Improvement Of Metabolism Research Articles

Calebin A attenuated inflammation in RAW264.7 macrophages and adipose tissue to improve hepatic glucose metabolism and hyperglycemia in high-fat diet-fed obese mice

The increased incidence of obesity, which become a global health problem, requires more functional food products with minor side and excellent effects. Calebin A (CbA) is a non-curcuminoid compound, which is reported to be an effective treatment for lipid metabolism and thermogenesis. However, its ability and mechanism of action in improving obesity-associated hyperglycemia remain unclear. This study was designed to explore the effect and mechanism of CbA in hyperglycemia via improvement of inflammation and glucose metabolism in the adipose tissue and liver in high-fat diet (HFD)-fed mice. After 10 weeks fed HFD, obese mice supplemented with CbA (25 and 100 mg/kg) for another 10 weeks showed a remarkable reducing adiposity and blood glucose. CbA modulated M1/M2 macrophage polarization, ameliorated inflammatory cytokines, and restored adiponectin as well as Glut 4 expression in the adipose tissue. In the in vitro study, CbA attenuated pro-inflammatory markers while upregulated anti-inflammatory IL-10 in LPS + IFNγ-generated M1 phenotype macrophages. In the liver, CbA attenuated steatosis, inflammatory infiltration, and protein levels of inflammatory TNF-α and IL-6. Moreover, CbA markedly upregulated Adiponectin receptor 1, AMPK, and insulin downstream Akt signaling to improve glycogen content and increase Glut2 protein. These findings indicated that CbA may be a novel therapeutic approach to treat obesity and hyperglycemia phenotype targeting on adipose inflammation and hepatic insulin signaling.

Metabolic Effects of Ketogenic Diets: Exploring Whole-Body Metabolism in Connection with Adipose Tissue and Other Metabolic Organs.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body's dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.

Innovative solution or cause for concern? The use of continuous glucose monitors in people not living with diabetes: A narrative review.

Continuous glucose monitors (CGMs) have expanded their scope beyond indicated uses for diabetes management and are gaining traction among people not living with diabetes (PNLD). CGMs track in time glucose levels and are proposed as tools for the early detection of abnormal glucose and a potential solution for its normalisation through behavioural change, particularly, diet personalisation and motivation of physical activity. This becomes relevance given the growing incidence of metabolic conditions, such as type 2 diabetes mellitus (T2DM). Clinical guidelines, however, do not recommend CGMs in contexts outside type 1 diabetes (T1DM) or insulin-treated T2DM. Therefore, there is a visible disconnect between the indicated and real-world usage of these medical devices. While the commercial market for CGMs in PNLD is expanding rapidly, a comprehensive and evidence-based evaluation of the devices' utility in this population has not been done. Therefore, this review aims to formulate a working model for CGM utility in PNLD as proposed by the 'health and wellness' market that advertises and distributes it to these individuals. We aim to critically analyse the available research addressing components of the working model, that is (1) detection of abnormal glucose; (2) behavioural change, and (3) metabolic health improvement. We find a lack of consistent and high-quality evidence to support the utility of CGMs for these purposes. We identify significantly under-reserved areas including clinical benchmarks and scoring procedures for CGM measures, device acceptability, and potential adverse effects of CGMs on eating habits in PNLD. We also raise concerns about the robustness of available CGM research. In the face of these research gaps, we urge for the commercial claims suggesting the utility of the device in PNLD to be labelled as misleading. We argue that there is a regulatory inadequacy that fuels 'off-label' CGM distribution and calls for the strengthening of post-market clinical follow-up oversight for CGMs. We hope this will help to avert the continued misinformation risk to PNLD and 'off-label' exacerbation of health disparities.

Targeting mitochondria for ovarian aging: new insights into mechanisms and therapeutic potential.

Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have identified mitochondria as pivotal players in the aging of ovaries, influencing various hallmarks and pathways governing this intricate process. In this review, we discuss the multifaceted role of mitochondria in determining ovarian fate, and outline the pivotal mechanisms through which mitochondria contribute to ovarian aging. Specifically, we emphasize the potential of targeting mitochondrial dysfunction through innovative therapeutic approaches, including antioxidants, metabolic improvement, biogenesis promotion, mitophagy enhancement, mitochondrial transfer, and traditional Chinese medicine. These strategies hold promise as effective means to mitigate age-related fertility decline and preserve ovarian health. Drawing insights from advanced researches in the field, this review provides a deeper understanding of the intricate interplay between mitochondrial function and ovarian aging, offering valuable perspectives for the development of novel therapeutic interventions aimed at preserving fertility and enhancing overall reproductive health.

Effects of combined training on nonshivering thermogenic activity of muscles in individuals with overweight and type 2 diabetes.

Increased thermogenic activity has shown to be a promising target for treating and preventing obesity and type 2 diabetes (T2DM). Little is known about the muscular influence on nonshivering thermogenesis (NST), and it remains unclear whether physical training and potential metabolic improvements could be associated with changes in this type of thermogenic activity. The present study aimed to assess muscular NST activity in overweight and T2DM before and after a combined training period (strength training followed by aerobic exercise). Nonshivering cold-induced 18-fluoroxyglucose positron emission computed tomography (18F-FDG PET/CT) was performed before and after 16 weeks of combined training in 12 individuals with overweight and T2DM. The standard uptake value (SUV) of 18F-FDG was evaluated in skeletal muscles, the heart and the aorta. Muscles in the neck region exhibit higher SUV pre- and posttraining. Furthermore, a decrease in glucose uptake by the muscles of the lower and upper extremities and in the aorta was observed after training when adjusted for brown adipose tissue (BAT). These pre-post effects are accompanied by increased cardiac SUV and occur concurrently with heightened energy expenditure and metabolic improvements. Muscles in the neck region have greater metabolic activity upon exposure to cold. In addition, combined training appears to induce greater NST, favoring the trunk and neck region compared to limbs based on joint work and adaptations between skeletal muscles and BAT.

Free essential amino acid feeding improves endurance during resistance training via DRP1-dependent mitochondrial remodelling.

Loss of muscle strength and endurance with aging or in various conditions negatively affects quality of life. Resistance exercise training (RET) is the most powerful means to improve muscle mass and strength, but it does not generally lead to improvements in endurance capacity. Free essential amino acids (EAAs) act as precursors and stimuli for synthesis of both mitochondrial and myofibrillar proteins that could potentially confer endurance and strength gains. Thus, we hypothesized that daily consumption of a dietary supplement of nine free EAAs with RET improves endurance in addition to the strength gains by RET. Male C57BL6J mice (9weeks old) were assigned to control (CON), EAA, RET (ladder climbing, 3 times a week), or combined treatment of EAA and RET (EAA+RET) groups. Physical functions focusing on strength or endurance were assessed before and after the interventions. Several analyses were performed to gain better insight into the mechanisms by which muscle function was improved. We determined cumulative rates of myofibrillar and mitochondrial protein synthesis using 2H2O labelling and mass spectrometry; assessed ex vivo contractile properties and in vitro mitochondrial function, evaluated neuromuscular junction (NMJ) stability, and assessed implicated molecular singling pathways. Furthermore, whole-body and muscle insulin sensitivity along with glucose metabolism, were evaluated using a hyperinsulinaemic-euglycaemic clamp. EAA+RET increased muscle mass (10%, P<0.05) and strength (6%, P<0.05) more than RET alone, due to an enhanced rate of integrated muscle protein synthesis (19%, P<0.05) with concomitant activation of Akt1/mTORC1 signalling. Muscle quality (muscle strength normalized to mass) was improved by RET (i.e., RET and EAA+RET) compared with sedentary groups (10%, P<0.05), which was associated with increased AchR cluster size and MuSK activation (P<0.05). EAA+RET also increased endurance capacity more than RET alone (26%, P<0.05) by increasing both mitochondrial protein synthesis (53%, P<0.05) and DRP1 activation (P<0.05). Maximal respiratory capacity increased (P<0.05) through activation of the mTORC1-DRP1 signalling axis. These favourable effects were accompanied by an improvement in basal glucose metabolism (i.e., blood glucose concentrations and endogenous glucose production vs. CON, P<0.05). Combined treatment with balanced free EAAs and RET may effectively promote endurance capacity as well as muscle strength through increased muscle protein synthesis, improved NMJ stability, and enhanced mitochondrial dynamics via mTORC1-DRP1 axis activation, ultimately leading to improved basal glucose metabolism.

