Significant Weight Reduction Research Articles

482-P: Behavioral Assessment of 10kHz Spinal Cord Stimulation–Mediated Pain Relief in a Rat Model of Painful Diabetic Neuropathy

Painful diabetic neuropathy (PDN) is a serious complication of diabetes and occurs in approximately 20% of diabetic patients. In a recent RCT, 10kHz spinal cord stimulation (10kHz SCS) was shown to be a promising therapy for PDN, in both pain reduction and possible neurological improvements (Petersen et al 2021). In this study, we aimed to observe the behavioral effects of 10kHz SCS on PDN using streptozotocin (STZ)-induced diabetic rats. We established four testing groups: Naïve controls, STZ controls, STZ+Sham SCS, and STZ+10kHz SCS. A single effective dose (60 mg/kg) of the cytotoxic agent STZ caused the rats to become hyperglycemic within 72 hours and lasted for several weeks. These STZ-injected rats also showed a significant and continuous reduction in body weight in comparison to Naïve control rats. Using the von Frey test for mechanical allodynia, we observed that 14 days of 24h/day low-intensity (30% of motor threshold) 10kHz SCS significantly elevated the mechanical pain withdrawal thresholds compared to STZ controls or STZ+Sham SCS animals, reaching statistical equivalence to Naïve controls. In a thermal preference assay, all animals exhibited a training effect towards less activity and more preference to the room temperature side vs the non-painful heat side of a two-temperature chamber over the several-week protocol. We found that STZ-injected animals demonstrated significantly less exploration activity in the 10min testing periods compared to Naïve controls but neither the thermal preference nor the total distance they traveled were restored after 14 days of 10kHz SCS. Our results demonstrate that 10 kHz SCS resulted in behavioral outcomes reflective of the mechanical pain reduction in the PDN rodent model. These findings provide supporting evidence for the recent RCT data and underscore the conclusion that 10kHz SCS can effectively treat patients with refractory PDN. Disclosure D.Wang: Employee; Nevro Corp. D.Lee: Employee; Nevro Corp. K.Lee: Employee; Nevro Corp. Z.B.Kagan: Employee; Nevro Corp. K.Bradley: Employee; Nevro Corp.

73-LB: Tirzepatide 5, 10, and 15 mg vs Injectable Semaglutide 0.5 mg for the Treatment of Type 2 Diabetes—An Indirect Treatment Comparison

Semaglutide (sema) 0.5 mg is part of type 2 diabetes (T2D) standard of care as initial maintenance dose. While there has been a study conducted on TZP and sema 1.0 mg, showing TZP superiority, currently there is no head-to-head study comparing TZP and sema 0.5 mg. Therefore, the objective of this analysis was to evaluate the efficacy and safety of TZP and sema 0.5 mg using adjusted indirect comparisons. Adjusted indirect comparisons were performed using the Bucher method to compare the relative efficacy and safety of TZP 5, 10, 15 mg and sema 0.5 mg via a common comparator (sema 1.0 mg) based on trial results from SURPASS-2 (TZP vs sema 1.0 mg) and SUSTAIN 7 (sema 0.5 and 1.0 mg vs dulaglutide 0.75 and 1.5 mg). All TZP doses showed statistically significant greater reductions in HbA1c, weight and BMI from baseline to week 40 compared to sema 0.5 mg (Figure). TZP demonstrated a comparative safety profile for adverse events (AEs) but patients had statistically significant greater odds of treatment discontinuations due to AEs for TZP 10 and 15 mg. All TZP doses demonstrated no statistically significant differences vs sema 0.5 mg in the odds or likelihood of gastrointestinal AEs. In these adjusted indirect comparisons the extent of differences between TZP and sema 0.5 mg regarding HbA1c and weight reductions provide insights on their comparative effectiveness in the absence of a head-to-head study. Disclosure K. M. Pantalone: Consultant; AstraZeneca, Bayer Inc., Corcept Therapeutics, Diasome, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi, Research Support; Bayer Inc., Merck & Co., Inc., Novo Nordisk, Twin Health, Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk. S. Tofe: Advisory Panel; Lilly, Novo Nordisk, Research Support; Lilly, Novo Nordisk, Speaker's Bureau; Lilly, Novo Nordisk. L. Fan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J. S. Paik: None. K. T. Ranta: Employee; Eli Lilly and Company. H. Sapin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. B. Osumili: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

46-LB: Effect of Nonnutritive Sweetener (Sucralose) on Gut Microbiome in Asian Indian adults with Type 2 Diabetes—A Randomized Clinical Trial

