used, return to normal activity, and QoL assessment (International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form [ICIQ-UI-SF]) before and after discharge from hospital. RESULTS: Patients amongst the two groups were normally distributed with no statistically significant differences in patient's demographic data and comorbidities. The mean hospital stay was longer and the return to normal activity was delayed in Group I compared to Group II. The highest mean postoperative pain score was recorded in Group I. The overall morbidity was 12.9% and 4.68% in groups I and II, respectively. The mean (SD) overall cost was 2571.65 (254.8) and 3502.34 (196.9) Egyptian pounds (local currency) in groups I and II, respectively, being insignificantly lower in Group I when compared to Group II (P > 0.05). There were statistically significant differences between groups I and II for operative time, hospital stay, and postoperative pain scores. However, the differences in hospital cost amongst Group I and Group II were in favour of Group I. Post-surgical outcome was categorised into either complete cure (dry) or improved or failed with no significant differences in success rate and QoL amongst the study groups. The mean (SD) change in the QoL score was 10.95 (4.19) and 12.32 (4.1) in groups I and II, respectively. The higher success rate (complete cure) was in Group II, at 93.75%. Also, a statistically significant improvement of >70% of mean ICIQ-UI-SF score was shown in all groups when compared to baseline on both the 1- and 6-month follow-up visits. CONCLUSION: Autologous grafts should be considered as a repair option in females with SUI in countries were health insurance policies do not cover the cost of synthetic materials in many instances. The cost-effectiveness of synthetic TOT slings, as a minimally invasive procedure with lower overall morbidity, has yet to be confirmed in larger scale studies with longer periods of follow-up, to confirm the durability of its successful outcomes and be considered as the primary treatment of choice in female SUI.

Pulmonary vasculitis.

Systemic vasculitides frequently affect the pulmonary vasculature. As the signs and symptoms of pulmonary vasculitis are variable and nonspecific, diagnosis and treatment represent a real challenge. Vasculitides should be given consideration, as these diseases present severe manifestations of rapidly progressing pulmonary disease. Examining other organs usually affected by vasculitides (e.g., the skin and kidneys) and determining autoantibody levels are essential to a better management of the disease. A radiological study would also contribute to establishing a diagnosis. The lungs are commonly involved in small-vessel vasculitis, anti-glomerular basement membrane disease, and vasculitides associated with antineutrophil cytoplasmic antibodies. Associated life-threatening diffuse alveolar haemorrhages and irreversible damage to other organs-usually the kidneys-are severe complications that require early diagnosis. Vasculitides are rare diseases that affect multiple organs. An increasing number of treatments-including biological agent-based therapies-requiring cooperation between specialists and centers have become available in the recent years. In the same way, clinicians should be familiar with the complications associated with immunosuppressive therapies.

Multifunctional Nanoparticles Enable Efficient Oral Delivery of Biomacromolecules via Improving Payload Stability and Regulating the Transcytosis Pathway.

In oral delivery of biomacromolecules, ligand-modified nanoparticles (NPs) have emerged as a promising tool to improve the epithelial uptake of the loaded protein/peptide. Unfortunately, the stability and the transport mechanisms of the biotherapeutics during the intracellular transportation still remained unclear, leading to the poor transepithelial efficiency. Additionally, developing novel approaches to simultaneously monitor the payload bioactivity during the transport processes is veritably benefit for keeping their bioactivity. In the present study, EGP peptide (KRKKKGKGLGKKRDPCLRKYK), a ligand with high affinity to heparan sulfate proteoglycans (HSPGs), was found remarkably increasing the cellular uptake (4.5-fold) and also surprisingly achieving high transcytosis efficiency (4.2-fold) of poly(lactide- co-glycolide) NPs on Caco-2 cell monolayer. Compared with unmodified NPs (C NPs), EGP modified NPs (EGP NPs) exhibited more desirable colloidal stability within epithelia. In the subsequent study, the bioactivity of encapsulated insulin during the cellular transportation was innovatively monitored by a glucose consumption assay. Inspiringly, EGP NPs could mostly retain the bioactivity of loaded insulin whereas insulin from INS-C NPs was significantly degraded. Then the detailed mechanism study revealed that the binding of EGP to HSPGs played a vital role on NP transportation. Unlike C NPs being delivered in the endo/lysosomal pathway, EGP NPs were involved in caveolae-mediated transport, which contributes to the efficient avoidance of the lysosomal entrapment and sequentially facilitates the direct apical-to-basolateral transcytosis. The enhanced absorption of EGP NPs was confirmed in in situ intestinal loop models. Most importantly, oral administrated INS-EGP NPs generated a strong hypoglycemic response on diabetic rats with 10.2-fold and 2.6-fold increase in bioavailability compared with free insulin and INS-C NPs, respectively. The work provided an innovative strategy to monitor the payload bioactivity during the transport processes and proposed a novel aspect to increase oral bioavailability of biomacromolecules via improving payload stability and regulating the transcytosis pathway of nanocarriers.

