Improved Glucose Homeostasis Research Articles

Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice

Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.

Impacts of time-restricted feeding on middle-aged and old mice with obesity.

Time-restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time-restricted feeding on treating pre-existing obesity in old animals. The study utilized middle-aged and old high fat diet-induced obese mice and subjected them to 8h daily time-restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time-restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle-aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time-restricted feeding improves metabolic health and has beneficial effects in combating diet-induced obesity in aged obese mice. KEY POINTS: Contrary to in young obese mice, in old obese mice time-restricted feeding did not significantly reduce body fat but decreased lean mass. Time-restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet-induced obesity. Time-restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss.

Atractylodes Lancea and Its Constituent, Atractylodin, Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease via AMPK Activation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), which encompasses a spectrum of conditions ranging from simple steatosis to hepatocellular carcinoma, is a growing global health concern associated with insulin resistance. Since there are limited treatment options for MASLD, this study investigated the therapeutic potential of Atractylodes lancea, a traditional herbal remedy for digestive disorders in East Asia, and its principal component, atractylodin, in treating MASLD. Following 8 weeks of high-fat diet (HFD) feeding, mice received oral doses of 30, 60, or 120 mg/kg of Atractylodes lancea. In HFD-fed mice, Atractylodes lancea treatment reduced the body weight; serum triglyceride, total cholesterol, and alanine aminotransferase levels; and hepatic lipid content. Furthermore, Atractylodes lancea significantly ameliorated fasting serum glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance levels in response to HFD. Additionally, a glucose tolerance test demonstrated improved glucose homeostasis. Treatment with 5 or 10 mg/kg atractylodin also resulted in anti-obesity, anti-steatosis, and glucose-lowering effects. Atractylodin treatment resulted in the downregulation of key lipogenic genes (Srebf1, Fasn, Scd2, and Dgat2) and the upregulation of genes regulated by peroxisome proliferator-activated receptor-α. Notably, the molecular docking model suggested a robust binding affinity between atractylodin and AMP-activated protein kinase (AMPK). Atractylodin activated AMPK, which contributed to SREBP1c regulation. In conclusion, our results revealed that Atractylodes lancea and atractylodin activated the AMPK signaling pathway, leading to improvements in HFD-induced obesity, fatty liver, and glucose intolerance. This study suggests that the phytochemical, atractylodin, can be a treatment option for MASLD.

Fibroblast growth factor 1 (FGF1) improves glucose homeostasis, modulates gut microbial composition, and reduces inflammatory responses in rainbow trout (Oncorhynchus mykiss) fed a high-fat diet

High-fat diets (HFDs) are widely used in aquaculture due to their lipid and protein-conserving effects, thereby reducing feed costs. However, prolonged feeding of HFD often leads to metabolic disorders in fish, such as disruption of hepatic lipid homeostasis, liver injury, and disruption of glucose homeostasis. Fibroblast growth factor 1 (FGF1) plays an essential role in controlling glucose levels in the body and dampening immune reactions. However, its impact on teleosts remains poorly researched. The therapeutic potential of recombinant FGF1 (rFGF1) was examined in a 6-week culture experiment involving rainbow trout (Oncorhynchus mykiss) that were fed an HFD. The results revealed that rFGF1 significantly reduced serum glucose levels and hepatic PEPCK and G6PC activities, but improved hepatic glycogen (P < 0.05), compared to the HFD + PBS group. Further experiments indicated that the inhibitory effect of rFGF1 on hepatic gluconeogenesis was mediated by the cAMP signaling pathway and was dependent on the high expression of PDE4D. In addition, rFGF1 increased hepatic glycogen content, which involves the AKT-GSK3β axis. Despite this increase, rFGF1 did not lead to glycogen storage disease, as shown by reduced hepatic inflammation as a result of decreased GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), and elevated SOD (superoxide dismutase) in the rFGF1-treated group, accompanied by decreased il-1β, il-6, and xbp-1, and elevated nrf2 and number of hepatocyte autophagosomes. Alterations in gut microbes and short-chain fatty acids (SCFAs) were noted, indicating that rFGF1 caused a notable rise in intestinal Lactobacillus, acetic acid, and butyric acid levels. This study investigated the molecular mechanisms of rFGF1 on glucose metabolism and inflammatory responses in an HFD-fed rainbow trout model, providing new insights to improve the regulation of glucose metabolism in carnivorous fish.