Background: Non-Nutritive Sweeteners (NNS) can help reduce calorie intake when substituted for added sugar. Some studies have reported detrimental effect of NNS on gut microbiome when given at high doses in animal models. Clinical studies have been done mostly in small sample sizes. This study aims to evaluate the effect of using sucralose in coffee, tea and fruit juices on gut microbiome in Asian Indian adults with type 2 diabetes (T2D). Method: A parallel arm, randomized trial was carried out for 12 weeks in adults with T2D aged 30-50 yrs and glycated haemoglobin between 7-11 %. Participants were randomized into Intervention group (sucralose added in beverages) and Control group (No sucralose). Both groups received standard of care for diabetes. Faecal samples were collected from participants, V3-V4 libraries were generated and sequenced using illumina Miseq NGS. Alpha and beta diversity were derived for both groups to assess within and between groups changes. Ratio of fermicutes to bacteroidetes was also computed. Results: Interim data of 38 participants who completed the study (Control group, n=14 and Intervention group, n=24) was analysed for changes in operational taxonomical units (OTU) of gut microbiome. Major phyla detected across all samples were Fermicutes, Actinobacteria, Bacteroidetes, Proteobacteria and Verrucomicrobiota. Alpha and beta diversity analysis showed no significant changes between intervention and control groups. Fermicutes to bacteroidetes ratio did not show any significant difference between groups. At end of 12 weeks significant reduction in body weight (p<0.004) and body fat % (p<0.04) was observed in the intervention group. Conclusion: Use of sucralose in beverages produced no significant change in gut microbiome in Asian Indian adults with T2D but helped in reduction of body weight and body fat. Clinical trial registry: CTRI/2021/04/032686 Disclosure V. Mohan: None. K. Abirami: None. G. Rajagopal: None. P. Soundararajan: None. R. Unnikrishnan: None. R. Anjana: None. S. Vasudevan: None. K. Kamala: None. Funding Zydus Wellness Products Ltd.

876-P: Effectiveness and Tolerability of Intensification of Canagliflozin Dose from 100 mg to 300 mg Daily In Patients with Type 2 Diabetes in Real Life—The INTENSIFY Study

There is a paucity of data evaluating the strategy of intensification of canagliflozin therapy by increasing the dose from canagliflozin 100 mg/d (CANA100) to canagliflozin 300 mg/d (CANA300), since all clinical trials compared both doses separately. The aim of this multicentric study was to assess in real life the effectiveness and tolerability of the intensification of canagliflozin to 300 mg/d in patients with T2DM and suboptimal metabolic control with CANA100. The primary outcome variables were changes in A1c and weight at the end of the follow-up. 317 patients met the inclusion criteria (age 62.2 years, A1c 7.55%, weight 88.6 kg). Median time of treatment with CANA300 was 20.8 months. Switching to CANA300 induced a significant decrease in A1c (-0.47%) and weight (-2.9 kg), both p<0.0001. The percentage of patients with A1c <7% increased significantly from 26.7% with CANA100 to 51.6% with CANA300 (p<0.0001). In those individuals with poor glycemic control (A1c >8%, mean 9.0%), A1c was significantly reduced by -1.24% (p<0.0001). There were significant improvements in FPG (-14.8 mg/dl), SBP (-5.3 mmHg) and DBP (-3,1 mmHg), all p<0.05. Serum liver enzymes and albuminuria also decreased significantly. Considering the entire treatment period (initial treatment with CANA100 and later switch to CANA300), with a median follow-up of 38.8 months, patients achieved a statistically significant overall reduction in A1c (-1.30%), weight (-5.8 kg), SBP (-9.6 mmHg) and DBP (-4.7 mmHg), all p<0.0001. 7.9% of patients discontinued CANA300; the most frequent causes of withdrawals were genital mycotic infections (1.9%) and urinary tract infections (0.9%). In summary, intensification of canagliflozin therapy to CANA300 achieved further significant and clinically relevant reductions in A1c, weight, and BP in patients with T2DM. The effectiveness of the switch was particularly relevant in those patients with higher A1c levels. Disclosure J.J. Gorgojo-Martinez: Advisory Panel; AstraZeneca, Bayer Inc., Novo Nordisk. Research Support; Eli Lilly and Company, Mundipharma, Novo Nordisk. Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Mundipharma, Novo Nordisk, Amarin Corporation. P.J. Ferreira-Ocampo: None. A. Galdon-Sanz Pastor: None. J.J. Cárdenas-Salas: Speaker's Bureau; Novo Nordisk, Mundipharma, Lilly, AstraZeneca. Other Relationship; Mylan, Amgen Inc., Almirall, S.A. T. Antón-Bravo: Speaker's Bureau; Abbott Nutrition, AstraZeneca, Eli Lilly and Company. Advisory Panel; Fresenius Kabi. Speaker's Bureau; Novo Nordisk, Daiichi Sankyo. Advisory Panel; Sanofi. Other Relationship; Mundipharma. M. Brito: Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk, Sanofi. Advisory Panel; Sanofi. Speaker's Bureau; Almirall, S.A., Boehringer-Ingelheim, Esteve. Advisory Panel; Esteve, AstraZeneca. Research Support; Mundipharma. F. Almodovar-Ruiz: None. Funding Mundipharma International Limited