Development of Novel Tools for Dissection of Central Versus Peripheral Dopamine D2-Like Receptor Signaling in Dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

The enduring metabolic improvement of combining dual amylin and calcitonin receptor agonist and semaglutide treatments in a rat model of obesity and diabetes.

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 mo, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide, and the combination lowered body weight significantly compared with the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels and improved glucose tolerance compared with vehicle-treated rats. Furthermore, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared with vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss, as well as improved glucose control. Furthermore, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs.NEW & NOTEWORTHY These studies describe the benefit of combining dual amylin and calcitonin receptor agonists (DACRA) with semaglutide for long-term treatment of obesity and type 2 diabetes. Combination treatment induced sustained weight loss and improved glucose control. A DACRA-driven reduction in a serological biomarker of cardiac fibrosis indicated a reduced risk of complications. These results highlight DACRAs as a promising candidate for combination treatment of obesity and type 2 diabetes and related long-term complications.

Astragalin protects against lipopolysaccharide-triggered acute liver injury through suppression of necroptosis and inflammation and improvement of energy metabolism

Acute liver injury (ALI) is a prevalent clinical condition featured by liver inflammation and functional abnormalities resulting from various causes. Prolonged damage to liver cells can progress to chronic inflammation, fibrosis, and cirrhosis. Astragalin (AST), a natural flavonoid present in traditional medicinal and edible plants, exhibits anti-inflammatory and antioxidative properties, making it a potential therapeutic candidate for ALI. Using network pharmacology analysis, we explored the targets and pathways implicated in the regulation of AST against ALI. Our study using an ALI mouse model showed that AST effectively mitigates oxidative stress and inflammation induced by lipopolysaccharide (LPS), offering protection against LPS-induced ALI. The mechanism may involve inhibiting the tumor necrosis factor-α-driven necroptosis pathway and downregulating the hypoxia-inducible factor-1α/pyruvate kinase M2 signaling pathway, thereby suppressing enhanced glycolysis-mediated inflammatory response. Through the synergistic modulation of multiple targets and pathways, AST emerges as a promising therapeutic option for ALI, offering potential for clinical application.

Lipid-encapsulated mRNA encoding an extended serum half-life interleukin-22 ameliorates metabolic disease in mice

ObjectiveInterleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models. MethodsC57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis–inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed. ResultsMSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22–treated mice, and these effects were shown to be durable. ConclusionsThese results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.

Correlation analysis between the changes in plasma ghrelin level and weight loss after sleeve gastrectomy combined with fundoplication

BackgroundLaparoscopic sleeve gastrectomy combined with fundoplication (LSGFD) can significantly control body weight and achieve effective anti-reflux effects. The aim of this study is to investigate the correlation between the alteration in Ghrelin levels and weight loss following SGFD, and to compare Ghrelin levels, weight loss and metabolic improvements between SG and SGFD, with the objective of contributing to the existing body of knowledge on SGFD technique in the management of patients with obesity and gastroesophageal reflux disease (GERD).MethodsA retrospective analysis was conducted on the clinical data of 115 obese patients who underwent bariatric surgery between March 2023 and June 2023 at the Department of Minimally Invasivew Surgery, Hernia and Abdominal Wall Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region. The subjects were divided into two groups based on surgical methods: sleeve gastrectomy group (SG group, 93 cases) and sleeve gastrectomy combined with fundoplication group (SGFD group, 22 cases). Clinical data, such as ghrelin levels before and after the operation, were compared between the two groups, and the correlation between changes in ghrelin levels and weight loss effectiveness after the operation was analyzed. Results: Three months after the operation, there was no significant difference in body mass, BMI, EWL%, fasting blood glucose, triglyceride, cholesterol, and uric acid levels between the SG and SGFD groups (P > 0.05). However, the SGFD group exhibited a significant decrease in body weight, BMI, and uric acid levels compared to preoperative levels (P < 0.05), while the decrease in ghrelin levels was not statistically significant (P > 0.05). Logistic regression analysis indicated that ghrelin levels three months after the operation were influential in postoperative weight loss.ConclusionThe reduction of plasma Ghrelin level in patients after SGFD is not as obvious as that in patients after SG, but it can make obese patients get the same good weight loss and metabolic improvement as patients after SG. Ghrelin level at the third month after operation is the influencing factor of postoperative weight loss.