5124 Increased Copeptin May Reflect Vasopressin-Related Metabolic Changes After Bariatric Surgery

Abstract Disclosure: F. Galbiati: None. A. Aulinas Maso: None. I. Becetti: None. M. Lauze: None. V. Singhal: None. E.A. Lawson: Research Investigator; Self; received research funding and study drug from Tonix Pharmaceuticals. M. Bredella: None. M. Bredella: None. M. Misra: Advisory Board Member; Self; key opinion leader for Lumos Pharma. Consulting Fee; Self; Up To Date, Receives royalties. Objective: Vasopressin (AVP) is a neurohormone that decreases fat mass, promotes muscle regeneration, improves glucose homeostasis, and protects against hypoglycemia in animals and humans. Copeptin, a stable cleavage product of AVP, is positively associated with body mass index (BMI), insulin resistance, and metabolic syndrome in adults, suggesting an adaptive increase in AVP to counteract metabolic disruption. Similarly, copeptin was positively correlated with BMI in children. Metabolic and bariatric surgery (MBS) is highly effective at reducing metabolic complications of obesity, and underlying mechanisms may provide insights into novel therapeutics for obesity management. No study has investigated copeptin pre- and post-MBS in humans. We hypothesized that after MBS, (1) copeptin would increase and (2) increased copeptin would be associated with improved metabolic parameters. Methods: Longitudinal study in 64 adolescents and young adults (78% females; age [mean±SD] 18.7±2.8 years) with obesity (BMI 45.6±6.8 kg/m2). 34 underwent MBS (sleeve gastrectomy or Roux-en-Y gastric bypass) and 30 underwent non-surgical (NS) lifestyle management. We measured fasting circulating copeptin, %fat, and lean mass by dual-energy X-ray absorptiometry, hemoglobin A1c (HbA1c), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) at baseline and 12 months. Results: Groups were similar for age, sex, race, and pubertal stage. Baseline BMI and %fat were higher in MBS (p≤.012). Baseline copeptin, %lean mass, HbA1c, and HOMA-IR did not differ across groups (p≥.103). MBS vs NS 12-month changes were [median(IQR)]: BMI -29.0 (-33.7, -16.5)% and 0.54 (-3.10, +4.37)%; %fat -8.03 (-13.33, -4.25) and -0.68 (-2.92, 0.64); %lean mass 7.73 (3.45, 12.38) and 0.83 (-.58, 2.73); HbA1c -0.40 (-0.52, -0.20) and -0.10 (-0.20, -0.02); HOMA-IR (mean±SD) -2.47±2.17 and 0.76±2.42 (ps≤.001). Baseline copeptin was correlated negatively with %fat (rho=-.25; p=.045), and positively with %lean mass (trend-level rho=.25, p=0.051). Copeptin increased in the MBS group and decreased in the NS group (time-x;-treatment effect: p=.017). Overall, copeptin change was correlated negatively with %fat change (rho=-.29; p=.025) and positively with %lean mass change (trend-level rho=0.24, p=.070). Copeptin change was positively correlated with changes in %lean mass (rho=.37, p=.045), HbA1c (rho=.46; p=.010), and HOMA-IR (rho=.53; p=.004), only after MBS. Conclusion: Overall, increase in copeptin over 12 months was associated with improved body composition, suggesting that increased AVP following MBS may contribute to its associated metabolic improvements. However, within the MBS group, improved glucose homeostasis was associated with reductions in copeptin, suggesting a possible protective mechanism against post-bariatric hypoglycemia. Presentation: 6/2/2024

12509 Identification Of Novel Exercise Training-induced Circulating Proteins: Hemostatic, Apoptotic, And Key Neuronal Factors