1704-P: Efficacy and Safety of Tirzepatide for Weight Loss—A Meta-analysis of Randomized Controlled Trials

Tirzepatide (TZP) is a new dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes and shown to have substantial efficacy on weight loss. We performed a meta-analysis to assess the efficacy and safety of TZP for weight loss. We searched PubMed, Cochrane and Embase up until July 2022 for RCTs comparing TZP with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratios (OR) were utilized, respectively, for continuous and binary outcomes. Of 397 search results, 6 studies were included, with 4036 participants. Pooled analysis showed that TZP 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight change ranging from -7.7 kg (95% CI -11.0, -4.4; p < 0.001) to -11.8 kg (95% CI -17.4, -6.2; p < 0.001) - Figure 1A. The MD in percent change in weight ranged from -8.1% (95% CI -11.0, -5.2; p < 0.001) to -12.4% (95% CI -17.2, -7.5; p < 0.001) - Figure 1B. Adverse events were more frequent with TZP compared with placebo, especially with the 15 mg dose, with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p < 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p < 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p < 0.001). The results support that TZP leads to a significant reduction in body weight and may be a valuable therapeutic option for weight management, despite an increase in gastrointestinal side effects. Disclosure Y.L.L.Mesquita: None. I.P.Calvi: None. I.R.Marques: None. S.A.Cruz: None. E.M.H.Padrao: None. R.Cardoso: None. F.Moura: None. V.V.Rafalskiy: None.

541-P: Role of Personalized Digital Lifestyle Program in Improving Outcomes in People with Diabetes—Real-World Evidence from Indian Cohort

Background: Diabetes self-management is neglected practice among people with diabetes (PwD). OneCare-IMPACT Program provides lifestyle modification through easily accessible virtual DSME program leading to a positive behavioral change. Methods: Study was conducted in PwD (n=173) enrolled in a 12-week OneCare-IMPACT program. Data were collected at baseline and 3 months for demographics, glycemic parameters, medicines and program engagement. Results: Mean HbA1c (%) improved significantly from 8.9 ± 2.2 to 7.1 ±1.3, p <.001, effect size (d= 0.8). 56.1% had HbA1c<7% at 3-month compared to 18.5% at baseline. Significant change was seen in FPG and PPPG (mg/dl) of −54.85 (±71.02) and −77.58 (±100.79) respectively. Weight reduced significantly from 76.9 ± 17.5 kg to 74.1 ±16.2 kg (p <.001, d=0.7) and BMI by −0.8kg/m2, (p<.001). From baseline, 31% and 8% of patients reduced weight by ≥5% and ≥10% respectively. A majority of the patients had an absolute reduction in diabetes medications. A significant correlation (r=0.3) noted between weight decline and follow-up HbA1c (p=.005). Mean attendance in program was 75% which correlated well with the outcomes. Conclusions: OneCare-IMPACT program enhances glycemic outcomes in PwD with a significant weight reduction encouraging for further RCTs to evaluate the role of digital DSMEs in developing countries like India. Disclosure Z.Fatema: Employee; Wellwork Technologies Private Limited, India. D.Kamath: Employee; Wellworks Technologies Pvt Ltd. S.Agarwal: Employee; Wellworks Technologies Private Limited. S.Aswathiah: None. B.Sooragonda: None.

Development of flax/basalt/PA11 bio-composites: optimal formulation and modelling of the quasi-static behaviour

Environmental impact is becoming increasingly important in the automotive industry, with car manufacturers looking to reduce CO2 emissions through cleaner engines and structural weight reduction. Composite materials offer an excellent alternative to standard steels with significant weight reduction and the ability to produce functional parts (Rangappa et al., Polymer Composites, 2022,43, 645–691), (Jeyaguru et al., Polymer Composites, 2022, 43, 3902–3914), (Sanjay et al., Journal of Cleaner Production, 2018, 172, 566–581). The main objective of this study is to investigate the potential of a new and unique hybrid bio-composite material combining flax and basalt fibers and PA11 polymer. This material design is studied with the idea of reducing the moisture sensitivity, variabilities, and uncertainties of vegetal fibers by the presence of basalt fibers. The first step consists of developing a new hybrid composite material and studying its quasi-static mechanical behaviour when subjected to different humidity levels. Then, a multi-scale non-linear homogenization approach is proposed to support the interpretation of the characterization test results. The experimental results show the benefits of the hybridization. In fact, the hybrid composite is 20% stiffer than the flax/PA11 composite, 8% lighter than the basalt/PA11 composite and has a reduced dispersion of its mechanical properties, 52% lower than the flax/ PA11 composite. Considering the promising properties of the hybrid composite, we have investigated the possibility of developing the front hood of a sports car using this material. The first results highlight a potential mass gain of 18% at iso-performance with the original front hood. The following steps will be devoted to the numerical and experimental validation.

