Improved Glucose Uptake Research Articles

Independent and combined effects of calorie restriction and AICAR on glucose uptake and insulin signaling in skeletal muscles from 24-month-old female and male rats.

We assessed the effects of two levels of calorie restriction (CR; eating either 15% or 35% less than ad libitum, AL, food intake for 8 weeks) by 24-month-old female and male rats on glucose uptake (GU) and phosphorylation of key signaling proteins (Akt; AMP-activated protein kinase, AMPK; Akt substrate of 160kDa, AS160) measured in isolated skeletal muscles that underwent four incubation conditions (without either insulin or AICAR, an AMPK activator; with AICAR alone; with insulin alone; or with insulin and AICAR). Regardless of sex: (1) neither CR group versus the AL group had greater GU by insulin-stimulated muscles; (2) phosphorylation of Akt in insulin-stimulated muscles was increased in 35% CR versus AL rats; (3) prior AICAR treatment of muscle resulted in greater GU by insulin-stimulated muscles, regardless of diet; and (4) AICAR caused elevated phosphorylation of acetyl CoA carboxylase, an indicator of AMPK activation, in all diet groups. There was a sexually dimorphic diet effect on AS160 phosphorylation, with 35% CR exceeding AL for insulin-stimulated muscles in male rats, but not in female rats. Our working hypothesis is that the lack of a CR-effect on GU by insulin-stimulated muscles was related to the extended duration of the ex vivo incubation period (290 min compared to 40-50 min that was previously reported to be effective). The observed efficacy of prior treatment of muscles with AICAR to improve glucose uptake in insulin-stimulated muscles supports the strategy of targeting AMPK with the goal of improving insulin sensitivity in older females and males.

Mushrooms and Fungi and Their Biological Compounds with Antidiabetic Activity: A Review.

Mushrooms have been used by humans for centuries as food and medicine because they have been shown to affect certain diseases. Mushrooms for medicinal purposes have been consumed in the form of extracts and/or biomass of the mycelium or fruiting body. The beneficial health effects of mushrooms are due to their content of bioactive compounds (polysaccharides, proteins, ergosterol, lectins, etc.). On the other hand, diabetes is one of the metabolic diseases that affects the population worldwide, characterized by hyperglycemia that involves a defective metabolism of insulin, a hormone secreted by β cells and that mainly stimulates glucose absorption by the cells. However, it also affects the metabolism of carbohydrates, fats and proteins; poor control of this disease leads to serious damage to eyesight, kidneys, bones, heart, skin, blood vessels, nerves, etc. It has been reported that the consumption of some mushrooms helps control and treat diabetes, since among other actions, they promote the secretion of insulin by the pancreas, help reduce blood glucose and have α-glucosidase inhibitory activity which improves glucose uptake by cells, which are effects that prescription medications have for patients with diabetes. In that sense, this manuscript shows a review of scientific studies that support the abilities of some mushrooms to be used in the control and/or treatment of diabetes.

A Comparative Study on the Efficacy and Mechanism of Improving Glucose Uptake of Cannabis Root and Stem Extracts

A Comparative Study on the Efficacy and Mechanism of Improving Glucose Uptake of <i>Cannabis</i> Root and Stem Extracts

Exploring the potential of Lindernia ciliata: isolation, characterization, and pharmacological evaluation of its anti-diabetic properties

We isolated two phytoconstituents using bioassay guided isolation for anti-diabetic property from the hydroalcoholic extract of Lindernia ciliata (Colsm.) Pennell (Family: Linderniaceae). We assessed the anti-diabetic potential using various assays, including the glucose absorption assay, glucose uptake in isolated rat abdominal muscle assay, insulin secretion by RIN-5F cells assay, α-amylase inhibition activity, and DPP-4 inhibition assay. The results from our study indicated that the ethanol and water fractions obtained from the hydroalcoholic extract significantly improved glucose uptake, demonstrating promising anti-diabetic properties. Further investigation led to the isolation of two distinct compounds, LCF-1 (IUPAC name: 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one) (LCF-1) and LCF-2 (IUPAC name: 3S,10R,13R,17R)-17-[(2R,5R)-5-ethyl-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol). Consequently, our findings suggest that LCF-1 and LCF-2 are two phytoconstituent derived from the hydroalcoholic extract of L. ciliata, could serve as a potential source of anti-diabetic agents. This highlights its suitability for further development in the creation of herbal pharmaceuticals for diabetes treatment.