Effect of fibre additions to flatbread flour mixes on glucose kinetics: a randomised controlled trial.

We previously found that guar gum (GG) and chickpea flour (CPF) added to flatbread wheat flour lowered postprandial blood glucose (PPG) and insulin responses dose dependently. However, rates of glucose influx cannot be determined from PPG, which integrates rates of influx, tissue disposal and hepatic glucose production. The objective was to quantify rates of glucose influx and related fluxes as contributors to changes in PPG with GG and CPF additions to wheat-based flatbreads. In a randomised cross-over design, twelve healthy males consumed each of three different 13C-enriched meals: control flatbreads (C), or C incorporating 15 % CPF with either 2 % (GG2) or 4 % (GG4) GG. A dual isotope technique was used to determine the time to reach 50 % absorption of exogenous glucose (T 50 %abs, primary objective), rate of appearance of exogenous glucose (RaE), rate of appearance of total glucose (RaT), endogenous glucose production (EGP) and rate of disappearance of total glucose (RdT). Additional exploratory outcomes included PPG, insulin, glucose-dependent insulinotropic peptide and glucagon-like peptide 1, which were additionally measured over 4 h. Compared with C, GG2 and GG4 had no significant effect on T 50 %abs. However, GG4 significantly reduced 4-h AUC values for RaE, RaT, RdT and EGP, by 11, 14, 14 and 64 %, respectively, whereas GG2 showed minor effects. Effect sizes over 2 and 4 h were similar except for significantly greater reduction in EGP for GG4 at 2 h. In conclusion, a soluble fibre mix added to flatbreads only slightly reduced rates of glucose influx, but more substantially affected rates of postprandial disposal and hepatic glucose production.

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice.

OBJECTIVE: Non-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogaster and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance. METHODS: Adult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. RESULTS: Within the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight. CONCLUSIONS: We show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition.

Skeletal effect of casein and whey protein intake during catch-up growth in young male Sprague-Dawley rats.

The aim of the present study was to determine whether the type of protein ingested influences the efficiency of catch-up (CU) growth and bone quality in fast-growing male rats. Young male Sprague-Dawley rats were either fed ad libitum (controls) or subjected to 36 d of 40 % food restriction followed by 24 or 40 d of re-feeding with either standard rat chow or iso-energetic, iso-protein diets containing milk proteins - casein or whey. In terms of body weight, CU growth was incomplete in all study groups. Despite their similar food consumption, casein-re-fed rats had a significantly higher body weight and longer humerus than whey-re-fed rats in the long term. The height of the epiphyseal growth plate (EGP) in both casein and whey groups was greater than that of rats re-fed normal chow. Microcomputed tomography yielded significant differences in bone microstructure between the casein and whey groups, with the casein-re-fed animals having greater cortical thickness in both the short and long term in addition to a higher trabecular bone fraction in the short term, although this difference disappeared in the long term. Mechanical testing confirmed the greater bone strength in rats re-fed casein. Bone quality during CU growth significantly depends on the type of protein ingested. The higher EGP in the casein- and whey-re-fed rats suggests a better growth potential with milk-based diets. These results suggest that whey may lead to slower bone growth with reduced weight gain and, as such, may serve to circumvent long-term complications of CU growth.