Studies on teratogenic and maternal effects of Trichothecene (TCT) extracted from Fusarium and Trichoderma culture on pregnant Albino Mice

Mycotoxins (frequently referred to as secondary metabolites of toxigenic fungi) are commonly found in foodstuffs and are essential because of their association with disease. The current study investigated the teratogenic potential characteristics of T-2 trichothecenes mycotoxins produced by Fusarium and Trichoderma, which are reportedly toxic to humans and animals in pregnant mice. T-2 toxin is a cytotoxic secondary fungal metabolite that belongs to the trichothecene mycotoxin family. T2 was administered intraperitoneally to Pregnant females as a single injection at levels of 50, 75,100, and 125 ppb on one of the gestation days 7-11 during the pregnancy period. A significant reduction in mean fetal body weight and various fetal malformations (i.e., external and skeletal) were observed following maternal exposure to T2. This is the first report to implicate this mycotoxin T -2 as a teratogen in our region. Our study revealed that T-2 toxin 125 ppm exposure was enough to cause abortion in pregnant mice within several days. Keywords: T2 toxin, trichothecenes, mycotoxins, fungi, pregnant mice

Multivariate analysis of enriched landfill soil consortia provide insight on the community structural perturbation and functioning during low-density polyethylene degradation

Plastic-enriched sites like landfills have immense potential for discovery of microbial consortia that can efficiently degrade plastics. In this study, we used a combination of culture enrichment, high-throughput PacBio sequencing of 16 S rRNA and the ITS gene, Fourier transform infrared (FTIR), and scanning electron microscopy (SEM) to examine the compositional and diversity perturbations of bacterial and fungal consortia from landfill soils and their impact on low-density polyethylene (LDPE) film biodegradation over a 90-day period. Results showed that enrichment cultures effectively utilized LDPE as a carbon source for cellular growth, resulting in significant weight reduction (22.4% and 55.6%) in the films. SEM analysis revealed marked changes in the micrometric surface characteristics (cracks, fissures, and erosion) and biofilm formation in LDPE films. FTIR analyses suggested structural and functional group modification related to C-H (2831–2943 cm⁻¹), and CH₂ (1400 cm⁻¹) stretching, CO and CC (680–950 cm⁻¹) scission, and CO incorporation (3320–3500 cm⁻¹) into the carbon backbone, indicative of LDPE polymer biodegradation. Enrichment cultures had lower diversity and richness of microbial taxa compared to soil samples, with LDPE as a carbon source having a direct influence on the structure and functioning of the microbial consortia. A total of 26 bacterial and 12 fungal OTU exhibiting high relative abundance and significant associations (IndVal > 0.7, q < 0.05) were identified in the enrichment culture. Bacterial taxa such as unclassified Parvibaculum FJ375498, Achromobacter xylosoxidans, unclassified Chitinophagaceae PAC002331, unclassified Paludisphaera and unclassified Comamonas JX898122, and six fungal species (Galactomyces candidus, Trichosporon chiropterorum, Aspergillus fumigatus, Penicillium chalabudae, Talaromyces thailandensis, and Penicillium citreosulfuratum) were identified as the putative LDPE degraders in the enrichment microbial consortium cultures. PICRUSt2 metagenomic functional profiling of taxonomic bacterial taxa abundances in both landfill soil and enrichment microbial consortia also revealed differential enrichment of energy production, stress tolerance, surface attachment and motility pathways, and xenobiotic degrading enzymes important for biofilm formation and hydrolytic/oxidative LDPE biodegradation. The findings shed light on the composition and structural changes in landfill soil microbial consortia during enrichment with LDPE as a carbon source and suggest novel LDPE-degrading bacterial and fungal taxa that could be explored for management of polyethylene pollution.

Effect of organic photovoltaic and red-foil transmittance on yield, growth and photosynthesis of two spinach genotypes under field and greenhouse conditions