Abstract Disclosure: A. Shalit: None. M. Vamvini: None. P. Nigro: None. L.K. Simpson: None. H. Pan: None. J.M. Dreyfuss: None. L.J. Goodyear: Grant Recipient; Self; Daiichi Sankyo. R.J. Middelbeek: None. Exercise training induces a plethora of health benefits including improved glucose homeostasis, decreased cardiovascular disease, and improved cognitive function. An emerging concept is that many of these beneficial effects of exercise are mediated through the secretion of humoral factors into the blood. Identification of these exercise-regulated factors hold promise for novel treatments for disease. Here, we performed proteomic analysis to discover novel circulating factors in response to endurance exercise training in human participants. Given that nutritional status can affect the circulating proteome, another aim was to determine if proteomic adaptations to exercise training have similar effects under both fasted and random-fed conditions. Sedentary normoglycemic participants (3M/5F, age 22-41y) performed a supervised 10-week exercise training program, which by week 4 was 4x60 min exercise at 65-70% V̇O2peak. Fasted and random-sampling morning blood draws were collected pre-training and between 24-72 hours following the final training session. Proteomic detection was by SOMAscan. Exercise training significantly improved V̇O2peak by 17% (p=0.003). Out of 1,310 detected proteins, exercise training significantly changed 293 proteins in the fasted state and 360 proteins in the random-sampling state (p&amp;lt;0.05). Integration showed that 172 proteins were changed under both nutritional conditions (123 upregulated and 49 downregulated). Gene Set Enrichment Analysis (GSEA) of the commonly upregulated proteins showed that training resulted in enrichment in neuronal, hemostatic, and apoptotic pathways, whereas the downregulated proteins were enriched in neuronal and extracellular matrix processes. Since neuronal pathways were identified in both up and downregulated proteins, we focused our analysis there, identifying 31 upregulated and 4 downregulated neuronally-associated proteins. Importantly, exercise training reduced levels of CDK5, a protein that is hyperactivated in neurodegeneration and Alzheimer's disease. Moreover, GSTP1, a direct inhibitor of CDK5, along with downstream proteins inhibited by CDK5 (RAC1, STUB1, 14-3-3ε/YWHAE, HSP90AA1, CFL1), were significantly increased following exercise training.In conclusion, exercise training regulates circulating factors involved in neuronal, hemostatic, apoptotic, and extracellular matrix pathways, with these effects being independent of nutritional status. Our finding of exercise training-induced decreases in multiple proteins of the CDK5 pathway, a pathway whose downregulation is associated with neuroprotection, identify CDK5 as a novel and potentially important mediator of the beneficial effects of exercise training on cognitive function. Presentation: 6/1/2024

A Moderately High-Fat Diet with Proper Nutrient Quality Improves Glucose Homeostasis, Linked to Downregulation of Intestinal CD36 Mediated by the Loss of Desulfovibrio.

The global prevalence of type 2 diabetes mellitus has become a major public health challenge. Dietary intervention is a cornerstone of diabetes management, yet the optimal macronutrient composition remains an open question. In this study, mice were fed a western (W) diet, a moderately high-fat (MHF) diet, a high-protein-high-carbohydrate (HPHC) diet, or a high-protein-low-carbohydrate (HPLC) diet for 22 weeks to compare the effects of different dietary patterns on glucose homeostasis. Our results showed that a MHF diet, under consistent nutrient quality, was most beneficial for glucose metabolism. The MHF diet reduced two key inducers of diabetes─lipid accumulation and inflammation. Downregulation of intestinal CD36 induced by loss of Desulfovibrio colonization restrained lipid absorption and lipopolysaccharide (LPS) transport, which played a crucial role in MHF-mediated resistance to lipid accumulation and inflammation. The findings endorse a dietary pattern featuring MHF of appropriate nutrient quality as an effective strategy for diabetes management.

Metabolomic Fingerprints of Medical Therapy Versus Bariatric Surgery in Patients With Obesity and Type 2 Diabetes: The STAMPEDE Trial.

