Improved Glucose Tolerance Research Articles

Low-Dose Chidamide Treatment Displays Sex-Specific Differences in the 3xTg-AD Mouse.

Epigenetic compounds have become attractive small molecules for targeting the multifaceted aspects of Alzheimer's disease (AD). Although AD disproportionately affects women, most of the current literature investigating epigenetic compounds for the treatment of AD do not report sex-specific results. This is remarkable because there is rising evidence that epigenetic compounds intrinsically affect males and females differently. This manuscript explores the sexual dimorphism observed after chronic, low-dose administration of a clinically relevant histone deacetylase inhibitor, chidamide (Tucidinostat), in the 3xTg-AD mouse model. We found that chidamide treatment significantly improves glucose tolerance and increases expression of glucose transporters in the brain of males. We also report a decrease in total tau in chidamide-treated mice. Differentially expressed genes in chidamide-treated mice were much greater in males than females. Genes involved in the neuroinflammatory pathway and amyloid processing pathway were mostly upregulated in chidamide-treated males while downregulated in chidamide-treated females. This work highlights the need for drug discovery projects to consider sex as a biological variable to facilitate translation.

Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.

Dysosmobacter welbionis effects on glucose, lipid, and energy metabolism are associated with specific bioactive lipids

The newly identified bacterium Dysosmobacter welbionis J115T improves host metabolism in high-fat diet (HFD)-fed mice. To investigate mechanisms, we used targeted lipidomics to identify and quantify bioactive lipids produced by the bacterium in the culture medium, the colon, the brown adipose tissue (BAT), and the blood of mice. In vitro, we compared the bioactive lipids produced by D. welbionis J115T versus the probiotic strain Escherichia coli Nissle 1917. D. welbionis J115T administration reduced body weight, fat mass gain, and improved glucose tolerance and insulin resistance in HFD-fed mice. In vitro, 19 bioactive lipids were highly produced by D. welbionis J115T as compared to Escherichia coli Nissle 1917. In the plasma, 13 lipids were significantly changed by the bacteria. C18-3OH was highly present at the level of the bacteria, but decreased by HFD treatment in the plasma and normalized in D. welbionis J115T–treated mice. The metabolic effects were associated with a lower whitening of the BAT. In the BAT, HFD decreased the 15-deoxy-Δ12,14-prostaglandin J2, a peroxisome proliferator–activated receptor (PPAR-γ) agonist increased by 700% in treated mice as compared to HFD-fed mice. Several genes controlled by PPAR-γ were upregulated in the BAT. In the colon, HFD-fed mice had a 60% decrease of resolvin D5, whereas D. welbionis J115T–treated mice exhibited a 660% increase as compared to HFD-fed mice. In a preliminary experiment, we found that D. welbionis J115T improves colitis. In conclusion, D. welbionis J115T influences host metabolism together with several bioactive lipids known as PPAR-γ agonists.

Reinstating acute-phase insulin release among sedentary adults at high risk for type 2 diabetes with Yoga and Walking based lifestyle modification

BackgroundWe compared the impact of 2 lifestyle modifying physical activities, yoga (YBLM) or walking (WBLM) on impaired beta cell function (IBF) or insulin resistance (IR) in restoring acute phase insulin release (APIR) among prediabetes at high risk for type 2 diabetes (HRDM). MethodMale and female adults (N = 42, 38.1 ± 4.8 years) with abdominal obesity (Male:103 ± 8.1 cm) Female: 92 ± 11.1 cm), randomized into YBLM (n = 20) and WBLM (n = 22), were monitored for the practice of the intervention, 45 min a day/5 days a week for 12 weeks. Blood sample was collected at 0th minute to estimate the level of Fasting Blood Glucose (FBG), Sr. Insulin and lipid profile and at 10th minute (APIR). IBF, IR and sensitivity (IS) reading were checked in HOMA-2 calculator. ResultWilcoxon sign rank t-test denoted an improved APIR among the subjects with IBF (p = 0.008) and not among the subjects with IR (p = 0.332). However, regression analysis yielded an improved APIR among subjects with IBF (F(1,10) = 7.816, p = 0.002) with the management of body weight and lipid profile and IR (F(1,13) = 17.003, p = 0.001) being found influenced with selected lipid components. In all, during the post assessment period, an impressive boost in APIR was manifested among people shifted to Normoglycemia (n = 14, 35.9%). ConclusionIntriguingly, we postulate the potential role of YBLM over WBLM in the management of lipid profile and body weight on accelerating APIR either through improved Beta cell compensation or by sensitizing skeletal muscles regulating IR, helping improve glucose tolerance resulting in either remission or management of prediabetes.