The galloping rise in global population in recent years and the accompanying increase in food and energy demands has created land use crisis between food and energy production, and eventual loss of agricultural lands to the more lucrative photovoltaics (PV) energy production. This experiment was carried out to investigate the effect of organic photovoltaics (OPV) and red-foil (RF) transmittance on growth, yield, photosynthesis and SPAD value of spinach under greenhouse and field conditions. Three OPV levels (P0: control; P1: transmittance peak of 0.11 in blue light (BL) and 0.64 in red light (RL); P2: transmittance peak of 0.09 in BL and 0.11 in RL) and two spinach genotypes (bufflehead, eland) were combined in a 3 × 2 factorial arrangement in a completely randomized design with 4 replications in the greenhouse, while two RF levels (RF0: control; RF1: transmittance peak of 0.01 in BL and 0.89 in RL) and two spinach genotypes were combined in a 2 × 2 factorial in randomized complete block design with four replications in the field. Data were collected on growth, yield, photosynthesis and chlorophyll content. Analysis of variance (ANOVA) showed significant reduction in shoot weight and total biomass of spinach grown under very low light intensities as a function of the transmittance properties of the OPV cell used (P2). P1 competed comparably (p > 0.05) with control in most growth and yield traits measured. In addition, shoot to root distribution was higher in P1 than control. RF reduced shoot and total biomass production of spinach in the field due to its inability to transmit other spectra of light. OPV-RF transmittance did not affect plant height (PH), leaf number (LN), and SPAD value but leaf area (LA) was highest in P2. Photochemical energy conversion was higher in P1, P2 and RF1 in contrast to control due to lower levels of non-photochemical energy losses through the Y(NO) and Y(NPQ) pathways. Photo-irradiance curves showed that plants grown under reduced light (P2) did not efficiently manage excess light when exposed to high light intensities. Bufflehead genotype showed superior growth and yield traits than eland across OPV and RF levels. It is therefore recommended that OPV cells with transmittance properties greater than or equal to 11% in BL and 64% in RL be used in APV systems for improved photochemical and land use efficiency.

Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes.

To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron. This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID. Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05). Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses. gov identifier: NCT04617275.

Genetic deletion of Kvβ2 (AKR6) causes loss of muscle function and increased inflammation in mice.

The voltage-gated potassium channels (Kv) are complex ion channels with distinct roles in neurotransmission, electrical conductivity of the heart, and smooth and striated muscle functions. Previously, we demonstrated that deletion of Kvβ2 in mice results in decreased Pax7 protein levels, hindlimb muscles and body weights, and fiber type switching. In the present study, we tested the hypothesis that Kvβ2 regulates skeletal muscle function in mice. The young and old Kvβ2 knockout (KO) and wildtype (WT) mice were utilized to test the aging phenotype and skeletal muscle function. Consistent with our previous finding, we found a significant reduction in hindlimb skeletal muscles mass and body weight in young Kvβ2 KO mice, which was also significantly reduced in old Kvβ2 KO mice compared with age-matched WT mice. Forelimb grip strength, and the hindleg extensor digitorum longus (EDL) muscles force-frequency relations were significantly decreased in young and old Kvβ2 KO mice compared to age-matched WT mice. Analysis of transmission electron microscopy images of EDL muscles in young mice revealed a significant reduction in the sarcomere length for Kvβ2 KO vs. WT. Hematoxylin and eosin-stained tibialis anterior muscles cryosections displayed a significant decrease in the number of medium (2,000-4,000µm2) and largest (>4,000µm2) myofibers area in young Kvβ2 KO vs. WT mice. We also found a significant increase in fibrotic tissue area in young Kvβ2 KO mice compared with age-matched WT mice. Analysis of RNA Seq data of the gastrocnemius muscles (GAS) identified significant increase in genes involved in skeletal muscle development, proliferation and cell fate determination, atrophy, energy metabolism, muscle plasticity, inflammation, and a decrease in circadian core clock genes in young Kvβ2 KO vs. WT mice. Several genes were significantly upregulated (384 genes) and downregulated (40 genes) in young Kvβ2 KO mice compared to age-matched WT mice. Further, RT-qPCR analysis of the GAS muscles displayed a significant increase in pro-inflammatory marker Il6 expression in young Kvβ2 KO mice compared to age-matched WT mice. Overall, the present study shows that deletion of Kvβ2 leads to decreased muscles strength and increased inflammation.

Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside.

High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in skeletal muscle is still inconclusive. We fed male C57BL/6J mice with an HFD (60% fat) ± 400 mg/kg·bw NR for 24 weeks. C2C12 myotube cells were treated with 0.25 mM palmitic acid (PA) ± 0.5 mM NR for 24 h. Indicators for IR and mitochondrial dysfunction were analyzed. NR treatment alleviated IR in HFD-fed mice with regard to improved glucose tolerance and a remarkable decrease in the levels of fasting blood glucose, fasting insulin and HOMA-IR index. NR-treated HFD-fed mice also showed improved metabolic status regarding a significant reduction in body weight and lipid contents in serum and the liver. NR activated AMPK in the skeletal muscle of HFD-fed mice and PA-treated C2C12 myotube cells and upregulated the expression of mitochondria-related transcriptional factors and coactivators, thereby improving mitochondrial function and alleviating oxidative stress. Upon inhibiting AMPK using Compound C, NR lost its ability in enhancing mitochondrial function and protection against IR induced by PA. In summary, improving mitochondrial function through the activation of AMPK pathway in skeletal muscle may play an important role in the amelioration of IR using NR.

Regulation of enteric nervous system via sacral nerve stimulation in opioid-induced constipated rats.

