Significant Reduction In Body Weight Research Articles

Glycemic Control and Body Weight Reduction with Once-Weekly Semaglutide in Colombian Adults with Type 2 Diabetes: Findings from the COLIBRI Study.

Type 2 diabetes is a prevalent condition. The change in glucose control and body weight with the use of once-weekly semaglutide was evaluated in individuals with Type 2 diabetes in Colombia. This was a real-world, multi-centre, single-arm study involving adults in Colombia with Type 2 diabetes treated with once-weekly subcutaneous semaglutide for approximately 26 weeks. The primary endpoint assessed the change in glycated hemoglobin (HbA1c) from baseline to end of study. Secondary endpoints included changes in body weight from baseline to end of study. The study also explored the proportion of participants achieving predefined HbA1c targets and weight-loss responses at the end of the study. Data from 225 patients across 11 centers were collected. Most patients were women (65%), and the mean age of the population was 57 years with a median HbA1c of 7.6% and a median body weight of 86 kg. After approximately 26 weeks, semaglutide was associated with a significant reduction in HbA1c of -0.88 and a body weight reduction of -4.04kg. The proportion of patients with HbA1c < 7% increased from 32 to 66% at end of study. Patients treated with once-weekly semaglutide experienced a clinically significant reduction in HbA1c and body weight. These results are in line with previous clinical trials.

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Long-term effects of ipragliflozin and pioglitazone on metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: 5 year observational follow-up of a randomized, 24 week, active-controlled trial: Effect of ipragliflozin in MASLD.

We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction-associated steatotic liver disease (MASLD), identical to those of pioglitazone. In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated. At 5 years, the mean liver-to-spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (-4.0%, P = 0.0075 and -7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB-4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone. Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years.

THE EFFICACY OF VERY LOW CALORIE KETOGENIC DIET (VLCKD) ON CARDIO–METABOLIC PROFILE IN PATIENTS WITH OBESITY

Abstract Background Obesity is associated with alterations in cardiac structure and haemodynamics leading to cardiovascular mortality and morbidity. Very low calorie ketogenic diet (VLCKD) has been proposed as an effective intervention to achieve a significant weight loss in obese patients in a short time period. Furthermore, hyperketonemia induced by VLCKD is associated with beneficial cardiovascular effects. In addition, ketogenic diet is able to prevent mitochondrial fission, improve mitochondrial function, suppress oxidative stress and attenuate cardiac myocytes apoptosis in the heart of mice. Aim To evaluate the role of VLCKD on cardio–metabolic risk factors, cardiac dysfunction and myocardial remodelling in obese patients. Materials and Methods Ten obese patients treated with VLCKD were enrolled. All patients were characterized from an anthropometric, cardio–metabolic and echocardiographic point of view at baseline and 8 weeks after VLCKD treatment. In addition, each patient underwent measurement of global myocardial work efficiency (GWE), a novel indicator that accounts for deformation and afterload, which may provide additional value for assessment of myocardial function. The insulin resistance (IR) was evaluated by HOMA–IR. Results As expected, all the patients showed a significant reduction in body weight and an overall improvement of body composition parameters after VLCKD. Weight (kg) (from 105.1 ± 18.2 to 83.7 ± 16.7, P &amp;lt;0.05), BMI (kg/m2) (from 40.1 ± 4.7 to 31.8 ± 4.8, P= 0.002) and waist circumference (cm) (from 115 ± 13.6 to 101.8 ± 12.4, p &amp;lt; 0.05) were significantly lower after VLCKD treatment. VLCKD treatment improved also significantly fasting glucose levels (P &amp;lt;0.05), fasting insulin levels (P =0.004), HOMA–IR values (P &amp;lt;0.001), lipid profile and systolic and diastolic blood pressure levels. In addition, the echocardiogram evaluation showed an improved in end–diastolic left ventricular volume, end–systolic left ventricular volume, left ventricular mass and left ventricular mass index. Interestingly, a significantly changes in GWE was observed (P&amp;lt;0.05). Conclusion Although preliminary, our data suggest that VLCKD treatment is able to reduce cardio–metabolic risk factors and to improve cardiac dysfunction and myocardial function.

