KLF3 impacts insulin sensitivity and glucose uptake in skeletal muscle.

Skeletal muscle is one of the predominant sites involved in glucose disposal, accounting for approximately 80% of postprandial glucose uptake, and plays a critical role in maintaining glycemic homeostasis. Dysregulation of energy metabolism in skeletal muscle is involved in developing insulin resistance and type 2 diabetes (T2D). Transcriptomic responses of skeletal muscle to exercise found that the expression of Klf3 was increased in T2D Goto-Kakizaki (GK) rats and decreased after exercise with improved hyperglycemia and insulin resistance, implying that Klf3 might be associated with insulin sensitivity and glucose metabolism. We also found that knockdown of Klf3 promoted basal and insulin-stimulated glucose uptake in L6 myotubes, while overexpression of Klf3 resulted in the opposite. Through pairwise comparisons of L6 myotubes transcriptome, we identified 2256 and 1988 differentially expressed genes in Klf3 knockdown and overexpression groups, respectively. In insulin signaling, the expression of Slc2a4, Akt2, Insr and Sorbs1 was significantly increased by Klf3 knockdown and decreased with klf3 overexpression; Ptprf and Fasn were markedly downregulated in klf3 reduced group and upregulated in klf3 overexpressed group. Moreover, downregulation of Klf3 promoted the expression of GLUT4 and AKT proteins, as well as the translocation of GLUT4 to the cell membrane in the basal situation, and enhanced insulin sensitivity, characterized by increased insulin-stimulated GLUT4 translocation and AKT, TBC1D1 and TBC1D4 phosphorylation, while overexpression of Klf3 showed contrary results. These results suggest that Klf3 affects glucose uptake and insulin sensitivity via insulin signal transduction and intracellular metabolism, offering a novel potential treatment strategy for T2D.

Fecal microbiota transplantation derived from mild cognitive impairment individuals impairs cerebral glucose uptake and cognitive function in wild-type mice: Bacteroidetes and TXNIP-GLUT signaling pathway.

Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced 18F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.

The novel family of Warbicin® compounds inhibits glucose uptake both in yeast and human cells and restrains cancer cell proliferation.

Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1Δ mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1Δ strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1Δ strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin ® A as a compound restoring growth on glucose of the yeast tps1Δ mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin ® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin ® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1Δ cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin ® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism.

In Vitro and In Silico Analysis of PTP1B Inhibitors from Cleistocalyx operculatus Leaves and Their Effect on Glucose Uptake.

As part of our ongoing research on new anti-diabetic compounds from ethnopharmacologically consumed plants, two previously undescribed lupane-type triterpenoids (1 and 2) with dicarboxylic groups, an undescribed nor-taraxastane-type triterpenoid (3), and 14 known compounds (4-17) were isolated from the leaves of Cleistocalyx operculatus. Extensive spectroscopic analysis (IR, HRESIMS, 1D, and 2D NMR) was used for structure elucidation, while the known compounds were compared to reference data reported in the scientific literature. All the isolates (1-17) were evaluated for their inhibitory effects on the protein tyrosine phosphatase 1B (PTP1B) enzyme. Compounds 6, 9, and 17 showed strong PTP1B inhibitory activities. The mechanism of PTP1B inhibition was studied through enzyme kinetic experiments. A non-competitive mechanism of inhibition was determined using Lineweaver-Burk plots for compounds 6, 9, and 17. Additionally, Dixon plots were employed to determine the inhibition constant. Further insights were gained through a structure-activity relationship study and molecular docking analysis of isolated compounds with the PTP1B crystal structure. Moreover, all isolates (1-17) were tested for their stimulatory effects on the uptake of 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) in differentiated 3T3-L1 adipocyte cells. Compounds 6, 13, and 17 exhibited strong glucose absorption stimulation activity in a dose-dependent manner.

Role of bariatric surgery in improving diabetic cardiomyopathy: Molecular mechanisms and therapeutic perspectives (Review).