Improving glucose tolerance of a fungal β-glucosidase: structure-based rational design approach

Improving glucose tolerance of a fungal β-glucosidase: structure-based rational design approach

Supplementation of cyanidin-3-O-β-glucoside-rich haskap (Lonicera caerulea L.) berry extract attenuates hepatic lipid dysregulation in diet-induced obese mice

Haskap (Lonicera caerulea L.) berry is enriched in anthocyanins, primarily cyanidin-3-O-β-glucoside (C3G). It remains unknown whether C3G counteracts metabolic alterations of the pathogenesis of obesity. In this study, mice were fed high-fat high-sucrose (HFHS) diet supplemented either with C3G-rich extract (HFHS + CE) or berry powder with low C3G (HFHS + BP). Mice fed HFHS + CE displayed short-term protection against weight gain, independent of food intake. HFHS + CE mice had lower hepatic diacylglycerols and triacylglycerols content and reduced expression of key lipogenic transcription factors. These metabolic changes also translated into improved glucose tolerance and insulin sensitivity. 16S rRNA sequencing revealed altered gut microbiota composition in the HFHS + CE group. In summary, we demonstrate that C3G enrichment in the HFHS diet attenuates short-term weight gain, decreases hepatic lipid content by suppressing key lipogenic gene expression and improves glucose homeostasis during obesity development, supporting the therapeutic utility of C3G as a bioactive phytonutrient to manage obesity-related complications.

Design, synthesis and evaluation of 2-pyrimidinylindole derivatives as anti-obesity agents by regulating lipid metabolism

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.

Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis.

This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia.

Ketone ester administration improves glycemia in obese mice.

During periods of prolonged fasting/starvation, the liver generates ketones [i.e., β-hydroxybutyrate (βOHB)] that primarily serve as alternative substrates for ATP production. Previous studies have demonstrated that elevations in skeletal muscle ketone oxidation contribute to obesity-related hyperglycemia, whereas inhibition of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate-limiting enzyme of ketone oxidation, can alleviate obesity-related hyperglycemia. As circulating ketone levels are a key determinant of ketone oxidation rates, we tested the hypothesis that increases in circulating ketone levels would worsen glucose homeostasis secondary to increases in muscle ketone oxidation. Accordingly, male C57BL/6J mice were subjected to high-fat diet-induced obesity, whereas their lean counterparts received a standard chow diet. Lean and obese mice were orally administered either a ketone ester (KE) or placebo, followed by a glucose tolerance test. In tandem, we conducted isolated islet perifusion experiments to quantify insulin secretion in response to ketones. We observed that exogenous KE administration robustly increases circulating βOHB levels, which was associated with an improvement in glucose tolerance only in obese mice. These observations were independent of muscle ketone oxidation, as they were replicated in mice with a skeletal muscle-specific SCOT deficiency. Furthermore, the R-isomer of βOHB produced greater increases in perifusion insulin levels versus the S-isomer in isolated islets from obese mice. Taken together, acute elevations in circulating ketones promote glucose-lowering in obesity. Given that only the R-isomer of βOHB is oxidized, further studies are warranted to delineate the precise role of β-cell ketone oxidation in regulating insulin secretion.NEW & NOTEWORTHY It has been demonstrated that increased skeletal muscle ketone metabolism contributes to obesity-related hyperglycemia. Since increases in ketone supply are key determinants of organ ketone oxidation rates, we determined whether acute elevations in circulating ketones following administration of an oral ketone ester may worsen glucose homeostasis in lean or obese mice. Our work demonstrates the opposite, as acute elevations in circulating ketones improved glucose tolerance in obese mice.

Quercetin improves white adipose tissue redox homeostasis in ovariectomized rats.

Estrogen deficiency is a well-known hallmark of menopause and is associated with oxidative stress and metabolic dysfunction. Quercetin (Q), a flavonoid found in fruits and vegetables, has demonstrated anti-inflammatory effects in experimental models of metabolic disorders. In this study, we aimed to investigate the effects of quercetin on retroperitoneal white adipose tissue (rWAT) redox homeostasis and systemic metabolic parameters in ovariectomized (OVX) rats. Female Wistar rats at 3 months old were divided into the following experimental groups: sham-operated treated with vehicle (DMSO 10% + PBS - 1 mL/kg); OVX (vehicle treated) and OVX-Q (25 mg/kg) - via oral gavage, daily for 5 weeks. Q did not prevent weight gain but improved glucose tolerance and blood cholesterol profile, and attenuated uterine atrophy in OVX rats. Furthermore, Q had a protective effect on rWAT, once the OVX-Q group presented lower oxidative stress levels, and reduced levels of the pro-inflammatory cytokine tumor necrosis factor alpha, compared to the OVX group. Q improved antioxidant enzyme activities such as superoxide dismutase and catalase and decreased reactive oxygen species production, in OVX-Q rats. It was followed by increased levels of total thiol content and lower lipid peroxidation. Moreover, Q reduced senescent-related genes p16INK4a and p19ARF expression which were higher in the OVX group. In conclusion, quercetin supplementation improved redox homeostasis and reduced senescence-related markers, and inflammation in rWAT, which was reflected in preserved systemic metabolic health parameters in OVX rats. These findings suggest that quercetin may have therapeutic potential for the management of metabolic disorders associated with menopause-induced estrogen deficiency.

Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

Altered function of arcuate leptin receptor expressing neuropeptide Y neurons depending on energy balance

ObjectiveOne of leptin's main targets in the hypothalamus are neuropeptide Y (NPY) neurons, with selective deletion of leptin receptors (Lepr) specifically in Npy neurons resulting in major alterations of energy partitioning between fat and bone mass. However, the specific action of these Npy+/Lepr+ neurons compared to Npy-negative Lepr (Npy−/Lepr+) neurons in regard to energy homeostasis regulation is unknown. MethodsSpecific AAV viral vectors were generated using DREADD and INTRSECT technology and used in male LeprCre/+ and LeprCre/+;NpyFlp/+ mice to assess the effect of activating either all Lepr neurons or specifically Npy+/Lepr+ or Npy−/Lepr+ neurons only on feeding, energy homeostasis control, and body composition. ResultsSelective stimulation of Npy+/Lepr+ neurons led to an immediate decrease in respiratory quotient followed by a delayed increase in food intake in standard chow fed, but interestingly not in high fat diet (HFD) fed mice. In addition, stimulation of Npy+/Lepr+ neurons led to a robust increase in brown adipose tissue thermogenesis and improved glucose tolerance. These effects were not observed in standard chow fed mice when Npy−/Lepr+ expressing neurons were specifically activated, suggesting the effects of leptin on these parameters are driven by NPY. However, under HFD condition when leptin levels are elevated, the stimulation of the Npy−/Lepr+ neurons increased food intake, physical activity and energy expenditure. Interestingly, chronic stimulation of Npy-positive Lepr neurons was able to increase bone mass independently of bodyweight, whilst chronic stimulation of the Npy−/Lepr+ neurons resulted in increased bodyweight and fat mass with proportionate increases in bone mass. ConclusionsTogether, these data indicate that leptin signalling through Npy-positive Lepr-expressing neurons controls energy partitioning via stimulation of thermogenesis, energy expenditure, and the use of fat as a fuel source. However, under prolonged HFD, leptin resistance may occur and actions of leptin signalling through Npy-negative Lepr hypothalamic neurons may exacerbate excess food intake.

Polyphenolic compounds from Idesia polycarpa Maxim. fruits ameliorate non-alcoholic fatty liver disease by modulating lipid metabolism in oleic acid-induced HepG2 cells and high-fat diet-induced mice

Previous reports have suggested that Idesia polycarpa Maxim. (I. polycarpa) fruits possess properties for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), owing to its lipid-lowering and anti-oxidant activities. In this study, ethyl acetate extract (EAE) of I. polycarpa fruits supplementation reduced body weight gain and inflammatory cytokines secretion, improved glucose tolerance and insulin sensitivity, and alleviated hepatic steatosis in high-fat diet (HFD)-fed mice. Of note, a total of eight polyphenolic compounds were isolated and identified from EAE, among which 1-[(6′-O-(Z)-p-coumar-oyl)-β-D-glucopyranosyl]-oxy-2-phenol (compound 2) exhibited better lipid-lowering activity in oleic acid (OA)-induced HepG2 cells than other compounds. Moreover, using hepatic steatosis cell model and PPAR-luciferase reporter system, we found that compound 2 reduced lipid accumulation and lipotoxicity, and inhibited inflammatory reaction via the PPAR-α-mediated improvement of lipid metabolism. This experiment will provide a theoretical basis for intervention with I. polycarpa fruits in delaying the occurrence and development of NAFLD.

Beneficial effects of empagliflozin and liraglutide on the cerebral microcirculation of diabetic rats.