Antidiabetic property of fractions and pure compounds from Andrographis paniculata

Chlorophyll-free fractions of Andrographis paniculata were investigated for glucose uptake and lipid reduction in 3T3-L1 adipocytes. At 25 µg/ml, the acid fraction concentration enhanced glucose uptake by 82%. Basic and neutral fractions at 100 µg/ml enhanced glucose uptake by 82% and 78%, respectively. The three fractions showed improved glucose uptake compared to the crude extract (25% uptake at 50 μg/ml). GC-MS analysis of the fractions revealed the presence of chemicals with antidiabetic activities. The neutral fraction was prioritised for pure compound isolation to provide known andrographolide (1), 14-deoxyandrographolide (2), and a novel compound, 3-epi-11,12-didehydro-14-deoxyandrographolide (5). At a concentration of 1 µM, compounds 2 and 5 are as effective as 10 mM metformin in glucose uptake. They also reduce lipid accumulations in 3T3-L1 adipocytes by decreasing the size and number of lipid droplets. The activities of fractions and compounds support the use of A. paniculata in treating type 2 diabetes.

Network pharmacology-based elucidation of bioactive compounds and experimental exploration of antidiabetic mechanisms of Hydrolea zeylanica

This investigation systematically explored the underlying antidiabetic mechanism of Hydrolea zeylanica (HZH) by the approach of network pharmacology and experimental validation in restoring glucose homeostasis, and inflammation in high fat diet fed-streptozotocin (HFD/STZ)-induced type II diabetes (T2DM) rats. Network pharmacology analysis was conducted on 32 bioactive components of HZH. In silico ADME prediction, and physicochemical analysis of 32 compounds were used to assess their drug-likeness. Common targets between selected compounds, and T2DM were subjected for GO enrichment. Compound-target-pathway network was predicted with selected compounds and targets. HZH (300 and 400 mg/kg) were considered for GLUTs expression, and inflammation cytokines in T2DM rats. Network pharmacology showed the core relationship between 13 selected compounds, and 194 key target genes in insulin resistance, type II diabetes mellitus, insulin signaling pathways in T2DM. AKT1, AKT2, GSK3B, IL6, INSR, MAPK8, PPARA, GLUT1, GLUT2, GLUT4 were observed as the key targets in PPI network. HZH-400 significantly restored glucose homeostasis, and inflammatory markers in T2DM rats. It altered GLUT2, GLUT4 expression in liver, and skeletal muscle to normal. Bioactive compounds of HZH were found to control blood sugar level by modulating insulin resistance, type II diabetes mellitus, insulin signaling pathways, and glucose homeostasis, which in turn improved glucose uptake, insulin production in diabetes as shown in network pharmacology and glucose transporter expression studies.

Natural Functional Beverages as an Approach to Manage Diabetes

Diabetes mellitus is a chronic disease, commonly associated with unhealthy habits and obesity, and it is becoming a serious health issue worldwide. As a result, new approaches to treat diabetes are required, and a movement towards more natural approaches is emerging. Consuming fruit and vegetables is advised to prevent diabetes since they contain several bioactive compounds. A simple and effective strategy to include them in the diets of diabetic and obese people is through beverages. This review aims to report the anti-diabetic potentials of different vegetable and fruit beverages. These functional beverages demonstrated in vitro potential to inhibit α-glucosidase and α-amylase enzymes and to improve glucose uptake. In vivo, beverage consumption showed a reduction of blood glucose, increase of insulin tolerance, improvement of lipid profile, control of obesity, and reduction of oxidative stress. This suggests the potential of vegetable- and fruit-based functional beverages to be used as a natural innovative therapy for the management of diabetes.