Diabetic cardiomyopathy (DCM), a significant complication of diabetes mellitus, is marked by myocardial structural and functional alterations due to chronic hyperglycemia. Despite its clinical significance, optimal treatment strategies are still elusive. Bariatric surgery via sleeve gastrectomy and Roux-en-Y gastric bypass have shown promise in treating morbid obesity and associated metabolic disorders including improvements in diabetes mellitus and DCM. The present study reviews the molecular mechanisms by which bariatric surgery improves DCM, offering insights into potential therapeutic targets. Future research should further investigate the mechanistic links between bariatric surgery and DCM, to evaluate the benefits and limitations of these surgical interventions for DCM treatment. The present study aims to provide a foundation for more effective DCM therapies, contributing to the advancement of patient care.

Effects of Obesity and Exercise on Hepatic and Pancreatic Lipid Content and Glucose Metabolism: PET Studies in Twins Discordant for BMI.

Obesity and sedentarism are associated with increased liver and pancreatic fat content (LFC and PFC, respectively) as well as impaired organ metabolism. Exercise training is known to decrease organ ectopic fat but its effects on organ metabolism are unclear. Genetic background affects susceptibility to obesity and the response to training. We studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. We recruited 12 BMI-discordant monozygotic twin pairs (age 40.4, SD 4.5 years; BMI 32.9, SD 7.6, 8 female pairs). Ten pairs completed six months of training intervention. We measured hepatic insulin-stimulated glucose uptake using [18F]FDG-PET and fat content using magnetic resonance spectroscopy before and after the intervention. At baseline LFC, PFC, gamma-glutamyl transferase (GT), and hepatic glucose uptake were significantly higher in the heavier twins compared to the leaner co-twins (p = 0.018, p = 0.02 and p = 0.01, respectively). Response to training in liver glucose uptake and GT differed between the twins (Time*group p = 0.04 and p = 0.004, respectively). Liver glucose uptake tended to decrease, and GT decreased only in the heavier twins (p = 0.032). In BMI-discordant twins, heavier twins showed higher LFC and PFC, which may underlie the observed increase in liver glucose uptake and GT. These alterations were mitigated by exercise. The small number of participants makes the results preliminary, and future research with a larger pool of participants is warranted.

Extract of Phyllanthus emblica L. fruit stimulates basal glucose uptake and ameliorates palmitate-induced insulin resistance through AMPK activation in C2C12 myotubes.

BACKGROUND: The fruit of Phyllanthus emblica L., a traditional medicine in China and India, is used to treat diabetes mellitus. Its water extract (WEPE) has demonstrated hypoglycemic effects in diabetic rats, but its mechanisms on glucose utilization and insulin resistance in skeletal muscle remain unclear. Therefore, this study aims to investigate the effects and underlying mechanisms of WEPE on glucose utilization and insulin resistance using C2C12 myotubes. METHODS: Effects of WEPE on glucose uptake, GLUT4 translocation, and AMPK and AKT phosphorylation were investigated in C2C12 myotubes and palmitate-treated myotubes. An AMPK inhibitor and siRNA were used to explore the mechanisms of WEPE. Glucose uptake was determined using a 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG) uptake assay, and protein expression and GLUT4 translocation were assessed via western blotting. RESULTS: In normal myotubes, WEPE significantly stimulated glucose uptake and GLUT4 translocation to the plasma membrane at concentrations of 125 and 250 µg/mL. This was accompanied by an increase in the phosphorylation of AMPK and its downstream targets. However, both compound C and AMPK siRNA blocked the WEPE-induced GLUT4 translocation and glucose uptake. Moreover, pretreatment with STO-609, a calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß) inhibitor, inhibited WEPE-induced AMPK phosphorylation and attenuated the WEPE-stimulated glucose uptake and GLUT4 translocation. In myotubes treated with palmitate, WEPE prevented palmitate-induced insulin resistance by enhancing insulin-mediated glucose uptake and AKT phosphorylation. It also restored the insulin-mediated translocation of GLUT4 from cytoplasm to membrane. However, these effects of WEPE on glucose uptake and GLUT4 translocation were blocked by pretreatment with compound C. CONCLUSIONS: WEPE significantly stimulated basal glucose uptake though CaMKKß/AMPK pathway and markedly ameliorated palmitate-induced insulin resistance by activating the AMPK pathway in C2C12 myotubes.