Treatment of mice with maternal intermittent fasting to improve the fertilization rate and reproduction.

Maternal intermittent fasting (MIF) can have significant effects on several tissue and organ systems of the body, but there is a lack of research on the effects on the reproductive system. So, the aim of our study was to analyze the effects of MIF on fertility. B6C3F1Crl (C57BL/6N × C3H/HeN) male and female mice were selected for the first part of the experiments and were analyzed for body weight and fat weight after administration of the MIF intervention, followed by analysis of sperm counts and activation and embryo numbers. Subsequently, two strains of mice, C57BL/6NCrl and BALB/cJRj, were selected and administered MIF to observe the presence or absence of vaginal plugs for the purposes of mating success, sperm and oocyte quality, pregnancy outcome, fertility status and in vitro fertilization (IVF). Our results showed a significant reduction in body weight and fat content in mice receiving MIF intervention in B6C3F1Crl mice. Comparing the reproduction of the two strains of mice. However, the number of litters was increased in all MIF interventions in C57BL/6NCrl, but not statistically significant. In BALB/cJRj, there was a significant increase in the number of pregnant females as well as litter size in the MIF treatment group, as well as vaginal plugs, and IVF. There was also an increase in sperm activation and embryo number and the MIF intervention significantly increased sperm count and activation. Our results suggest that MIF interventions may be beneficial for reproduction in mice.

Effect of knocking out mouse Slc44a4 on colonic uptake of the microbiota-generated thiamine pyrophosphate and on colon physiology.

Humans/mammals obtain vitamin B1 from dietary and gut microbiota sources. Considerable amount of the microbiota generated vitamin exists in the form of thiamine pyrophosphate (TPP), and colonocytes are capable of absorbing TPP via a specific carrier-mediated process that involves the colonic TPP transporter (cTPPT; encoded by SLC44A4). Little is known about the relative contribution of SLC44A4 toward total colonic carrier-mediated TPP uptake, and its role in colon physiology. To address these issues, we generated an Slc44a4 knockout (KO) mouse model (by Cre-Lox recombination) and found a near complete inhibition in colonic carrier-mediated 3H-TPP uptake in the Slc44a4 KO compared to Wild-type-littermates (WT). We also observed a significant reduction in KO mice body weight and a shortening of their colon compared to WT. Using RNAseq and Ingenuity Pathway Analysis (IPA) approaches, we found that knocking out the colonic Slc44a4 to lead to changes in level of expression of many genes, including up-regulation in those associated with intestinal inflammation/colitis. Finally, we found that the Slc44a4 KO mice to be more susceptible to the effect of the colitogenic dextran sodium sulfate (DSS) compared to WT animals, a finding that lends support to the recent prediction by multiple genome-wide association studies (GWAS) that the SLC44A4 is a possible colitis susceptibility gene. In summary, results of these investigations show that the Slc44a4 is the predominant/only transporter involved in colonic uptake of TPP, that the transporter is important for colon physiology, and that its deletion increases susceptibility to inflammation.

A randomized controlled trial of an app-based intervention on physical activity and glycemic control in people with type 2 diabetes.