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective procedures to treat and manage type 2 diabetes (T2D). However, the underlying metabolic adaptations that mediate improvements in glucose homeostasis remain largely elusive. The purpose of this study was to identify metabolic signatures associated with biochemical resolution of T2D after medical therapy (MT) or bariatric surgery. Plasma samples from 90 patients (age 49.9 ± 7.6 years; 57.7% female) randomly assigned to MT (n = 30), RYGB (n = 30), or SG (n = 30) were retrospectively subjected to untargeted metabolomic analysis using ultra performance liquid chromatography with tandem mass spectrometry at baseline and 24 months of treatment. Phenotypic importance was determined by supervised machine learning. Associations between change in glucose homeostasis and circulating metabolites were assessed using a linear mixed effects model. The circulating metabolome was dramatically remodeled after SG and RYGB, with largely overlapping signatures after MT. Compared with MT, SG and RYGB profoundly enhanced the concentration of metabolites associated with lipid and amino acid signaling, while limiting xenobiotic metabolites, a function of decreased medication use. Random forest analysis revealed 2-hydroxydecanoate as having selective importance to RYGB and as the most distinguishing feature between MT, SG, and RYGB. To this end, change in 2-hydroxydecanoate correlated with reductions in fasting glucose after RYGB but not SG or MT. We identified a novel metabolomic fingerprint characterizing the longer-term adaptations to MT, RYGB, and SG. Notably, the metabolomic profiles of RYGB and SG procedures were distinct, indicating equivalent weight loss may be achieved by divergent effects on metabolism.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.

Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition in females, suggesting that the benefits of acarbose on AD may be largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a WD.

Changes in pancreatic steatosis by computed tomography 24 months after sleeve gastrectomy in youth with severe obesity

BackgroundPancreatic steatosis has been associated with obesity and the metabolic syndrome. Studies in adults have demonstrated improvement in pancreatic steatosis following sleeve gastrectomy (SG) with concomitant improvement in glucose homeostasis. ObjectivesTo examine changes in pancreatic steatosis in youth with severe obesity 24 months following SG. SettingAcademic hospital system. MethodsForty-seven youth (13–24 years) with severe obesity (37 females) were followed for 24 months; 23 had SG and 24 were nonsurgical (NS) controls. Attenuations of the pancreas and spleen were measured using computed tomography (CT) at baseline, 12- and 24-month follow-up. Subjects underwent magnetic resonance imaging (MRI) for subcutaneous and visceral adipose tissue (SAT, VAT), dual energy x-ray absorptiometry (DXA) for body composition, blood sampling for glycated hemoglobin (A1C), and fasting and postprandial insulin and glucose. Linear mixed effects (LMEs) models were used to compare within- and between-group changes over 24 months. ResultsAt baseline, SG had higher body mass index (BMI) versus NS (P = .033). Over 24 months, significant reductions were noted in weight, BMI, VAT, SAT, fat mass (FM), and lean mass (LM) in the SG versus NS groups (P ≤ .0001). There was a significant 24-month decrease in pancreatic steatosis in the SG group (P = .006). In the whole group, 24-month reductions in pancreatic steatosis correlated with BMI and FM decreases. No associations were found between pancreatic steatosis and glucose homeostasis parameters. ConclusionsPancreatic steatosis measured by CT improved after SG in youth. Further studies are needed to understand the relationship between pancreatic steatosis and glucose homeostasis.

Resveratrol stimulates brown of white adipose via regulating ERK/DRP1-mediated mitochondrial fission and improves systemic glucose homeostasis.

Diabetes mellitus and metabolic homeostasis disorders may benefit from white adipose tissue (WAT) browning, which is associated with mitochondrial fission. Resveratrol, a dietary polyphenol, exhibits beneficial effects against abnormalities related to metabolic diseases. However, it remains unknown whether resveratrol contributes to WAT browning by regulating mitochondrial fission. We administered resveratrol (0.4% mixed with control) to db/db mice for 12 weeks, measuring body weight, oral glucose tolerance, insulin tolerance, and histological changes. The uncoupling protein 1 (UCP1) and dynamin-related protein 1 (DRP1) expressions in the epididymal WAT were assessed via immunoblotting. We found that resveratrol improved systemic glucose homeostasis and insulin resistance in db/db mice, which was associated with increased UCP1 in epididymal WAT. Resveratrol-treated mice exhibited more fragmented mitochondria and increased phosphorylation of DRP1 in the epididymal WAT of the db/db mice. These results were further confirmed in vitro, where resveratrol induced extracellular signal-regulated kinase (ERK) signaling activation, leading to phosphorylation of DRP1 at the S616 site (p-DRP1S616) and mitochondrial fission, which was reversed by an ERK inhibitor in 3T3-L1 adipocytes. Resveratrol plays a role in regulating the phosphorylation of ERK and DRP1, resulting in the promotion of beige cells with epididymal WAT and the improvement of glucose homeostasis. Our present study provides novel insights into the potential mechanism of resveratrol-mediated effects on WAT browning, suggesting that it is, at least in part, mediated through ERK/DRP1-mediated mitochondrial fission.