Evaluation of Clinical Variables Affecting Myocardial Glucose Uptake in Cardiac FDG PET.

PURPOSE: Cardiac 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG PET) is widely used to assess myocardial viability in patients with ischemic heart disease. While sufficient glucose uptake is a prerequisite for accurate interpretation of cardiac viability, there are a lack of data on which clinical variables have the most significant impact on myocardial glucose metabolism. Therefore, this study was designed to evaluate several clinical variables that could affect myocardial glucose metabolism. METHODS: A total of 214 consecutive cases were retrospectively enrolled in this study. All subjects received 250 mg of acipimox and underwent glucose loading as preparation for cardiac FDG PET/CT. Three-dimensional regions of interest (ROIs) were drawn on PET/CT fusion images. Myocardial glucose uptake ratio (MGUR = SUVmax of LV myocardium/SUVmean of liver) was then calculated. Multiple clinical variables including body mass index (BMI), blood glucose levels at different times, administered insulin dosage, lipid profiles, and ejection fraction were measured and analyzed for correlation with myocardial glucose uptake. After dichotomizing the subjects based on a BMI of 25, each group's MGUR was compared. RESULTS: Myocardial uptake showed significant correlations with BMI (r = -0.162, p = 0.018), HbA1c (r = -0.150, p = 0.030), and triglyceride levels (r = -0.137, p = 0.046). No other clinical variables showed a significant correlation with myocardial glucose uptake. After multiple linear regression analysis, BMI (p = 0.032) and HbA1c (p = 0.050) showed a correlation with MGUR. In group analysis, after dividing patients based on BMI, the obese group showed significantly lower myocardial uptake than the non-obese group (3.8 ± 1.9 vs. 4.4 ± 2.1, p = 0.031). CONCLUSIONS: Among several clinical variables, BMI and HbA1c levels were related to myocardial glucose uptake. A prospective study would be needed to examine whether a protocol that additionally considers BMI and HbA1c levels is necessary for the current cardiac FDG PET protocol.

Biophysical Analysis of a Minimalistic Kidney Model Expressing SGLT1 Reveals Crosstalk between Luminal and Lateral Membranes and a Plausible Mechanism of Isosmotic Transport.

We extended our model of the S1 tubular segment to address the mechanisms by which SGLT1 interacts with lateral Na/K pumps and tight junctional complexes to generate isosmotic fluid reabsorption via tubular segment S3. The strategy applied allowed for simulation of laboratory experiments. Reproducing known experimental results constrained the range of acceptable model outputs and contributed to minimizing the free parameter space. (1) In experimental conditions, published Na and K concentrations of proximal kidney cells were found to deviate substantially from their normal physiological levels. Analysis of the mechanisms involved suggested insufficient oxygen supply as the cause and, indirectly, that a main function of the Na/H exchanger (NHE3) is to extrude protons stemming from mitochondrial energy metabolism. (2) The water path from the lumen to the peritubular space passed through aquaporins on the cell membrane and claudin-2 at paracellular tight junctions, with an additional contribution to water transport by the coupling of 1 glucose:2 Na:400 H2O in SGLT1. (3) A Na-uptake component passed through paracellular junctions via solvent drag in Na- and water-permeable claudin-2, thus bypassing the Na/K pump, in agreement with the findings of early studies. (4) Electrical crosstalk between apical rheogenic SGLT1 and lateral rheogenic Na/K pumps resulted in tight coupling of luminal glucose uptake and transepithelial water flow. (5) Isosmotic transport was achieved by Na-mediated ion recirculation at the peritubular membrane.