We investigated the effects of a physical activity encouragement intervention based on a smartphone personal health record (PHR) application (app) on step count increases, glycemic control, and body weight in patients with type 2 diabetes (T2D). In this 12-week,single-center, randomized controlled, 12-week extension study, patients with T2D who were overweight or obese were randomized using ratio 1:2 to a group using a smartphone PHR app (control group) or group using the app and received individualized motivational text messages (intervention group) for 12weeks. During the extension period, the sending of the encouraging text messages to the intervention group was discontinued. The primary outcome was a change in daily step count after 12weeks and analyzed by independent t-test. The secondary outcomes included HbA1c, fasting glucose, and body weight analyzed by paired or independent t-test. Of 200 participants, 62 (93.9%) and 118 (88.1%) in the control and intervention group, respectively, completed the 12-week main study. The change in daily step count from baseline to week 12 was not significantly different between the two groups (P = 0.365). Among participants with baseline step counts < 7,500 steps per day, the change in the mean daily step count at week 12 in the intervention group (1,319 ± 3,020) was significantly larger than that in control group (-139 ± 2,309) (P = 0.009). At week 12, HbA1c in the intervention group (6.7 ± 0.5%) was significantly lower than that in control group (6.9 ± 0.6%, P = 0.041) and at week 24, changes in HbA1c from baseline were significant in both groups but, comparable between groups. Decrease in HbA1c from baseline to week 12 of intervention group was greater in participants with baseline HbA1c ≥ 7.5% (-0.81 ± 0.84%) compared with those with baseline HbA1c < 7.5% (-0.22 ± 0.39%) (P for interaction = 0.014). A significant reduction in body weight from baseline to week 24 was observed in both groups without significant between-group differences (P = 0.370). App-based individualized motivational intervention for physical activity did not increase daily step count from baseline to week 12, and the changes in HbA1c levels from baseline to week 12 were comparable. ClinicalTrials.gov (NCT03407222).

Effects of penthiopyrad on the hypothalamic-pituitary-thyroid (HPT) axis in zebrafish

Exposure to specific pesticides has been demonstrated to alter normal thyroid function of aquatic vertebrates. This study aimed to investigate the impact of penthiopyrad (PO) on the thyroid function of zebrafish, further elucidating its toxic mechanisms on the early developmental stages of zebrafish. Exposure to sublethal doses of PO (0.3–1.2 mg/L) for 8 days from 2 h after fertilization resulted in a significant reduction in larval swim bladder size and body weight, accompanied by developmental abnormalities such as pigment deposition and abnormal abdominal development. Perturbations in the hypothalamic-pituitary-thyroid (HPT) axis in larvae manifested as a marked upregulation of crh, tg, ttr, and ugt1ab expression, alongside downregulation of trβ expression, culminating in elevated thyroxine (T4) and triiodothyronine (T3) levels. Additionally, molecular docking results suggest that PO and its metabolites may disrupt the binding of thyroid hormones to thyroid hormone receptor beta (TRβ), compromising the normal physiological function of TRβ. These findings highlight the PO-induced adverse effects on the HPT axis of larvae under sublethal doses, eventually leading to abnormal development and growth inhibition.

Development of intestine-targeted microcapsules for enhanced delivery of fucoxanthin: A strategy to mitigate lipid accumulation in vitro and in vivo

The development of intestine-targeted microcapsules using spray drying without maltodextrin is still a challenge. Herein, intestine-targeted fucoxanthin-loaded microcapsules (Fx-MIC) were developed using the spray drying method. The microcapsules were formed by homogenizing fucoxanthin/conjugated linoleic acid (Fx/CLA) and whey protein isolate/Arabic gum (WPI/AG) mixture, followed by spray drying without maltodextrin. The effect of the ratio of Fx/CLA to WPI/AG in Fx-MIC on their morphology and encapsulation efficiency was evaluated. An Fx/CLA-to-WPI/AG ratio of 1:3 yielded a uniform particle size and the highest encapsulation efficiency (91.11%). In vitro simulated digestion demonstrated that Fx-MIC effectively protected Fx from premature release in the stomach and exhibited a release efficiency of 66.08% in the intestine. The digestion product of Fx-MIC effectively inhibited 3T3-L1 cell differentiation and lipid accumulation, demonstrating its ability to reduce lipid accumulation in vitro. Moreover, in high-fat diet (HFD)-induced obesity mice, Fx-MIC exhibited significant reductions in body weight, liver weight, and fat mass. Additionally, Fx-MIC demonstrated notable effects on lowering blood lipid levels and mitigating liver damage. In conclusion, the use of Fx-MIC facilitated the targeted release of Fx, thereby enhancing its anti-obesity effects. This promising result suggests potential applications of Fx-MIC in the food industry.