Anti-adipogenesis and anti-obesity potential of alliin mediated by modulating glycolipid metabolism via activating PPARγ signaling.

Garlic exhibits hypolipidemic, hypoglycemic, and cardiovascular benefits. The inconsistent results of garlic preparations on adipogenesis have caused more confusion in the public and academia. The compounds responsible for the anti-adipogenesis effect of garlic remain unknown. The present study aimed to verify the real anti-adipogenesis and anti-obesity component in garlic and explored its possible effects in metabolic syndrome. We verified the real anti-adipogenesis and anti-obesity components of garlic in 3T3-L1 preadipocytes and a 10-week-high fat diet (HFD)-induced obese mice. In vitro, two water-soluble and four typical lipid-soluble compounds of garlic were tested for their anti-adipogenesis. Then, the water-soluble compound, alliin, and two processing methods produced garlic oils, were evaluated in vivo study. Mice received oral administration of alliin (25mg/kg) and garlic oils (15mg/kg) daily for 8weeks. Serum lipids, parameters of obesity, and indicators involved in regulating glycolipid metabolism were examined. Our findings confirmed that both water-soluble and lipid-soluble organosulfur compounds of garlic contributed to garlic's anti-adipogenesis effect, in which water-soluble sulfides, especially alliin, exhibited greater potency. Alliin possessed potent effects of anti-obesity and improvement in glucose and lipid metabolism in HFD-induced obese mice. Alliin mediated these effects partly attributed to its modulation of enzymatic activities within glycolipid metabolism and activating PPARγ signaling pathway. In contrast to odorous lipid-soluble sulfides, alliin is odorless, stable, and safe, and is an ideal nutraceutical or even medicinal candidates for the treatment of metabolic diseases. Alliin could be used to standardize the quality of garlic products.

Chemerin regulates glucose and lipid metabolism by changing mitochondrial structure and function associated with androgen/androgen receptor.

The adipokine chemerin contributes to exercise-induced improvements in glucose and lipid metabolism; however, the underlying mechanism remains unclear. We aimed to confirm the impact of reduced chemerin expression on exercise-induced improvement in glycolipid metabolism in male diabetic (DM) mice through exogenous chemerin administration. Furthermore, the underlying mechanism of chemerin involved in changes in muscle mitochondria function mediated by androgen/androgen receptor (AR) was explored by generating adipose-specific and global chemerin knockout (adipo-chemerin-/- and chemerin-/-) mice. DM mice were categorized into the DM, exercised DM (EDM), and EDM + chemerin supplementation groups. Adipo-chemerin-/- and chemerin-/- mice were classified in the sedentary or exercised groups and fed either a normal or high-fat diet. Exercise mice underwent a 6-wk aerobic exercise regimen. The serum testosterone and chemerin levels, glycolipid metabolism indices, mitochondrial function, and protein levels involved in mitochondrial biogenesis and dynamics were measured. Notably, exogenous chemerin reversed exercise-induced improvements in glycolipid metabolism, AR protein levels, mitochondrial biogenesis, and mitochondrial fusion in DM mice. Moreover, adipose-specific chemerin knockout improved glycolipid metabolism, enhanced exercise-induced increases in testosterone and AR levels in exercised mice, and alleviated the detrimental effects of a high-fat diet on mitochondrial morphology, biogenesis, and dynamics. Finally, similar improvements in glucose metabolism (but not lipid metabolism), mitochondrial function, and mitochondrial dynamics were observed in chemerin-/- mice. In conclusion, decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, likely through changes in androgen/AR signaling.NEW & NOTEWORTHY Decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, which is likely mediated by androgen/androgen receptor expression. This study is the first to report the regulatory mechanism of chemerin in muscle mitochondria.