The Effects of Acute Beetroot Juice Intake on Glycemic and Blood Pressure Responses When Controlling for Medication in Individuals with Type 2 Diabetes: A Pilot Study.

Physical inactivity and poor dietary choices contribute to the rise in cardiometabolic diseases in the United States. It remains critical to identify strategies that may mitigate the negative impact of these behaviors. Several studies have shown that the consumption of dietary inorganic nitrate may improve vascular health and glucose regulation in animal models and some human studies. However, the improvements in glucose regulation have yet to be corroborated in humans with type 2 diabetes (T2D). Therefore, the purpose of this study was to assess the acute effects of beetroot juice (BRJ) on glycemic and hemodynamic responses in individuals with T2D while controlling for medication. Seven participants with a clinical diagnosis of T2D were recruited into this study and were temporarily removed from blood pressure- and glucose-lowering medications. Hemodynamic measurements (pulsewave velocity) and an oral glucose tolerance test (glycemic response) were measured following consumption of either BRJ or a denitrolized placebo. Saliva and blood samples were collected at baseline and two and four hours post supplementation to measure changes in nitrate and nitrite concentrations. We detected significant improvements in total plasma glucose exposure (p = 0.022) and the SVR change score (p = 0.009) in the BRJ condition. This study demonstrated that BRJ consumption can improve oral glucose tolerance in individuals with T2D while controlling for medication; however, future larger-cohort randomized controlled trials are needed to confirm if BRJ is a viable treatment for glucose control in individuals with T2D.

Relation of Insulin Resistance to Brain Glucose Metabolism in Fasting and Hyperinsulinemic States: A Systematic Review and Meta-Analysis.

CONTEXT: Abnormal brain glucose metabolism may cause cognitive disease in type 2 diabetes, yet the relation between insulin resistance and brain glucose metabolism has not been systematically described. OBJECTIVE: We evaluated the impact of metabolic condition (fasting vs insulin stimulation, e.g., from hyperinsulinemic clamp) on the association between insulin resistance of different etiologies and brain glucose metabolism. DATA SOURCES: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception until February 2022. STUDY SELECTION: Of 656 unique records, we deemed thirty-one eligible. Criteria were studies assessing brain glucose metabolism (uptake or metabolic rate) by 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography ([18F]-FDG-PET) in individuals characterized by measures of or clinical proxies for insulin resistance (e.g., type 2 diabetes and obesity). DATA EXTRACTION: Two independent investigators extracted data and assessed study quality. DATA SYNTHESIS: We applied random-effects models to pool Hedge's g standardized mean differences. Insulin resistance was associated with decreased brain glucose metabolism during fasting (-0.47SD, 95%CI: -0.73 to -0.22, p<0.001, I2=71%) and increased metabolism during insulin stimulation (1.44SD, 95%CI: 0.79 to 2.09, p=0.002, I2=43%). Contrary to type 2 diabetes and other insulin resistance-related conditions, obesity was not associated with brain hypometabolism in fasting states (0.29SD, 95%CI: -0.81 to 1.39). CONCLUSIONS: Metabolic conditions modify associations between insulin resistance and brain glucose metabolism, i.e. most individuals with insulin resistance display hypometabolism during fasting and hypermetabolism during insulin stimulation.

Metabolomic Profiling of Adipose Tissue in Type 2 Diabetes: Associations with Obesity and Insulin Resistance.

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions.

Measurement of hepatic glucose (18F-fluorodeoxyglucose) uptake with positron emission tomography-magnetic resonance imaging in fumonisin B intoxicated rabbit bucks.