Anti-obesity potentiality of Lactiplantibacillus plantarum E2_MCCKT isolated from a fermented beverage, haria: a high fat diet-induced obese mice model study.

Obesity is a growing epidemic worldwide. Several pharmacologic drugs are being used to treat obesity but these medicines exhibit side effects. To find out the alternatives of these drugs, we aimed to assess the probiotic properties and anti-obesity potentiality of a lactic acid bacterium E2_MCCKT, isolated from a traditional fermented rice beverage, haria. Based on the 16S rRNA sequencing, the bacterium was identified as Lactiplantibacillus plantarum E2_MCCKT. The bacterium exhibited in vitro probiotic activity in terms of high survivability in an acidic environment and 2% bile salt, moderate auto-aggregation, and hydrophobicity. Later, E2_MCCKT was applied to obese mice to prove its anti-obesity potentiality. Adult male mice (15.39 ± 0.19g) were randomly divided into three groups (n = 5) according to the type of diet: normal diet (ND), high-fat diet (HFD), and HFD supplemented with E2_MCCKT (HFT). After four weeks of bacterial treatment on the obese mice, a significant reduction of body weight, triglyceride, and cholesterol levels, whereas, improvements in serum glucose levels were observed. The bacterial therapy led to mRNA up-regulation of lipolytic transcription factors such as peroxisome proliferator-activated receptor-α which may increase the expression of fatty acid oxidation-related genes such as acyl-CoA oxidase and carnitine palmitoyl-transferase-1. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol-regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase genes. In protein expression study, E2_MCCKT significantly increased IL-10 expression while decreasing pro-inflammatory cytokine (IL-1Ra and TNF-α) expression. In conclusion, the probiotic Lp. plantarum E2_MCCKT might have significant anti-obesity effects on mice.

Orally Ingested Self-Powered Stimulators for Targeted Gut-Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

Acupoints catgut embedding recovers leptin resistance via improving autophagy progress mediated by AMPK-mTOR signaling in obese mice

PurposeLeptin resistance represents a primary pathological manifestation in obesity. Investigating potential treatments and associated mechanisms to restore leptin sensitivity is crucial for effective obesity management. This study aimed to explore the therapeutic potential of acupoints catgut embedding (ACE) in addressing obesity and its associated leptin resistance. MethodsA simple obesity model was established by subjecting C57 male mice to a high-fat diet (HFD) for 12 weeks, followed by ACE treatment administered to half of the obese mice for a duration of 4 weeks. The levels of leptin and its receptor-lepRb, were assessed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. Autophagy progression markers were evaluated through quantitative polymerase chain reaction (qPCR) and Western blot analysis. Also, the liver autophagosomes were photographed using electron microscopy. The role of autophagy in regulating leptin resistance was elucidated using an autophagy suppression model. ResultsComparative analyses demonstrated that ACE treatment resulted in a significant reduction in body weight and blood lipid levels compared to the HFD group. Furthermore, serum leptin levels decreased, while liver lepRb expression increased following ACE treatment. The mRNA and protein expression levels of autophagy in liver were adjusted by ACE treatment. Interestingly, the beneficial effects of ACE were attenuated upon the administration of an autophagy inhibitor. Additionally, ACE treatment led to the activation of the AMPK-mTOR signaling pathway, a crucial regulator of autophagy. ConclusionThese findings suggest that ACE therapy holds promise for recovering leptin resistance by enhancing autophagy progression, mediated via the AMPK-mTOR signaling pathway in liver.