Association between ferritin, hemoglobin, and anemia response in jaktinib-treated patients with myelofibrosis: A post-hoc analysis of the ZGJAK006 study.

e18527 Background: Iron metabolism is disrupted in MF through the increased production of hepcidin, contributing to increased ferritin levels and iron-binding capacity, decreased serum iron levels and hemoglobin levels. Hepcidin production is upregulated by JAK/STAT pathway and BMP6/ACVR1/SMAD pathway. Jaktinib showed inhibition effects on JAK family and ACVR1 in preclinical studies. Anemia benefits with jaktinib treatment were observed in several clinical studies in MF pts. To explore the underlying mechanisms, we conducted a post-hoc analysis to investigate the change of ferritin levels during jaktinib treatment in MF pts with and without anemia response from a phase 2 study in pts who were intolerant to ruxolitinib (the ZGJAK006 study). Methods: Pts from the ZGJAK006 study were included if they were RBC transfusion dependent or with hemoglobin level ≤100 g/L at baseline. Transfusion dependence was assigned to pts with an average RBC transfusion of ≥2 U/month within 3 months prior to study drug administration. Pts without baseline ferritin results were excluded. Eligible pts were divided into 2 groups: anemia responders by week 24 and non-responders by week 24. Anemia response was defined as becoming RBC transfusion independent (defined by no transfusion in ≥12 consecutive weeks and hemoglobin ≥85 g/L) for transfusion-dependent pts or a ≥20 g/L increase in hemoglobin for non-transfusion-dependent pts with baseline hemoglobin ≤100 g/L. Results: A total of 39 pts were included in this post-hoc analysis, with 14 anemia responders and 25 non-responders. The baseline hemoglobin was similar in responders (median: 78.5 g/L) and non-responders (median: 78.0 g/L). The baseline levels of ferritin were higher than upper limit of normal in most pts (69.2%) with a median of 784.6 ng/mL in the overall population (697.5 ng/mL in responders and 785.0 ng/mL in non-responders). Ferritin decreased to 583.9 and 531.7 ng/mL at weeks 12 and 24, respectively. Notably, anemia responders had a fast reduction in ferritin and increase in hemoglobin compared to non-responders. In addition, the hemoglobin levels of those non-responders maintained were stable and eight non-responders had a ≥50% decrease in RBC infusion frequency or unit. Six (42.9%) of 14 responders and 10 (40.0%) of 25 non-responders achieved spleen volume reduction of ≥ 35% from baseline at week 24. Conclusions: In this post-hoc analysis of pts with anemic MF, jaktinib treatment led to improvement in iron metabolism and anemia. The results were in consistence with the known activities of jaktinib against JAK family and ACVR1. Moreover, similar spleen responses were observed for anemia responders and non-responders. Nevertheless, ferritin was the only marker of iron metabolism measured in this study, a translational biology study evaluating hepcidin may be needed to further support the clinical findings. Clinical trial information: NCT04217993 .

Thyroid function changes during growth hormone therapy in pediatric patients: a controlled study and review of recent data

Introduction: Growth hormone therapy is a cornerstone treatment for children with GHD and ISS. Its impact on the hypothalamic-pituitary-thyroid axis, however, has been a subject of ongoing research. This review compiles findings from several studies spanning three decades and contrasts them with recent data to enhance our understanding of thyroid function dynamics during GH therapy. Review of Literature: Early Observations (1992-2005) Pirazzoli et al. (1992) and Tang et al. (1997) were among the first to document changes in thyroid function due to GH therapy, noting enhanced peripheral conversion of T4 to T3 and a prevalence of subclinical hypothyroidism. Wyatt et al. (1998) reported significant decreases in T4 and increases in T3, indicating a notable shift in thyroid hormone levels early in GH therapy. Mid-Term Studies (2005-2015) Seminara et al. (2005) and Kalina-Faska et al. (2004) reported changes in thyroid function, particularly a decrease in T4 levels and a transient increase in fT3 during the early stages of GH therapy. · Recent Developments (2016-Present) Wang Ying and Liang Furong (2016) emphasized the need for vigilant monitoring of thyroid hormone levels, aligning with Zheng et al. (2014) who noted improvements in lipid metabolism without significant thyroid function impacts. Glynn et al. (2017, 2018) and Kucharska et al. (2021) focused on the complexities of the biological effects of GH-induced changes in thyroid hormones. Comparison with our Data Our recent study reveals subtle changes in thyroid function in GH-treated children with GHD and ISS. We observed a slight decrease in mean FT4 and an increase in mean TSH in the GH treatment group, stable TSH and decreased FT4 in the ISS treatment group, and significant decreases in both FT4 and TSH in the no-treatment group. These findings corroborate the trend seen in earlier studies, highlighting the multifaceted nature of thyroid function changes during GH therapy. Conclusions: The review underscores that GH therapy can significantly influence thyroid function, necessitating regular monitoring of thyroid hormone levels. The variation in thyroid responses suggests a complex interaction between GH therapy and the hypothalamic-pituitary-thyroid axis, which may be influenced by factors like age, severity of GHD, and duration of GH treatment.