This study aimed to evaluate the effects of the antidiabetics liraglutide, a GLP-1 analog, and empagliflozin, an SGLT-2 inhibitor, on the brain microcirculation of diabetic rats. Type 2 diabetes mellitus (DM) was experimentally induced in male Wistar rats by combining a high-fat diet and a low dose of streptozotocin (35 mg/kg). Liraglutide (100 μg/kg s.c.) and empagliflozin (10 mg/kg, oral) were administered for 5 weeks. Body weight was monitored periodically. Oral glucose tolerance, fasting glycemia, and blood triglycerides were evaluated after the treatments. Endothelial-leukocyte interactions in the brain microcirculation and structural capillary density were assessed. DM rats presented metabolic and cerebrovascular alterations. Liraglutide treatment decreased body weight and blood triglycerides of DM rats. Empagliflozin treatment improved glucose tolerance but only the combination therapy significantly reduced fasting blood glucose. Both treatments and their combination reduced leukocyte adhesion into the endothelium of brain venules. However, empagliflozin was more effective in preventing DM-induced microvascular rarefaction. These findings suggest that chronic treatment with SGLT2 inhibitors and GLP-1 receptor agonists may serve as potential therapeutic approaches to prevent microvascular complications associated with diabetes.

NOX2 deficiency exacerbates diet-induced obesity and impairs molecular training adaptations in skeletal muscle

The production of reactive oxygen species (ROS) by NADPH oxidase (NOX) 2 has been linked to both insulin resistance and exercise training adaptations in skeletal muscle. This study explores the previously unexamined role of NOX2 in the interplay between diet-induced insulin resistance and exercise training (ET). Using a mouse model that harbors a point mutation in the essential NOX2 regulatory subunit, p47phox (Ncf1*), we investigated the impact of this mutation on various metabolic adaptations. Wild-type (WT) and Ncf1* mice were assigned to three groups: chow diet, 60% energy fat diet (HFD), and HFD with access to running wheels (HFD + E). After a 16-week intervention, a comprehensive phenotypic assessment was performed, including body composition, glucose tolerance, energy intake, muscle insulin signaling, redox-related proteins, and mitochondrial adaptations. The results revealed that NOX2 deficiency exacerbated the impact of HFD on body weight, body composition, and glucose intolerance. Moreover, in Ncf1* mice, ET did not improve glucose tolerance or increase muscle cross-sectional area. ET normalized body fat independently of genotype. The lack of NOX2 activity during ET reduced several metabolic adaptations in skeletal muscle, including insulin signaling and expression of Hexokinase II and oxidative phosphorylation complexes. In conclusion, these findings suggest that NOX2 mediates key beneficial effects of exercise training in the context of diet-induced obesity.

Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.

The effects of early time restricted eating plus daily caloric restriction compared to daily caloric restriction alone on continuous glucose levels.

The median eating duration in the U.S. is 14.75h, spread throughout the period of wakefulness and ending before sleep. Food intake at an inappropriate circadian time may lead to adverse metabolic outcomes. Emerging literature suggests that time restricted eating (TRE) may improve glucose tolerance and insulin sensitivity. The aim was to compare 24-h glucose profiles and insulin sensitivity in participants after completing 12weeks of a behavioral weight loss intervention based on early TRE plus daily caloric restriction (E-TRE+DCR) or DCR alone. Eighty-one adults with overweight or obesity (age 18-50years, BMI 25-45kg/m2) were randomized to either E-TRE+DCR or DCR alone. Each participant wore a continuous glucose monitor (CGM) for 7days and insulin sensitivity was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR) at Baseline and Week 12. Changes in CGM-derived measures and HOMA-IR from Baseline to Week 12 were assessed within and between groups using random intercept mixed models. Forty-four participants had valid CGM data at both time points, while 38 had valid glucose, insulin, HOMA-IR, and hemoglobin A1c (A1c) data at both timepoints. There were no significant differences in sex, age, BMI, or the percentage of participants with prediabetes between the groups (28% female, age 39.2±6.9years, BMI 33.8±5.7kg/m2, 16% with prediabetes). After adjusting for weight, there were no between-group differences in changes in overall average sensor glucose, standard deviation of glucose levels, the coefficient of variation of glucose levels, daytime or nighttime average sensor glucose, fasting glucose, insulin, HOMA-IR, or A1c. However, mean amplitude of glycemic excursions changed differently over time between the two groups, with a greater reduction found in the DCR as compared to E-TRE+DCR (p=0.03). There were no major differences between E-TRE+DCR and DCR groups in continuous glucose profiles or insulin sensitivity 12weeks after the intervention. Because the study sample included participants with normal baseline mean glucose profiles and insulin sensitivity, the ability to detect changes in these outcomes may have been limited.