Abstract 3377: Exploring the role of obesity-induced exosome secretion and associated proteins in endometrial cancer pathogenesis: A roadmap for prevention through exosome inhibition

Abstract Introduction: Endometrial cancer (EC) is the leading gynecologic malignancy in the U.S., with obesity implicated in 57% of cases. This study explores the molecular workings of oncogenic protein expression (TMEM205, STAT5, and FAS) and their role in regulating exosome secretion. Understanding these mechanisms is crucial for unraveling pathways involved in obesity-related EC, informing the development of innovative strategies for prevention and treatment. Methods: The isolated exosomes were quantified using nanoparticle tracking analyzer (NTA) and their size measured by Transmission electron microscopy (TEM). TMEM205, STAT5, FAS and PIAS3 expression was confirmed by IHC, ELISA and RT-PCR in patient and high fat diet treated mouse tissue. Endometrial hyperplasia was developed in immunocompetent mice using high fat diet (HFD; 45 kcal% fat diet) for 16 weeks. Results: Our study investigates exosome secretion and the regulation of oncogenic proteins in adipose and uterine tissues from obese EC patients compared to non-obese EC samples. Analyzing the effects of a 45% kcal high-fat diet (HFD) on mice over 24 weeks, we observed higher body weight and increased adipose tissue in the HFD group, along with enlarged uterine horns and heightened inflammation. This correlated with elevated exosome secretion and increased expression of TMEM205, FAS and STAT5, while the tumor suppressor gene PIAS3 was downregulated. The identified small molecule inhibitor, DAP-5, selectively targeting TMEM205 and exosome secretion, demonstrated a significant reduction in body weight and adipose tissue accumulation when administered to HFD mice. Additionally, DAP-5 treatment restored normal uterine morphology and reduced the expression of exosome-related proteins. Conclusion: This study offers central insights into the mechanisms underlying obesity-mediated TMEM205 expression and exosome secretion, shedding light on their role in the pathogenesis of EC. Additionally, it provides pre-clinical evidence supporting the initiation of the first in-human studies for exosome-targeted therapies aimed at preventing obesity-mediated EC. Citation Format: Takahiko Sakaue, Kalpana Deepa Priya Dorayappan, Roman Zingarelli, Wafa Khadraoui, Muralidharan Anbalagan, John Wallbillich, Mark Wascovich, Pragyan Paramita, Adrian Suarez, Casey Cosgrove, Larry G. Maxwell, Hironori Koga, David O’Malley, David Cohn, Selvendiran Karuppaiyah. Exploring the role of obesity-induced exosome secretion and associated proteins in endometrial cancer pathogenesis: A roadmap for prevention through exosome inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3377.

Abstract 664: GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability

Abstract Chromosome instability (CIN) and Genetic instability is a common feature of malignant tumor cells, which may contribute to tumor progression and lead to drug resistance and tumor metastasis. KIF18A, a member of the kinesin-8 family, is an ATP dependent plus end microtubule motor protein. Studies have found that genetic depletion of KIF18A greatly impacts the chromosome alignment, elongation of mitotic spindles, activation spindle assembly checkpoint of CIN+ tumor cell and leads to cell death, while have little impact towards the survival of normal cells, making KIF18A an attractive therapeutic target for targeting the vulnerability of CIN related tumors. Here we report the pharmacology characterization of a “best in class” potential KIF18A inhibitor for CIN+ tumors. In vitro, GSC000190 inhibited KIF18A ATPase activity with a single nM potency and has great potency inhibiting growth of a wide range of TP53 mutant/CIN+ tumor cells. In vivo, GSC000190, at approximately one tenth of systematic exposure comparing to that of AMG650, the leading clinical KIF18A inhibitor, causes tumor shrinkage in multiple CDX models including ovarian, colon and lung cancers. In an HGSOC PDX model which is resistant to platinum and olaparib, GSC000190 induced strong tumor regression both as single agent and through combination without significant body weight reduction. PD study confirms a more elevated mitotic phosphorylated histone 3 (PH3) staining in GSC000190 treated tumor tissues, correlating with a better in vivo efficacy than that of AMG650. GSC000190 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GSC000190 is now under IND-enabling study and P1 study is planned in the second quarter of 2024. Legal entity responsible for the study: The authors. Disclosure: All authors have declared no conflicts of interest. Citation Format: Peng Tu, Chen Zhang, Biao Lu, Yuanfeng Xia, Fanglong Yang. GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 664.

Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice

Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse. To study the comparative efficacy and safety of SGLT-2i using real-world clinical data. We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively. Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin. Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.

Mediterranean-style dietary interventions in adults with cancer: a systematic review of the methodological approaches, feasibility, and preliminary efficacy.

Cancer and its treatments can lead to excess body fat, decreases in lean mass, cardiotoxicity, and other side effects. The Mediterranean diet (MED-diet) has the potential to improve clinical and supportive care outcomes. The aim of this systematic review was to evaluate the feasibility, safety, and efficacy of the MED-diet on health outcomes in adults with cancer. Three databases were searched from inception to February 2023. Eligible studies included randomised controlled trials testing a MED-diet intervention among adults with cancer. Within- and between-group differences for adherence, dietary intake and health outcomes were extracted. Fifteen studies describing fourteen interventions were included, and there were considerable differences in study design and implementation of the MED-diet. Studies were predominately in women with a history of breast cancer. The MED-diet was safe with no adverse events reported, and feasible with high adherence and/or increases in MED-diet-compliant foods. The MED-diet when applied with an energy restriction below estimated requirements for weight loss demonstrated reductions in body weight (range: -3.9 kg to -0.7 kg). Interventions that showed significant reductions in body weight also improved quality of life. There is limited evidence to evaluating the MED-diet on cardiovascular and inflammatory markers, and heterogenous MED-diet prescriptions impede definitive conclusions on these health outcomes. The MED-diet was feasible and safe for adults with cancer. There were reported benefits for weight loss following a MED-diet when an energy restriction was applied, however further evaluation to determine the effects on cardiometabolic biomarkers and other outcomes are required.

Effect of Corrective Exercise on Static Balance, Food Consumption, and Body Composition in the Early Period After Bariatric Surgery.

To determine the impact of corrective exercise program applied during the period of rapid weight loss following bariatric surgery on static balance, dietary intake, and body composition. Participants who had undergone Sleeve Gastrectomy (SG) surgery were divided into as Corrective Exercise Group (CEG), and Control Group (CG). CEG underwent a 12-week supervised corrective exercise program. Body composition and static balance of all participants were assessed before and after the study. Their physical activity levels and dietary intake were also evaluated. Following of the corrective exercise program, both groups exhibited significant reductions in body weight, BMI, fat mass, fat percentage, muscle mass, waist circumference-to-height ratio, and visceral adiposity values (p < 0.05). Additionally, the CEG showed increase in lean body mass percentage (p < 0.001). In measurements related to static balance, values for eyes-closed perimeter (p = 0.015), eyes-closed (p = 0.006), eyes-open (p = 0.028) ellipses area, average F-B speed, and eyes-open center of pressure in the X-axis (C.O.P.X.) sway distance significantly decreased in both groups (p = 0.025). However, the difference in eyes-open C.O.P.X. sway distance was found to be higher in the CG (mean difference = 8.67; p = 0.034). Postoperatively, there were significant decreases in energy, protein, fat, CHO (carbohydrate), CHO percentage, fiber, and iron values, while protein percentage (p < 0.001), vitamin D (p = 0.003), and B12 (p < 0.001) values increased. It has been observed that the corrective exercise program implemented in the early postoperative period following SG surgery had a positive impact on eyes-open static balance.