Analysis of weight loss, metabolism, and anti-reflux effect of sleeve gastrectomy combined with fundoplication as treatment of obesity complicated by gastroesophageal reflux disease

Objective: To explore the weight-loss, metabolism, and anti-reflux effect of laparoscopic sleeve gastrectomy combined with fundoplication (SGFD) as treatment of obesity complicated by gastroesophageal reflux disease (GERD) with the aim of identifying the best treatment for such patients. Methods: This was a retrospective cohort study. Relevant clinical data of 140 patients with obesity (body mass index≥30 kg/m2) complicated by GERD (confirmed by preoperative GerdQ score, gastroscope, upper gastrointestinal radiography, 24-hour pH monitoring of esophagus, and high-resolution esophageal manometry) who had undergone bariatric surgery in the Minimally Invasive Surgery, Hernia and Abdominal Surgery Department of the People's Hospital of Xinjiang Uygur Autonomous Region from January 2019 to February 2023 were collected. The participants were allocated to the following groups according to surgical procedure performed: sleeve gastrectomy group (SG group, 92 cases) versus SGFD (SGFD group, 48 cases). SGFD, a new type of anti-reflux weight loss surgery that achieves both anti-reflux and weight loss effects by a procedure involving "cutting first and then folding", was developed by our team. In this study, our main aim was to compare and analyze differences in outcomes between the SG and SGFD groups in terms of weight loss and improvements in metabolism and reflux 3 and 6 months postoperatively. Results: The 140 patients comprised 50 men and 90 women of average age 36.0±9.6 years and preoperative body mass index (BMI) (38.5±6.5) kg/m2. The average preoperative GERD score was 10.2±1.6. There were no significant differences in baseline characteristics between the SGFD and SG groups (all P>0.05). There were also no significant differences in postoperative hospital stay, intraoperative blood loss, or postoperative complications between the two groups (all P>0.05). However, the operation time was longer in the SGFD than SG group (137.5±10.5 minutes vs. 105.3±12.6 minutes, t=-15.131, P<0.001). Compared with preoperative values, fasting blood glucose, cholesterol, body mass, BMI, and GERD score were all lower 3 months postoperatively (all P<0.05). Six months postoperatively, triglyceride, uric acid, and DeMeester score were lower in the SGFD than SG group; however, the lower esophageal sphincter resting pressure was higher in the SGFD group (all P<0.05). There were no significant differences in weight loss indexes (body mass, BMI, percentage of excess body mass loss) or metabolic indexes (fasting blood glucose, triglyceride, cholesterol, and uric acid concentrations) between the SG and SGFD groups 3 and 6 months postoperatively (all P>0.05). However, anti-reflux indexes (GerdQ score, DeMeester score, and lower esophageal sphincter resting pressure) were all significantly better in the SGFD than SG group 6 months postoperatively (all P<0.05). Conclusion: Obese patients with GERD get good weight loss, metabolism improvement and anti-reflux effect after SGFD. SGFD is a safe and feasible surgical method, and its anti-reflux effect is better than SG at the 6th month after operation, so it is feasible.

Metformin: Therapeutic profile in the treatment of type 2 diabetes.

Metformin (dimethyl-biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a glucose-lowering agent in 1957, this medicine has emerged as a first-line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long-term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost-effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended-release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D.

Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice

Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

The role of pantothenic acid in alleviating hypoxia-induced liver injury of sub-adult grass carp (Ctenopharyngodon idellus): Possible mechanisms and implication

In aquaculture, hypoxia poses a significant threat to fish growth and survival. Despite this, there is limited research on the impact of pantothenic acid (PA) in enhancing the anti-hypoxia stress capability of fish. The primary objective of this study was to explore the effects and potential mechanisms of PA in alleviating hypoxia-induced liver injury in sub-adult grass carp. To achieve this, six experimental diets containing varying levels of PA (0.08, 11.95, 24.95, 37.95, 50.95, and 63.95 mg/kg) were formulated and administered to grass carp (initial weight 696.22 ± 2.45 g) for 63 days. Following the dietary intervention, the fish were segregated into hypoxia and control groups and treated for 96 h. The findings revealed that optimal PA levels could enhance the growth performance of sub-adult grass carp and ameliorate the adverse impacts of hypoxia. First, optimal PA levels reduced serum levels of glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), and lactate dehydrogenase (LDH), as well as mitigated hepatocyte vacuolization, improved liver and mitochondrial morphology, thereby alleviating hypoxia-induced liver injury. Furthermore, optimal PA levels were associated with increased contents of serum cortisol, glucose, liver glycogen, pyruvate, and the activities of Pantothenate kinase 2 (PanK2) and coenzyme A (CoA), while liver lactate content and LDH activity were reduced, indicating improvements in energy metabolism and PA utilization, potentially mediated by the down-regulation of hypoxia-inducible factor-1α (HIF-1α) mRNA level. Moreover, optimal PA levels decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, enhanced liver antioxidant capacity, down-regulated autophagy-related gene mRNA levels, and up-regulated autophagy receptor protein 62 (p62) protein level, suggesting a reduction in oxidative damage and autophagy. Finally, a rise in levels of mitochondrial quality control-related mRNAs such as mitofusin 1/2 (MFN1/2), dynamin-related protein-1 (DRP-1), and nuclear respiratory factor 1/2 (Nrf-1/2) was observed, together with increment in the protein levels of PTEN induced putative kinase 1 (PINK1), BCL-2 interacting protein 3 (BNIP3) and FUN14 domain-containing protein 1 (FUNDC1). These alterations hinted at the role of PA in preserving mitochondrial homeostasis. In conclusion, PA exhibited a protective role against hypoxia-induced liver injury by enhancing liver energy metabolism, bolstering antioxidant defenses, suppressing autophagy, and maintaining mitochondrial homeostasis. Through an assessment of percentage weight gain (PWG) and liver ROS level, the requirements of PA for promoting growth and resilience to hypoxia-induced liver injury in sub-adult grass carp were determined to be 37.44 mg/kg and 42.57 mg/kg, respectively.

Evaluation of metabolic changes in clinic attendees with therapeutic carbohydrate restriction

Background: Obesity and related metabolic health disorders are major clinical problems that have become increasingly prevalent worldwide.Aim: This before-after study examined the impact of therapeutic carbohydrate restriction (TCR) in managing metabolic health and promoting weight loss in a clinical setting using indirect calorimetry (IC).Setting: Data were collected from medical records obtained from a specialised allied health clinic focusing on metabolic health.Methods: The study analysed retrospective data from 202 overweight or obese participants (77% female, mean age 47.3) who received TCR as part of a behavioural modification programme involving multiple visits where their lifestyle, body composition and respiratory quotient (RQ), a key indicator of fat oxidation were recorded.Results: The study found that TCR improved fat oxidation in 84% of participants at short term visit (around 2 weeks), with an average weight loss of 1.8 kg. At medium term visit (around 12 weeks), 82% of participants maintained an increase in fat oxidation rate, with an average weight loss of 3.9 kg. In addition, among those with recorded body composition and waist circumference, 71% of weight lost was from fat, with an average reduction of 4.9 cm in waist measurements.Conclusion: This real-world study suggests that personalised TCR guided by IC can be an effective strategy for improving metabolic flexibility to help manage excess weight and related co-morbidities in a free-living population. Further research is needed to examine the long-term effects of TCR using this approach.Contribution: The utilisation of IC allows for the examination of individual shifts and improvements in metabolism among patients undergoing TCR.