Rabbit bucks (bodyweight 5 kg) underwent dietary intoxication with fumonisin B series mycotoxins (FB1 + FB2 + FB3, 15 mg/kg diet) for 14 days to test the applicability of positron emission tomography-magnetic resonance (PET MR) hybrid imaging in characterizing experimentally induced mild hepatotoxicosis. 18F-fluorodeoxyglucose (18F-FDG) radiotracer-aided imaging was performed before and after FBs administration on identical animals, and at both time points, blood was sampled for haematology and clinical chemistry. Kinetic PET image analysis revealed time-activity curves with uptake maxima below 1 min in the liver, renal cortex, portal vein, lung and coarctatio aortae. In the frame of static PET image analysis, based on the standardized uptake value (SUV), the so-called metabolic liver volume (MLV, liver volume defined by over 0.9 × average liver SUV) and the total liver glycolysis (TLG, MLV multiplied by the SUVmean) were calculated. Mycotoxicosis increased total liver glycolysis (p < 0.04) after 14 days and liver tissue TLG inhomogeneity was minimal. Pearson correlation between TLG and alkaline phosphatase (ALP) was positive (0.515), while negative with LDH and AST (- 0.721 and - 0.491, respectively). Results indicate a slight hepatic mycotoxin effect and significantly increased glucose uptake intensity, which has been sensitively detected with molecular imaging (18F-FDG PET MRI) in the rabbit model.

A ketogenic diet, regardless of fish oil content, does not affect glucose homeostasis or muscle insulin response in male rats.

Ketogenic diets (KDs) are very high in fat and low in carbohydrates. Evidence supports that KDs improve glucose metabolism in humans and rodents that are obese and/or insulin resistant. Conversely, findings in healthy rodents suggest that KDs may impair glucose homeostasis. In addition, most experimental KDs are composed of saturated and monounsaturated fatty acids, with almost no omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA). Evidence supports a beneficial role for n-3 LCPUFA on glucose homeostasis in the context of a metabolic challenge. To our knowledge, no study has examined whether the inclusion of n-3 LCPUFA affects the impact of a KD on glucose homeostasis. The objective of this study was to examine the impact of a KD on whole body glucose tolerance and skeletal muscle insulin response in rats and to determine if increasing the n-3 LCPUFA content in a KD with menhaden oil could improve metabolic outcomes. Male Sprague-Dawley rats were pair-fed one of a low-fat diet, high-fat diet, KD, or a KD supplemented with menhaden oil for 8 wk. No significant differences in whole body glucose tolerance, skeletal muscle insulin signaling, or skeletal muscle insulin-stimulated glucose uptake were detected between the dietary groups. Our findings suggest that KD feeding, with or without supplementation of n-3 LCPUFA, does not affect whole body glucose homeostasis or skeletal muscle insulin response under pair-feeding conditions.NEW & NOTEWORTHY Ketogenic diets (KDs) improve glucose metabolism in humans and rodents that are insulin resistant, but their impact is unclear in a healthy context. Furthermore, standard KDs typically lack beneficial omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFA). This study assessed whether supplementing a KD with n3-LCPUFA could alter glucose homeostasis or skeletal muscle insulin response. No differences were observed between a standard KD and a KD with n3-LCPUFA when energy intake was controlled.

Evaluation of bone marrow glucose uptake and adiposity in male rats after diet and exercise interventions.