A randomized, double-blind, active-controlled trial assessing the efficacy and safety of a fixed-dose combination (FDC) of MEtformin hydrochloride 1000 mg ER, SItagliptin phosphate 100 mg, and DApagliflozin propanediol 10 mg in Indian adults with type 2 diabetes: The MESIDA trial

ObjectiveTo assess the efficacy and safety of fixed-dose combinations (FDC) of triple-drug dapagliflozin, sitagliptin, and metformin (DSM) compared with FDC of two-drug sitagliptin and metformin (SM), in Indian adult patients with type 2 diabetes (T2D).MethodsA multicentric, randomized, double-blind, active-controlled, Phase 3 study (CTRI/2021/10/037461) was conducted on 274 Indian adult patients with T2D. Patients were randomized (1:1) to receive either an FDC of triple-drug (n = 137) dapagliflozin propanediol 10 mg, sitagliptin phosphate 100 mg, and metformin hydrochloride 1000 mg extended-release (DSM) or FDC of two-drug (n = 137) sitagliptin phosphate 100 mg and metformin hydrochloride 1000 mg sustained-release (SM), for 16 weeks. The primary endpoint was a change in HbA1c, while the secondary endpoints were changes in fasting plasma glucose (FPG), postprandial glucose (PPG), body weight, and safety.ResultsBoth DSM and SM FDCs reduced HbA1c significantly (-1.45% and -1.00%, respectively, both p < 0.0001), however, HbA1c lowering was superior with DSM (∆ -0.45%; p = 0.0005) compared to SM, at week 16. Similarly, both DSM and SM FDCs reduced FPG and PPG significantly, however, FPG (∆ -12.4 mg/dl; p = 0.003) and PPG reduction (∆ -18.45 mg/dl; p = 0.01) were significantly superior to DSM compared to SM, respectively. No significant reduction in body weight was observed between the two arms. Both FDCs were well tolerated.ConclusionFDC of DSM was superior to SM in reducing HbA1c, FPG, and PPG in Indian adults with T2D. Both triple and dual FDCs had optimal safety profiles.

Dynamic Changes in Adiponectin and Resistin Drive Remission of Cardiometabolic Risk Biomarkers in Individuals with Obesity Following Bariatric Surgery.

The remission of obesity-related diseases following bariatric surgery appears to result from the reorganization of metabolic and hormonal pathways involving adipokines. This study aimed to investigate the relationship between changes in body adiposity and serum adipokine levels, as well as the association between variations in adiponectin or resistin levels and cardiometabolic risk blood biomarkers before and after Roux-en-Y gastric bypass. A longitudinal and prospective study was conducted with bariatric surgery patients. Anthropometric, body composition and blood biochemical parameters were measured before and at 2 and 6 months post-surgery. The data were analyzed using ANOVA, Pearson or Spearman correlation, and simple linear regression with a significance level of p < 0.05. Among 36 mostly female patients aged 30 to 39 years, significant reductions in body weight (-26.8%), fat mass (-50%), waist circumference (-18%) and waist-to-height ratio (-22%) were observed post-surgery. Serum adiponectin levels increased (+107%), while resistin (-12.2%), TNF-α (-35%), and PAI-1 (-11.1%) decreased. Glucose, insulin, CRP, cholesterol, LDL-c, triglycerides, and vitamin D also decreased. Waist circumference variation showed a positive correlation with PAI-1 and TNF-α and a negative correlation with adiponectin. The total fat mass showed a positive correlation with PAI-1. Adiponectin variation correlated negatively with glucose, resistin, and CRP but positively with HDL-c. Resistin showed a positive correlation with insulin and CRP. In conclusion, 6 months post-bariatric surgery, reducing abdominal adiposity had a more significant impact on serum adipokine levels than total fat mass. Adiponectin increase and resistin decrease acted as endocrine mediators driving the remission of cardiometabolic risk biomarkers in individuals with obesity following Roux-en-Y gastric bypass.