Circadian Rhythms Metabolically Regulate Bone Marrow Retained Primitive Hematopoietic Stem Cell Size and Function

Most primitive hematopoietic stem cells (pHSC; LSK SLAM CD34 - EPCR +) are bone marrow (BM) retained in a quiescent non motile state, and are the only chemotherapy resistant HSC which requires their rapid exit from homeostatic quiescence on demand to prevent lethal hematology failure. Circadian rhythms induce daily release of progenitor cells and low levels of rarely cycling pHSCs to replenish the blood and lymphatics with new maturing cells. Metabolically, pHSCs are characterized by their dependence on glycolysis, with low mitochondrial activity and membrane potential (MMP), associated with higher competitive repopulation potential. However, if their metabolism is influenced by circadian cues is currently unknown. We report here that pHSCs at night are more glycolytic with higher surface expression of the glucose transporter Glut1, and higher glucose uptake. Repeated administration of the glucose analog, 2-deoxyglucose (2-DG), during daylight mimicked the night phenotype and enhanced HSC engraftment potential. However, nocturnal administration of 2-DG did not further improve glucose uptake nor HSC engraftment potential, suggesting glycolytic saturation. To further understand these metabolic oscillations of glucose uptake, we investigated the circadian, transcriptional signatures by single pHSC RNA-seq analysis. We found higher expression of mitophagy-related genes at night. Genes regulating mitochondrial function, were also significantly down regulated at night leading to low MMP in pHSC. While mitochondrial ROS levels were higher, cytoplasmic ROS levels were significantly reduced in pHSC at night. Importantly, we further found at night, low-functioning pHSC mitochondria to also undergo higher levels of fission as assessed by increased expression of the active mitochondrial fission marker, phospho-Drp1 (S616). To better understand the molecular pathways mediating daily circadian metabolic reprogramming between glycolysis and mitochondrial activity, we monitored our gene set enrichment analysis. We found the Wnt/b-catennin and HIF-1a signaling pathways to be significantly increased at night in pHSC. Active Wnt signaling, leads to enhanced b-catenin localization to the nucleus which is enhanced by downstream effector of Wnt activation, FOXM1. We observed higher total protein expression of FOXM1 at night. While its nuclear and cytoplasmic localization were reduced, we observed significantly higher FOXM1 levels in the mitochondria. FOXM1 localization to the energy powerhouse has been shown to inhibit mitochondrial activity. Blocking mitochondrial recruitment of FOXM1 with a specific canonical Wnt inhibitor at night led to upregulation of MMP, reversing mitochondrial metabolic responses in pHSC. Finally, daily genetic changes between night Wnt, HIF-1a and glycolysis, versus daylight GSK3b, m-TOR signaling and enhanced mitochondrial activity in BM retained pHSC, also led to cell size changes. We documented reduced quiescent pHSC size at night associated with their increased BM maintenance and higher repopulation potential. While larger sized pHSCs in the morning during the time of blood replenishment, increased their migration and development potential, for their rapid exit from quiescence on demand. Our study reveals daily circadian cues dynamically determine Wnt-mediated FOXM1 bidirectional shuttling between the nucleus and the mitochondria, leading to metabolic switching of pHSCs to maintain their cellular fitness. Our data define key signaling pathways controlling pHSC quiescence and diverse circadian metabolic activities for accumulated ROS and old mitochondria clearance and turnover, keeping them ready for rapid activation in alarm situations.

Impact of Eating a Carbohydrate-Restricted Diet on Cortical Atrophy in a Cross-Section of Amyloid Positive Patients with Alzheimer's Disease: A Small Sample Study.

A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer's disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.

Sesamol combats diabetogenic effects of atorvastatin through GLUT-4 expression and improved pancreatic viability.