Objectives: Obesity impairs bone marrow (BM) glucose metabolism. Adult BM constitutes mostly of adipocytes that respond to changes in energy metabolism by modulating their morphology and number. Here we evaluated whether diet or exercise intervention could improve the high-fat diet (HFD) associated impairment in BM glucose uptake (BMGU) and whether this associates with the morphology of BM adipocytes (BMAds) in rats. Methods: Eight-week-old male Sprague-Dawley rats were fed ad libitum either HFD or chow diet for 24 weeks. Additionally after 12 weeks, HFD-fed rats switched either to chow diet, voluntary intermittent running exercise, or both for another 12 weeks. BMAd morphology was assessed by perilipin-1 immunofluorescence staining in formalin-fixed paraffin-embedded tibial sections. Insulin-stimulated sternal and humeral BMGU were measured using [18F]FDG-PET/CT. Tibial microarchitecture and mineral density were measured with microCT. Results: HFD rats had significantly higher whole-body fat percentage compared to the chow group (17% vs 13%, respectively; p = 0.004) and larger median size of BMAds in the proximal tibia (815 µm2 vs 592 µm2, respectively; p = 0.03) but not in the distal tibia. Switch to chow diet combined with running exercise normalized whole-body fat percentage (p < 0.001) but not the BMAd size. At 32 weeks of age, there was no significant difference in insulin-stimulated BMGU between the study groups. However, BMGU was significantly higher in sternum compared to humerus (p < 0.001) and higher in 8-week-old compared to 32-week-old rats (p < 0.001). BMAd size in proximal tibia correlated positively with whole-body fat percentage (r = 0.48, p = 0.005) and negatively with humeral BMGU (r = -0.63, p = 0.02). HFD significantly reduced trabecular number (p < 0.001) compared to the chow group. Switch to chow diet reversed this as the trabecular number was significantly higher (p = 0.008) than in the HFD group. Conclusion: In this study we showed that insulin-stimulated BMGU is age- and site-dependent. BMGU was not affected by the study interventions. HFD increased whole-body fat percentage and the size of BMAds in proximal tibia. Switching from HFD to a chow diet and running exercise improved glucose homeostasis and normalized the HFD-induced increase in body fat but not the hypertrophy of BMAds.

Daily standing time, dietary fiber, and intake of unsaturated fatty acids are beneficially associated with hepatic insulin sensitivity in adults with metabolic syndrome.

Background: Obesity is associated with impaired glucose metabolism and hepatic insulin resistance. The aim was to investigate the associations of hepatic glucose uptake (HGU) and endogenous glucose production (EGP) to sedentary behavior (SB), physical activity (PA), cardiorespiratory fitness, dietary factors, and metabolic risk markers. Methods: Forty-four adults with metabolic syndrome (mean age 58 [SD 7] years, BMI ranging from 25-40kg/; 25 females) were included. HGU was measured by positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated by subtracting the glucose infusion rate during clamp from the glucose rate of disappearance. SB and PA were measured with hip-worn accelerometers (26 [SD3] days). Fitness was assessed by maximal bicycle ergometry with respiratory gas measurements and dietary intake of nutrients by 4-day food diaries. Results: HGU was not associated with fitness or any of the SB or PA measures. When adjusted for sex, age, and body fat-%, HGU was associated with whole-body insulin sensitivity (ß=0.58), water-insoluble dietary fiber (ß=0.29), energy percent (E%) of carbohydrates (ß=-0.32), saccharose (ß=-0.32), mono- and polyunsaturated fatty acids (ß=0.35, ß=0.41, respectively). EGP was associated with whole-body insulin sensitivity (ß=-0.53), and low-density lipoprotein cholesterol [ß=-0.31], and when further adjusted for accelerometry wear time, EGP was associated with standing [ß=-0.43]. (p-value for all< 0.05). Conclusions: Standing more, consuming a diet rich in fiber and unsaturated fatty acids, and a lower intake of carbohydrates, especially sugar, associate beneficially with hepatic insulin sensitivity. Habitual SB, PA, or fitness may not be the primary modulators of HGU and EGP. However, these associations need to be confirmed with intervention studies.

Red rice bran aqueous extract ameliorate diabetic status by inhibiting intestinal glucose transport in high fat diet/STZ-induced diabetic rats.

Red rice (Oryza sativa L.) consumption has grown recently, partly due to its potential health benefits in several disease prevention. The impact of red rice bran aqueous extract (RRBE) on intestinal glucose uptake and diabetes mellitus (DM) progression has not been thoroughly investigated. This study aimed to evaluate the effect of RRBE on ex vivo intestinal glucose absorption and its potential as an antihyperglycemic compound using a high-fat diet and streptozotocin (STZ)-induced diabetic rats. High-fat diet/STZ-induced diabetic rats were supplemented with either 1000 mg/kg body weight (BW) of RRBE, 70 mg/kg BW of metformin (Met), or a combination of RRBE and Met for 3 months. Plasma parameters, intestinal glucose transport, morphology, liver and soleus muscle glycogen accumulation were assessed. Treatment with RRBE, metformin, or combination markedly reversed hyperglycemia, hypertriglyceridemia, insulin resistance, and pancreatic morphology changes associated with T2DM. Correspondingly, all supplements effectively downregulated glucose transporters, resulting in a reduction of intestinal glucose transport-additionally, liver and soleus muscle glycogen accumulation was reduced in RRBE + Met treated group. Taken together, RRBE potentially suppressed intestinal glucose transporters' function and expression, reducing diabetic status.