Sacral nerve stimulation (SNS) has been employed for treating constipation. However, its mechanisms involving enteric nervous system (ENS) and motility are largely unknown. In this study, we investigated the possible ENS involvement of SNS in treating Loperamide-induced constipation in rats. Experiment-1 was designed to study the effects of acute SNS on whole colon transit time (CTT). In experiment-2, we induced constipation by Loperamide and then applied daily SNS or sham-SNS for 1 week. Choline acetyltransferase (ChAT), nitric oxide synthase (nNOS), and PGP9.5 in colon tissue were examined at the end of the study. Moreover, survival factors such as phosphorylated AKT (p-AKT) and Glial cell-derived neurotrophic factor (GDNF) were measures by immunohistochemistry (IHC) and western blot (WB). (1) SNS with one set of parameters shortened CTT starting at 90 min after phenol red administration (p < 0.05). (2) While Loperamide induced slow transit constipation with a significant reduction in fecal pellet number and feces wet weight, daily SNS for a week resolved constipation. (3) Moreover, SNS was able to shorten whole gut transit time comparing to sham-SNS (p = 0.01). (4) Loperamide reduced the number of PGP9.5 and ChAT positive cells, and downregulated ChAT protein expression and upregulated nNOS protein expression, whereas these detrimental effects were significantly reversed by SNS. (5) Furthermore, SNS increased expressions of both GDNF and p-AKT in colon tissue. (6) Vagal activity was reduced following Loperamide (p < 0.01); yet SNS normalized vagal activity. SNS with appropriate parameters improves opioid-induced constipation and reversed the detrimental effects of Loperamide on enteric neurons possibly via the GDNF-PI3K/Akt pathway.GRAPHICAL ABSTRACT.

Evaluation of feasibility and acceptability of a web-based diabetes prevention program (DPP) for diabetes risk reduction in Chinese Americans in New York City.

Intensive lifestyle intervention remains an effective modality to reduce diabetes incidence and delay the progression to type 2 diabetes. The primary aim of this study was to pilot-test the feasibility and acceptability of a culturally and linguistically tailored web-based DPP intervention among Chinese Americans with prediabetes living in New York City. Thirteen Chinese American participants with prediabetes were recruited to complete a 1-year web-based Diabetes Prevention Program (DPP) lifestyle intervention. Quantitative and qualitative measures such as retention rate and data collected from web-based questionnaires and focus groups were collected and analyzed to assess study feasibility and acceptability. Participants were receptive to the program through high engagement, retention and satisfaction. Retention rate was 85%. 92% of participants completed at least 16 sessions out of 22 sessions. Post-trial surveys indicated high satisfaction of 27.2/32 based on Client Satisfaction Questionnaire (CSQ-8) score. Participants expressed the program increased their knowledge and methods to prevent onset of type 2 diabetes such as incorporating healthy eating habits and increasing physical activities. Although not a primary outcome, there was a significant weight reduction of 2.3% at the end of month 8 of the program (p < 0.05). The culturally and linguistically adapted DPP via online platform successfully demonstrated feasibility and acceptability among Chinese Americans with prediabetes. Further evaluation of the web-based Chinese Diabetes Prevention Program in a larger trial is warranted.

EHealth weight loss interventions for adults with low income: A systematic review.

There is a tremendous opportunity for electronic health services (eHealth) to reach adults with low income who want to participate in weight loss interventions, but face barriers in access. This review (a) synthesizes and presents results from all studies evaluating the effectiveness of eHealth weight loss interventions for adults with low income and (b) describes the strategies used to tailor them to these groups. Electronic databases were searched for studies examining the effectiveness of eHealth weight loss interventions designed for adults with low income and screened for eligibility by two independent reviewers. All experimental study designs were included. Data were extracted, results were qualitatively synthesized, and studies were assessed for quality. Nine studies met the inclusion criteria (N = 1,606 total participants). Four studies reported significant reductions in weight of small to moderate magnitude among participants in eHealth interventions (M weight loss = -2.2 kg; SD = 1.6). Many studies did not describe how they tailored the intervention for adults with low income; however, studies that achieved significant results tended to use more tailoring strategies. Most studies reported high retention rates. Three studies were rated as strong quality, four as moderate, and two as weak. Evidence is limited that eHealth weight loss interventions for this population are effective in achieving clinically and statistically significant weight reductions. While interventions that used more tailoring strategies tended to be more effective, studies that use the rigorous methodology and describe interventions in more depth could better elucidate whether eHealth interventions are an effective approach in this population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A multi-targeted T-cell engagement of PD1-resistant colorectal cancer cells via delivery of glycopeptide conjugates.