Statin-associated diabetes (SAD) is an issue that has come to light after a series of recent clinical trials that has led to the issue of a black box warning for statins by the US FDA. However, the benefit of statin outweighs its risk. Nevertheless, experiments have been conducted to identify the mechanism by which statins aggravate the risk of diabetes only in a select population who bear the risk factors of obesity, sedentary lifestyle, hypertension, and other associated risk factors of lifestyle disorders. In this study, the possibility of utilization of a phyto-molecule, sesamol, for its ability to combat statin-associated diabetes using atorvastatin as the agent of choice has been explored. MMP assay and western blot was conducted to investigate the effects of atorvastatin on apoptotic cascade with sesamol as a protective agent was conducted in MIN-6 cells. Effect of the combination was tested in L6 cells with 2-NBDG uptake assay and as well as western blot for GLUT-4. A diet-induced hypercholesterolemia model was developed in an in vivo model animals and treated with atorvastatin and sesamol with histopathological analysis being carried out to evaluate the apoptotic markers and GLUT-4 presence. It was found that sesamol can combat pancreatic beta cell apoptosis via the internal apoptotic pathway activated by atorvastatin. With regards to muscle cells, sesamol could improve the GLUT-4 vesical production, but not improve glucose uptake which is inhibited by atorvastatin. These findings are further confirmed by animal studies. These findings indicate that sesamol can serve as a prototype molecule for further development and investigation of similar compounds to tackle SAD.

Lunasin ameliorates glucose utilization in C2C12 myotubes and metabolites profile in diet-induced obese mice benefiting metabolic disorders

AimsObesity is the main cause of low-grade inflammation and oxidation, resulting in insulin resistance. This study aimed to investigate the effects of a seed peptide lunasin on glucose utilization in C2C12 myotubes and the metabolite profiles in obese mice. Main methodsC2C12 myotubes were challenged by palmitic acid (PA) to mimic the obese microenvironment and inflammation, cell vitality, and glucose utilization were determined. C57BL6/j mice were divided into low-fat diet (LF), high-fat diet (HF), and HF with intraperitoneally injected lunasin (HFL) groups. Glucose intolerance and metabolite profiles of the tissues were analyzed. Key findingsIn vitro, C2C12 myotubes treated with lunasin showed decreased proinflammatory cytokines and increased cell vitality under palmitic acid conditions. Lunasin improved glucose uptake and glucose transporter 4 expression by activating insulin receptor substrate-1 and AKT phosphorylation. Next-generation sequencing revealed that lunasin regulates genes expression by promoting insulin secretion and decreasing oxidative stress. In vivo, HF mice showed increased tricarboxylic acid cycle and uric acid metabolites but decreased bile acids metabolites and specific amino acids. Lunasin intervention improved glucose intolerance and modulated metabolites associated with increased insulin sensitivity and decreased metabolic disorders. SignificanceThis study is the first to reveal that lunasin is a promising regulator of anti-inflammation, anti-oxidation, and glucose utilization in myotubes and ameliorating glucose uptake and metabolite profiles in obese mice, contributing to glucose homeostasis and benefiting metabolic disorders.

The PTP1B Inhibitor Trodusquemine (MSI-1436) Improves Glucose Uptake in Equine Metabolic Syndrome Affected Liver through Anti-Inflammatory and Antifibrotic Activity.