Optimization of Extraction and Purification of Flavonoids from Stigmaless Floral Residues of Crocus sativus L. and Their Stimulatory Effect on Glucose Uptake In Vitro.

Saffron, the dried stigma of Crocus sativus L., is a renowned spice and medicinal herb. During its production, a significant amount of floral residues, rich in bioactive compounds, are discarded as agricultural by-products. This study presents a novel approach to the sustainable utilization of these stigmaless floral residues (FRC) by optimizing the extraction and purification of their flavonoids, analyzing their chemical composition, and evaluating their effect on glucose uptake. The extraction of flavonoids from FRC was optimized using single-factor experiments and response surface methodology. The optimal conditions for extraction were an ethanol concentration of 67.7%, a temperature of 67.6 °C, a solid-to-liquid ratio of 1:30, an extraction time of 3 h, and two extractions. The crude extract obtained was then purified using macroporous resin HPD100, selected after comparing the adsorption and desorption characteristics of six different resins. The optimal purification parameters were an adsorption concentration of 40 mg/mL, a loading volume of 7 bed volumes (BV) at a flow rate of 3 BV/h, and 80% ethanol as the eluent with a volume of 4 BV. The resulting flavonoid-enriched extract (FFRC) had an experimental yield of 8.67% ± 0.01 and a flavonoid content of 128.30 ± 4.64 mg/g. The main flavonoids in FFRC were identified as kaempferol glycosides, isorhamnetin glycosides, and quercetin glycosides. Moreover, FFRC significantly stimulated glucose consumption and uptake in C2C12 myotubes, suggesting its potential utility as a natural hypoglycemic agent. This study contributes to the sustainable and value-added utilization of agricultural resources by providing data for the exploitation and application of flavonoids from saffron by-products.

1H and 31P Magnetic Resonance Spectroscopic Metabolomic Imaging: Assessing Mitogen-Activated Protein Kinase Inhibition in Melanoma.

The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine in melanoma. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels in the early stages of effective therapy and could be considered as metabolic imaging biomarkers for drug response. The present work demonstrates that these metabolic changes observed by 1H MRS and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for the early prediction of melanoma's response to MEK inhibition.

Noninvasive Quantification of Glucose Metabolism in Mice Myocardium Using the Spline Reconstruction Technique.

The spline reconstruction technique (SRT) is a fast algorithm based on a novel numerical implementation of an analytic representation of the inverse Radon transform. The purpose of this study was to compare the SRT, filtered back-projection (FBP), and the Tera-Tomo 3D algorithm for various iteration numbers, using small-animal dynamic PET data obtained from a Mediso nanoScan® PET/CT scanner. For this purpose, Patlak graphical kinetic analysis was employed to noninvasively quantify the myocardial metabolic rate of glucose (MRGlu) in seven male C57BL/6 mice (n=7). All analytic reconstructions were performed via software for tomographic image reconstruction. The analysis of all PET-reconstructed images was conducted with PMOD software (version 3.506, PMOD Technologies LLC, Fällanden, Switzerland) using the inferior vena cava as the image-derived input function. Statistical significance was determined by employing the one-way analysis of variance test. The results revealed that the differences between the values of MRGlu obtained via SRT versus FBP, and the variants of he Tera-Tomo 3D algorithm were not statistically significant (p > 0.05). Overall, the SRT appears to perform similarly to the other algorithms investigated, providing a valid alternative analytic method for preclinical dynamic PET studies.