e14571 Background: Glycan-based cancer immunotherapies are novel therapeutic strategies that use the pivotal role of aberrant glycosylation patterns in cancer progression. Targeting hybrid epitopes consisting of altered glycans and carrier peptides enhances the efficacy and specificity of the anti-tumor immune response. Here, we exploit ensembles of glycopeptide conjugates to steer a multi-targeted yet tumor-specific T-cell response, a technology we call GLAAD (glycopeptides with adjuvant and tumor-associated antigen delivery). By inducing T cells that recognize and eliminate tumor cells and promoting their antigenicity in a therapeutic setting, we show the potential of our GLAAD candidate GNU-101 to overcome the transient and heterogeneous responses frequently observed with traditional immunotherapies. Methods: Using the MC38 syngeneic mouse model of colorectal cancer (CRC) in a therapeutic setting, we tested whether GNU-101 reduces tumor burden when orally administered alone or combined with immune checkpoint inhibitors (ICI). On day 0, 20 C57/BL6J mice were injected subcutaneously with MC38 CRC cells in each flank. On day 6, mice were supplemented with 3% GNU-101 in the drinking water, while control mice received normal drinking water. On days 6, 9, 12, and 15, half of the mice in each group received an anti-PD1 antibody (aPD1), while the others received isotype control. On day 16, the mice were sacrificed. Results: In this therapeutic setting, a standalone therapy of GNU-101 successfully reduced tumor growth as demonstrated by a statistically significant reduction in both tumor volume and weight. As expected, the aPD1 therapy had only a non-significant effect on tumor growth. Remarkably, its efficacy was improved when combined with GNU-101, leading to a statistically significant reduction of &gt;90% in tumor volume and weight. The analysis of the immune cell population in the tumor microenvironment revealed the activation of CD8 T cells and a reduction of immunosuppressive signals, which likely mediates the anti-tumor efficacy of GNU-101. This was obvious by a higher abundance of CD8 T cells producing IFNγ and secreting granzyme B &amp; perforin and, conversely, lower amounts of Tim3+ CD8 T cells and regulatory T cells (FoxP3+ CD4 T cells) found in mice treated with GNU-101 vs control mice. Conclusions: We demonstrate the immunomodulatory and therapeutic potential of GNU-101 in a pre-clinical mouse study in which the growth of established tumors was significantly reduced, either as a standalone therapy or in combination with existing treatment. By specifically promoting anti-cancer CD8+ T cells while reducing immunosuppressive signals, this easy-to-administer glycopeptide has the potential to create the conditions for long-term cancer control and improve treatment outcomes in cancer that are frequently resistant to immunotherapy, such as many epithelial cancers.

An observational study comparing the effects of whey and vegan meal replacements containing PolyGlycopleX® over 12-weeks in healthy adults

PurposeBackground/Objectives: Protein-based meal replacements (MR) with viscous soluble fibre are known aids for weight loss. This study aims to compare the effects of new whey and vegan MR containing different amounts of PGX (PolyGlycopleX) on weight loss over 12 weeks, along with a calorie-restricted diet.Design/methodology/approachSubjects/Methods: Sixty-eight healthy adults of both sexes (53 women; 15 men; average age 47.1 years; BMI 31 ± 7.1 kg/m2 and weight 85.05 ± 23.3 kg) were recruited. Participants consumed a whey or vegan MR twice/d (5–10 g/day PGX) with a low-energy diet (1,200 kcal/day), over 12 weeks. Weight, height, waist and hip circumference were recorded (four time periods).FindingsResults: Forty-four participants completed the study. Results showed significant reductions in average body weight and at week 12, whey group was [−7.7 kg ± 0.9 (8.3%), p < 0.001] and vegan group was [−4.5 kg ± 0.8 (6.2%), p < 0.001)]. All participants (n = 44; BMI 27 to 33 kg/m2) achieved significant reductions in body measurements from baseline to week 12; p < 0.001. Conclusions: Supplementation of protein-based MR with PGX and a balanced, low-energy diet, appears to be an effective approach for short-term weight loss.Research limitations/implicationsAs the authors were evaluating if the MR as a whole (i.e. with PGX) caused weight loss from baseline over the 12 weeks, no comparators, i.e. just the MR without PGX, were used. Formulation of these new MRs resulted in a whey product with 5 g PGX and a vegan product with 2.5 g PGX. Only 2.5 g PGX could be formulated with the vegan protein due to taste and viscosity limitations. Study participants were not randomized and no control groups (e.g. no MR or MR without PGX but with energy restricted diet) were used. Furthermore, it is not clear whether the sort of protein alone or the combination with a higher amount of PGX (whey with 5 g PGX/serving vs vegan with 2.5 g PGX/serving) has contributed to these significant greater weight-loss effects. This was something the authors were testing, i.e. could only 2.5 g PGX/serving have an effect on weight loss for a vegan MR. These limitations would be somethings to evaluate in a subsequent randomized controlled study. Hence, the results of this study may serve as a good starting point for further sophisticated randomized controlled trials that can demonstrate causality – which the authors acknowledge as one of the fundamental limitations of an observational study design. Participants tracked their calories but adherence and compliance were self-assessed and they were encouraged to keep their exercise routine consistent throughout the study. Hence, these are further limitations. No control group was used in this study to observe the effect of the dietary intervention and/or physical activity on weight loss alone. However, a goal of the authors was to keep this study as close to a real-life situation as possible, where people would not be doing any of these measurements, to see if with minimal supervision or intervention, people can still lose weight and alter their body composition. Furthermore, differences in gender and the corresponding weight loss effects in response to MR-protein-based treatments could be evaluated in follow-up studies.Practical implicationsThis study indicates that the consumption of protein-based (animal, whey or plant, pea protein) MR incorporating the highly soluble viscous PGX is beneficial for weight loss when combined with a healthy-balanced, calorie-restricted diet. MRs at either 2.5 g or 5 g per serving (RealEasyTM with PGX) proved to be a highly effective as a short-term solution for weight loss. The observed results are encouraging, however, further long-term studies (i.e. randomized clinical trials RCT) are needed to confirm the clinical relevance. RCTs should focus on the individual effects of PGX and/or the different protein sources used in MRs, on weight loss and the maintenance of the reduced body weight, and should measure detailed blood parameters (lipid profiles, glucose etc.) as well as collect detailed exercise and food consumption diaries.Originality/valueTo the authors’ knowledge, this is the first study comparing a whey versus vegan, (as pea) protein-based MR that is supplemented with fibre PGX; thus, this work adds information to the already existing literature on fibre (such as PGX) and MRs regarding their combined weight loss effects. The purpose of this study was to observe if the novel protein-based (either whey or vegan versions) MR RealEasyTM with PGX at 2.5 or 5 g in addition to a calorie-restricted diet (total of 1,200 kcal/day) would aid in weight loss in individuals over a 12-weeks period. Adding increasing amounts of whey protein and soluble fibre can help reduce subsequent ad libitum energy intake which could help adherence to energy restricted diets, but whether similar effects are seen with vegan protein is unclear – this study does aim to address this.