Hyperactivation of protein tyrosine phosphatase (PTP1B) has been associated with several metabolic malfunctions ranging from insulin resistance, metaflammation, lipotoxicity, and hyperglycaemia. Liver metabolism failure has been proposed as a core element in underlying endocrine disorders through persistent inflammation and highly fibrotic phenotype. In this study, the outcomes of PTP1B inhibition using trodusquemine (MSI-1436) on key equine metabolic syndrome (EMS)-related alterations including inflammation, fibrosis, and glucose uptake have been analyzed in liver explants collected from EMS-affected horses using various analytical techniques, namely, flow cytometry, RT-qPCR, and Western blot. PTP1B inhibition using trodusquemine resulted in decreased proinflammatory cytokines (IL-1β, TNF-α, and IL-6) release from liver and PBMC affected by EMS and regulated expression of major proinflammatory microRNAs such as miR-802 and miR-211. Moreover, MSI-1436 enhanced the anti-inflammatory profile of livers by elevating the expression of IL-10 and IL-4 and activating CD4+CD25+Foxp3+ regulatory T cells in treated PBMC. Similarly, the inhibitor attenuated fibrogenic pathways in the liver by downregulating TGF-β/NOX1/4 axis and associated MMP-2/9 overactivation. Interestingly, PTP1B inhibition ameliorated the expression of TIMP-1 and Smad7, both important antifibrotic mediators. Furthermore, application of MSI-1436 was found to augment the abundance of glycosylated Glut-2, which subsequently expanded the glucose absorption in the EMS liver, probably due to an enhanced Glut-2 stability and half-life onto the plasma cell membranes. Taken together, the presented data suggest that the PTP1B inhibition strategy and the use of its specific inhibitor MSI-1436 represents a promising option for the improvement of liver tissue integrity and homeostasis in the course of EMS and adds more insights for ongoing clinical trials for human MetS management.

Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes.

Type 2 diabetes mellitus is a chronic metabolic disease with no cure. Adipose tissue is a major site of systemic insulin resistance. Sortilin is a central component of the glucose transporter -Glut4 storage vesicles (GSV) which translocate to the plasma membrane to uptake glucose from circulation. Here, using human adipocytes we demonstrate the presence of the alternatively spliced, truncated sortilin variant (Sort_T) whose expression is significantly increased in diabetic adipose tissue. Artificial-intelligence-based modeling, molecular dynamics, intrinsically disordered region analysis, and co-immunoprecipitation demonstrated association of Sort_T with Glut4 and decreased glucose uptake in adipocytes. The results show that glucagon-like peptide-1 (GLP1) hormone decreases Sort_T. We deciphered the molecular mechanism underlying GLP1 regulation of alternative splicing of human sortilin. Using splicing minigenes and RNA-immunoprecipitation assays, the results show that GLP1 regulates Sort_T alternative splicing via the splice factor, TRA2B. We demonstrate that targeted antisense oligonucleotide morpholinos reduces Sort_T levels and improves glucose uptake in diabetic adipocytes. Thus, we demonstrate that GLP1 regulates alternative splicing of sortilin in human diabetic adipocytes.

QSPR Analysis of Some Phenolic Compounds Present in Moringa Oleifera

QSPR analysis can be used in a variety of applications, such as drug discovery, materials science, and environmental chemistry. For example, QSPR models can be used to predict the toxicity of new chemicals, to design more effective drugs, or to optimize the properties of materials for specific applications. Phenolic compounds act as anti-oxidants, anti-carcinogenic, and anti-bacterial agents present in Moringa oleifera. These Phenolic compounds have significant antioxidant properties as they can scavenge free radicals, slow the aging process, and improve glucose uptake in muscles. They are also used to prevent the accumulation of lipids in the liver and subsequently prevent fatty liver disease, protect kidneys, prevent cancer, prevent whitening skin, chemopreventive for cancer, induce apoptosis in ovarian cancer, protect kidneys, decrease pro-inflammatory enzymes, and increase antioxidants enzymes. Furthermore, phenolic compounds inhibit enzymes linked to diabetes type-2 and they can be used to cure diabetes. Owing to the significance of these phenolic compounds, we carried out QSPR analysis using degree-based indices to know the physical characteristics affiliated with them. The outcomes indicate that these phenolic compounds could be investigated further by pharmacists and chemists when designing drugs using these topological indices values. Since the correlation for the topological indices has been discovered, positively correlated compounds may be considered for the combination of novel drug designs. Also, the computed results are useful to predict the physical properties of the phenolic compounds.

DNAJB3 attenuates ER stress through direct interaction with AKT.