Picalm, a novel regulator of GLUT4-trafficking in adipose tissue

ObjectivePicalm (phosphatidylinositol-binding clathrin assembly protein), a ubiquitously expressed clathrin-adapter protein, is a well-known susceptibility gene for Alzheimer's disease, but its role in white adipose tissue (WAT) function has not yet been studied. Transcriptome analysis revealed differential expression of Picalm in WAT of diabetes-prone and diabetes-resistant mice, hence we aimed to investigate the potential link between Picalm expression and glucose homeostasis, obesity-related metabolic phenotypes, and its specific role in insulin-regulated GLUT4 trafficking in adipocytes. MethodsPicalm expression and epigenetic regulation by microRNAs (miRNAs) and DNA methylation were analyzed in WAT of diabetes-resistant (DR) and diabetes-prone (DP) female New Zealand Obese (NZO) mice and in male NZO after time-restricted feeding (TRF) and alternate-day fasting (ADF). PICALM expression in human WAT was evaluated in a cross-sectional cohort and assessed before and after weight loss induced by bariatric surgery. siRNA-mediated knockdown of Picalm in 3T3-L1-cells was performed to elucidate functional outcomes on GLUT4-translocation as well as insulin signaling and adipogenesis. ResultsPicalm expression in WAT was significantly lower in DR compared to DP female mice, as well as in insulin-sensitive vs. resistant NZO males, and was also reduced in NZO males following TRF and ADF. Four miRNAs (let-7c, miR-30c, miR-335, miR-344) were identified as potential mediators of diabetes susceptibility-related differences in Picalm expression, while 11 miRNAs (including miR-23a, miR-29b, and miR-101a) were implicated in TRF and ADF effects. Human PICALM expression in adipose tissue was lower in individuals without obesity vs. with obesity and associated with weight-loss outcomes post-bariatric surgery. siRNA-mediated knockdown of Picalm in mature 3T3-L1-adipocytes resulted in amplified insulin-stimulated translocation of the endogenous glucose transporter GLUT4 to the plasma membrane and increased phosphorylation of Akt and Tbc1d4. Moreover, depleting Picalm before and during 3T3-L1 differentiation significantly suppressed adipogenesis, suggesting that Picalm may have distinct roles in the biology of pre- and mature adipocytes. ConclusionsPicalm is a novel regulator of GLUT4-translocation in WAT, with its expression modulated by both genetic predisposition to diabetes and dietary interventions. These findings suggest a potential role for Picalm in improving glucose homeostasis and highlight its relevance as a therapeutic target for metabolic disorders.

Chronic β3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.

Incidence of Postoperative Diabetes Mellitus After Roux-en-Y Reconstruction for Gastric Cancer: Retrospective Single-Center Cohort Study.

Sleeve gastrectomy is an effective surgical option for morbid obesity, and it improves glucose homeostasis. In patients with gastric cancer and type 2 diabetes mellitus (DM), gastrectomy, including total gastrectomy, is beneficial for glycemic control. This study aims to clarify the effects of gastrectomy and different reconstructive techniques on the incidence of postoperative DM in patients with gastric cancer. This retrospective, single-center, cohort study included 715 patients without DM who underwent total gastrectomy at the Tokyo Metropolitan Bokutoh Hospital between August 2005 and March 2019. Patients underwent reconstruction by Roux-en-Y (RY) gastric bypass or other surgical techniques (OT), with DM onset determined by hemoglobin A1c levels or medical records. Analyses included 2-sample, 2-tailed t tests; χ2 tests; and the Kaplan-Meier method with log-rank tests to compare the onset curves between the RY and OT groups, along with additional curves stratified by sex. A Swimmer plot for censoring and new-onset DM was implemented. Stratified data analysis compared the RY and OT reconstruction methods. The hazard ratio was 1.52 (95% CI 1.06-2.18; P=.02), which indicated a statistically significant difference in the incidence of new-onset diabetes between the RY and OT groups in patients with gastric cancer. The hazard ratio after propensity score matching was 1.42 (95% CI 1.09-1.86; P=.009). This first-of-its-kind study provides insight into how different methods of gastric reconstruction affect postoperative diabetes. The results suggest significant differences in new-onset DM after surgery based on the reconstruction method. This research highlights the need for careful surgical planning to consider potential postoperative DM, particularly in patients with a family history of DM. Future studies should investigate the role of gut microbiota and other reconstructive techniques, such as laparoscopic jejunal interposition, in developing postoperative DM.

PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1–3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects.

Despite the effectiveness of insulin injections in managing hyperglycemia in type 1 diabetes mellitus (T1DM), they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential and prospects of emerging treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, pancreatic islet cell transplantation, and teplizumab. We review emerging treatment modalities for T1DM, highlighting several promising strategies with varied mechanisms and outcomes. Mesenchymal stem cells demonstrate potential in modulating the immune response and preserving or restoring beta-cell function, although variability in sources and administration routes necessitates further standardization. Similarly, MSC-derived exosomes show promise in promoting beta-cell regeneration and immune regulation, supported by early-stage studies showing improved glucose homeostasis in animal models, albeit with limited clinical data. Gene therapy, utilizing techniques like CRISPR-Cas9, offers targeted correction of genetic defects and immune modulation; however, challenges in precise delivery and ensuring long-term safety persist. Islet allotransplantation and pancreatic islet cell transplantation have achieved some success in restoring insulin independence, yet challenges such as donor scarcity and immunosuppression-related complications remain significant. Teplizumab, an anti-CD3 monoclonal antibody, has demonstrated potential in delaying T1DM onset by modulating immune responses and preserving beta-cell function, with clinical trials indicating prolonged insulin production capability. Despite significant progress, standardization, long-term efficacy, and safety continue to pose challenges across these modalities. Conclusion: While these therapies demonstrate significant potential, challenges persist. Future research should prioritize optimizing these treatments and validating them through extensive clinical trials to enhance T1DM management and improve patient outcomes.

Croton gratissimus Burch Herbal Tea Exhibits Anti-Hyperglycemic and Anti-Lipidemic Properties via Inhibition of Glycation and Digestive Enzyme Activities.

Over the years, the world has continued to be plagued by type 2 diabetes (T2D). As a lifestyle disease, obese individuals are at higher risk of developing the disease. Medicinal plants have increasingly been utilized as remedial agents for managing metabolic syndrome. The aim of the present study was to investigate the in vitro anti-hyperglycemic and anti-lipidemic potential of Croton gratissimus herbal tea infusion. The inhibitory activities of C. gratissimus on carbohydrate (α-glucosidase and α-amylase) and lipid (pancreatic lipase) hydrolyzing enzymes were determined, and the mode of inhibition of the carbohydrate digestive enzymes was analyzed and calculated via Lineweaver-Burk plots and Michaelis Menten's equation. Its effect on Advanced Glycation End Product (AGE) formation, glucose adsorption, and yeast glucose utilization were also determined. High-performance liquid chromatography (HPLC) was used to quantify the possible phenolic compounds present in the herbal tea infusion, and the compounds were docked with the digestive enzymes. C. gratissimus significantly (p < 0.05) inhibited α-glucosidase (IC50 = 60.56 ± 2.78 μg/mL), α-amylase (IC50 = 35.67 ± 0.07 μg/mL), as well as pancreatic lipase (IC50 = 50.27 ± 1.51 μg/mL) in a dose-dependent (15-240 µg/mL) trend. The infusion also inhibited the non-enzymatic glycation process, adsorbed glucose effectively, and enhanced glucose uptake in yeast cell solutions at increasing concentrations. Molecular docking analysis showed strong binding affinity between HPLC-quantified compounds (quercetin, caffeic acid, gallic acid, and catechin) of C. gratissimus herbal tea and the studied digestive enzymes. Moreover, the herbal tea product did not present cytotoxicity on 3T3-L1 cell lines. Results from this study suggest that C. gratissimus herbal tea could improve glucose homeostasis and support its local usage as a potential anti-hyperglycemic and anti-obesogenic agent. Further in vivo and molecular studies are required to bolster the results from this study.