Cinnamomum cassia on Arterial Stiffness and Endothelial Dysfunction in Type 2 Diabetes Mellitus: Outcomes of a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Cinnamomum cassia is a medicinal plant whose use has demonstrated benefits on body weight, blood pressure, glucose, and lipids. This study aimed to evaluate the effect of C. cassia on arterial stiffness and endothelial dysfunction (ED) in patients with type 2 diabetes mellitus (T2DM). A randomized, double-blind, placebo-controlled clinical trial was carried out in 18 subjects aged 40-65 years, with a diagnosis of T2DM of one year or less since diagnosis and treated with Metformin 850 mg daily. Patients were randomly assigned to receive either C. cassia or a placebo in 1000 mg capsules, thrice a day, before each meal for 12 weeks. At baseline and after 12 weeks of intervention, brachial-ankle pulse wave velocity and Flow Mediated Dilation were measured, as well as body weight, body mass index (BMI), blood pressure (BP), fasting glucose (FG), glycated hemoglobin A1c (HbA1c), total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and very low density lipoprotein cholesterol, respectively, triglycerides, creatinine, and transaminases. The Mann-Whitney U test for differences between groups and the Wilcoxon signed-rank test for intragroup differences were used, and a P ≤ .05 was considered statistically significant. After C. cassia administration, statistically significant reductions in body weight (81.4 ± 10.4 kg vs. 79.9 ± 9.0 kg, P = .037), BMI (30.6 ± 4.2 kg/m2 vs. 30.1 ± 4.2 kg/m2, P = .018), and HbA1c (53 ± 5.4 mmol/mol vs. 45 ± 2.1 mmol/mol, P = .036) were observed. No changes statistically significant on arterial stiffness, ED, FG, BP, and lipids were observed. C. cassia administration decreases body weight, BMI, and HbA1c without statistically significant changes on arterial stiffness, ED, FG, BP, and lipids. CTR Number: NCT04259606.

Optimized Lightweight Frame for Intelligent New-energy Vehicles

In this paper, a joint optimization method based on multi-objective response surface approximation model and finite element simulation program is proposed to realize the lightweight optimization of new-energy vehicle frames. Under the premise of satisfying the constraints of strength, frequency and vibration, the thickness of different important parts is optimized to achieve the goal of minimizing the quality of intelligent vehicles. In order to obtain the stress distribution of each part and the vibration frequency of the frame, various finite element analyses of the intelligent vehicle frame are analyzed. In order to achieve optimization, this paper adopts the response surface method for multi-objective optimization. Sample data was generated by the central composite design, and the response surface optimization method was used to filter out 5 design variables that had a large impact on the frame. As a result, the weight of the frame was reduced from 25.05 kg to 19.86 kg, a weight reduction of 20.7%, achieving a significant weight reduction effect. This method provides important reference value and guiding significance for the optimization of frame and its lightweight. In this way, the design of the frame can be better optimized to make it lighter, thereby improving the performance of the smart car. At the same time, this method can also be applied to optimization problems in other fields to achieve more efficient and accurate optimization goals.