Metabolic stress involved in several dysregulation disorders such as type 2 diabetes mellitus (T2DM) results in down regulation of several heat shock proteins (HSPs) including DNAJB3. This down regulation of HSPs is associated with insulin resistance (IR) and interventions which induce the heat shock response (HSR) help to increase the insulin sensitivity. Metabolic stress leads to changes in signaling pathways through increased activation of both c-jun N-terminal kinase-1 (JNK1) and the inhibitor of κB inflammatory kinase (IKKβ) which in turn leads to inactivation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2). DNAJB3 interacts with both JNK1 and IKKβ kinases to mitigate metabolic stress. In addition DNAJB3 also activates the PI3K-PKB/AKT pathway through increased phosphorylation of AKT1 and its substrate AS160, a Rab GTPase-activating protein, which results in mobilization of GLUT4 transporter protein and improved glucose uptake. We show through pull down that AK T1 is an interacting partner of DNAJB3, further confirmed by isothermal titration calorimetry (ITC) which quantified the avidity of AKT1 for DNAJB3. The binding interface was identified by combining protein modelling with docking of the AKT1-DNAJB3 complex. DNAJB3 is localized in the cytoplasm and ER, where it interacts directly with AKT1 and mobilizes AS160 for glucose transport. Inhibition of AKT1 resulted in loss of GLUT4 translocation activity mediated by DNAJB3 and also abolished the protective effect of DNAJB3 on tunicamycin-induced ER stress. Taken together, our findings provide evidence for a direct protein-protein interaction between DNAJB3 and AKT1 upon which DNAJB3 alleviates ER stress and promotes GLUT4 translocation.

Akebia saponin D from Dipsacus asper wall. Ex C.B. Clarke ameliorates skeletal muscle insulin resistance through activation of IGF1R/AMPK signaling pathway

Ethnopharmacological relevanceDipsacus asper Wall. Ex C.B. Clarke (DA), a perennial herb, is one of the most commonly used herbs in Traditional Chinese Medicine for strengthening muscles and bones and regulating blood vessels. Akebia saponin D (ASD/AVI) is a triterpenoid saponin extracted from the root of DA, which has favorable pharmacological properties such as anti-osteoporosis, anti-apoptosis, liver protection and hypolipidemic. Aim of the studyTo explore the underlying mechanisms and regulatory role of Akebia saponin D (ASD/AVI) on high-fat diet-induced insulin resistance in skeletal muscle. Materials and methodsC2C12 cells were used to explore the best concentration in the skeletal muscle insulin resistance model in an in vitro experiment. The protective effect of AVI on insulin resistance and the corresponding signaling pathway were detected by glucose content measurement, quantitative PCR, and Western blot. A high-fat diet STZ-induced insulin resistance mice model was used to evaluate the protective function of AVI in vivo. After four weeks of treatment, ITT, OGTT, and treadmill tests were applied to examine insulin sensitivity and their serum and skeletal muscle tissues were collected for further analysis. ResultsAVI effectively reduced body weight, blood glucose levels and calorie intake in insulin-resistant mice, and reduced lipid accumulation and in their muscle tissue. AVI also improved glucose uptake and insulin sensitivity in both in vivo and in vitro experiments. Following AVI administration, there was an increase in the expression of the AMPK signaling pathway. Our experiments further confirmed that AVI specifically targets the IGF1R, thereby more effectively regulating the insulin signaling pathway. ConclusionAVI improves type 2 diabetes-induced insulin resistance in skeletal muscle by activating the IGF1R-AMPK signaling pathway, promoting glucose uptake and energy metabolism in IR.

Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria.

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.

Discovery of Potent Angiotensin-Converting Enzyme Inhibitors in Pomegranate as a Treatment for Hypertension.