Potential Benefit of Spices for Glycemic Control

The prevalence of hyperglycemia is increasing worldwide in large part due to the escalating prevalence of obesity. It can occur along with other disorders and diseases, contributing to escalating health costs and accumulating disabilities. Besides dietary approaches and availability of antidiabetic medications, other complementary approaches and adjunct therapies using biologically active botanical phytochemicals have received growing attention for managing type 2 diabetes mellitus. Spices are one source of these bioactive plant constituents, and considerable preclinical studies have investigated their possible health benefits. There also are an increasing number of human clinical trials assessing the ability of spices and their individual plant constituents to improve glucose homeostasis in those with type 2 diabetes mellitus and other dysglycemic conditions. This narrative review provides a summary of the human studies evaluating the effects of select spices on glucose homeostasis and highlights areas for future research.

Advances in metformin-delivery systems for diabetes and obesity management.

Metformin is a medication that is commonly prescribed to manage type 2 diabetes. It has been used for more than 60 years and is highly effective in lowering blood glucose levels. Recent studies indicate that metformin may have additional medical benefits beyond treating diabetes, revealing its potential therapeutic uses. Oral medication is commonly used to administer metformin because of its convenience and cost-effectiveness. However, there are challenges in optimizing its effectiveness. Gastrointestinal side effects and limitations in bioavailability have led to the underutilization of metformin. Innovative drug-delivery systems such as fast-dissolving tablets, micro/nanoparticle formulations, hydrogel and microneedles have been explored to optimize metformin therapy. These strategies enhance metformin dosage, targeting, bioavailability and stability, and provide personalized treatment options for improved glucose homeostasis, antiobesity and metabolic health benefits. Developing new delivery systems for metformin shows potential for improving therapeutic outcomes, broadening its applications beyond diabetes management and addressing unmet medical needs in various clinical settings. However, it is important to improve drug-delivery systems, addressing issues such as complexity, cost, biocompatibility, stability during storage and transportation, loading capacity, required technologies and biomaterials, targeting precision and regulatory approval. Addressing these limitations is crucial for effective, safe and accessible drug delivery in clinical practice. In this review, recent advances in the development and application of metformin-delivery systems for diabetes and obesity are discussed.

Metformin improves insulin resistance, liver healthy and abnormal hepatic glucolipid metabolism via IR/PI3K/AKT pathway in Ctenopharyngodon idella fed a high-carbohydrate diet

The effects and underlying mechanisms of metformin which can improve glucose homeostasis of fish have rarely been explored. This experiment aimed to explore the influence of metformin on growth performance, body composition, liver health, hepatic glucolipid metabolic capacity and IR/PI3K/AKT pathway in grass carp (Ctenopharyngodon idella) fed high-carbohydrate diets. A normal diet (Control) and high carbohydrate diets with metformin supplementation (0.00 %, 0.20 %, 0.40 %, 0.60 % and 0.80 %) were configured. Six groups of healthy fish were fed with the experimental diet for eight weeks. The results showed that the growth performance of grass carp was impaired in high carbohydrate diet. Impairment of IR/PI3K/AKT signalling pathway reduced insulin sensitivity, while hepatic oxidative stress damage and decreased immunity affected liver metabolic function. The glycolysis and lipolysis decrease while the gluconeogenesis and fat synthesis increase, which triggers hyperglycaemia and lipid deposition in the body. Metformin supplementation restored the growth performance of grass carp. Metformin improved IR/PI3K/AKT pathway signalling and alleviated insulin resistance, while liver antioxidant capacity and immunity were enhanced resulting in the restoration of liver health. The elevation of glycolysis and lipolysis maintains glycaemic homeostasis and reduces lipid deposition, respectively. These results suggest that metformin supplementation restores liver health and activates the IR/PI3K/AKT signalling pathway, ameliorating insulin resistance and glucose-lipid metabolism disorders caused by a high-carbohydrate diet. As judged by HOMA-IR, the optimum supplementation level of metformin in grass carp (C. idella) fed a high-carbohydrate diet is 0.67 %.