Antidiabetic Effect of Fermented Mesembryanthemum crystallinum L. in db/db Mice Involves Regulation of PI3K-Akt Pathway.

Type 2 diabetes (T2D) is a serious health issue with increasing incidences worldwide. However, current medications have limitations due to side effects such as decreased appetite, stomach pain, diarrhea, and extreme tiredness. Here, we report the effect of fermented ice plant (FMC) in the T2M mouse model of db/db mice. FMC showed a greater inhibition of lipid accumulation compared to unfermented ice plant extract. Two-week oral administration with FMC inhibited body weight gain, lowered fasting blood glucose, and improved glucose tolerance. Serum parameters related to T2D including insulin, glycosylated hemoglobin, adiponectin, and cholesterols were improved as well. Histological analysis confirmed the protective effect of FMC on pancreas and liver destruction. FMC treatment significantly increased the expression and phosphorylation of IRS-1, PI3K, and AKT. Additionally, AMP-activated protein kinase phosphorylation and nuclear factor erythroid 2-related factor 2 were also increased in the liver tissues of db/db mice treated with FMC. Overall, our results indicate the anti-diabetic effect of FMC; therefore, we suggest that FMC may be useful as a therapeutic agent for T2D.

Cordyceps cicadae polysaccharides alleviate hyperglycemia by regulating gut microbiota and its mmetabolites in high-fat diet/streptozocin-induced diabetic mice.

The polysaccharides found in Cordyceps cicadae (C. cicadae) have received increasing academic attention owing to their wide variety of therapeutic activities. This study evaluated the hypoglycemic, antioxidant, and anti-inflammatory effects of polysaccharides from C. cicadae (CH-P). In addition, 16s rDNA sequencing and untargeted metabolomics analysis by liquid chromatography-mass spectrometry (LC-MS) were used to estimate the changes and regulatory relationships between gut microbiota and its metabolites. The fecal microbiota transplantation (FMT) was used to verify the therapeutic effects of microbial remodeling. The results showed that CH-P treatment displayed hypoglycemic, antioxidant, and anti-inflammatory effects and alleviated tissue damage induced by diabetes. The CH-P treatment significantly reduced the Firmicutes/Bacteroidetes ratio and increased the abundance of Bacteroides, Odoribacter, Alloprevotella, Parabacteroides, Mucispirillum, and significantly decreased the abundance of Helicobacter and Lactobacillus compared to the diabetic group. The alterations in the metabolic pathways were mostly related to amino acid biosynthesis and metabolic pathways (particularly those involving tryptophan) according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Correlation analysis showed that Bacteroides, Odoribacter, Alloprevotella, Parabacteroides, and Mucispirillum were positively correlated with indole and its derivatives, such as 5-hydroxyindole-3-acetic acid. Indole intervention significantly improved hyperglycemic symptoms and insulin sensitivity, and increased the secretion of glucagon-like peptide-1 (GLP-1) in diabetic mice. FMT reduced blood glucose levels, improved glucose tolerance, and increased insulin sensitivity in diabetic mice. However, FMT did not significantly improve GLP-1 levels. This indicates that C. cicadae polysaccharides alleviate hyperglycemia by regulating the production of metabolites other than indole and its derivatives by gut microbiota. This study provides an important reference for the development of novel natural products.

Konjac glucomannan attenuate high-fat diet-fed obesity through enhancing β-adrenergic-mediated thermogenesis in inguinal white adipose tissue in mice.

Konjac glucomannan (KGM) has been reported to prevent high-fat diet-induced obesity, and we study investigated whether dietary supplementation with KGM can prevent obesity by increasing energy expenditure in inguinal white adipose tissue (iWAT) of high-fat diet (HF) -fed mice. Weaned mice fed the control diet (Con), HF, or HF plus KGM (8%, w/w, HFK) were divided into three groups. The results showed that 10-week supplementation with KGM significantly reduced partial adipose tissue weight and body weight, and improved glucose tolerance. Compared to the HF group, plasma lipid concentrations in the HFK group were greatly decreased to the control level. Moreover, transcriptomic research has shown that genes that are mainly associated with energy and lipid metabolism are significantly altered in iWAT. Mechanistically, KGM stimulated thermogenesis by promoting the expression of uncoupling protein-1 (UCP1) and the β3-adrenergic receptor (ADR3β). Taken together, our results suggest that dietary supplementation with konjac glucomannan can effectively alleviate obesity induced by a high-fat diet by activating ADR3β-mediated iWAT thermogenesis. Dietary supplementation with KGM can effectively alleviate high fat diet- induced obesity mice by via activating ADR3β-mediated thermogenesis of iWAT.