Pomegranate (Punica granatum L.) is associated with numerous health benefits due to its high levels of antioxidant polyphenolic substances. Since pomegranate extract has been shown to inhibit angiotensin-converting enzyme (ACE), the potential inhibitory effect of most of its main constituents against ACE is unknown. Therefore, we tested the activities of 24 major compounds, the majority of which significantly inhibited ACE. Notably, pedunculagin, punicalin, and gallagic acid were the most effective ACE inhibitors with IC50 values of 0.91, 1.12, and 1.77 μM, respectively. As demonstrated in molecular docking studies, compounds block ACE by forming multiple hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ions in ACE's C- and N-domains, consequently inhibiting ACE's catalytic activity. Also, the most active pedunculagin stimulated nitric oxide (NO) production, activated the endothelial nitric oxide synthase enzyme (eNOS), and significantly increased eNOS protein expression levels up to 5.3-fold in EA.hy926 cells. Furthermore, pedunculagin increased in cellular calcium (Ca2+) concentration promoted eNOS enzyme activation and reduced the production of reactive oxygen species (ROS). In addition, the active compounds improved glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. The results of these computational, in vitro, and cellular experiments provide further evidence to the traditional medicine that involves using pomegranates to treat cardiovascular diseases like hypertension.

Assessment of Antidiabetic and Anti-Inflammatory Activities of Carissa carandas Linn Extract: In Vitro and In Vivo Study

This study investigated the effects of aqueous fruit extracts of Carissa carandas (CCA) on inflammation and insulin resistance using an in vitro cellular model, in vivo high-fat diets, and a streptozotocin-induced type 2 diabetic (T2DM) rat model. CCA significantly ameliorated inflammation by decreasing nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Interestingly, CCA showed anti-insulin resistance activities, as it significantly improved glucose uptake and decreased glycerol release in LPS-induced 3T3-L1 adipocytes. In vivo studies showed that a high dose of 12-week oral supplementation of CCA (400 mg/kg BW/day) significantly reduced visceral fat, triglycerides, and cholesterol level in the blood of diabetic rats. Importantly, the metabolic parameters in both fasting and postprandial states, including fasting plasma glucose, HOMA-IR, and glucose intolerance, significantly improved, indicating its antihyperglycemic benefit in diabetic rats. Moreover, the results of the HOMA-β and histological examination suggested that pancreatic β-cell function and pancreatic morphological changes of the CCA and metformin treatments appeared to be better than those in non-treated diabetes, indicating the protective effect of CCA against pancreatic damage caused by hyperglycemia. In conclusion, the present study first reported that the C. carandas fruit extract has anti-inflammation and anti-insulin resistance, and subsequently improved glycemic control in the T2DM rat model.

Synthesis, Anti‐adipogenic, and Insulin‐sensitizing Potential of Benzosuberene‐alkyl Sulfone (BSAS) Analogues

AbstractObesity and diabetes are the leading cause of mortality worldwide. Promising modulators exhibiting insulin sensitivity and anti‐adipogenic actions are highly desirable. Organic sulfone analogues are prominent structural units present in diverse bioactive molecules. However, sulfones‐derived anti‐adipogenic agents are currently unavailable. Therefore, different benzosuberene‐alkyl sulfone (BSAS) analogues were synthesized inspired by the molecular diversity of the essential oil of Cedrus deodara. Among the series, five BSAS analogues were assessed in‐silico for their binding towards native Peroxisome Proliferator‐Activated Receptor Gamma (PPARγ) and further validated in‐vitro for their anti‐adipogenic potential in differentiated 3T3‐L1 pre‐adipocytes. Their ability to improve insulin sensitivity was also examined in L6 myotubes to ascertain their role in insulin resistance. Our results demonstrated that BSAS‐1 was the partial PPARγ agonist. It has reduced adipogenesis efficiently by downregulating adipogenic genes, resulting in lower triglyceride levels. BSAS‐1 lowered oxidative stress, protected myotubes from insulin resistance, and improved glucose uptake by promoting GLUT4 translocation. Overall, BSAS‐1 has the potential to treat obesity and obesity‐induced insulin resistance.