Modulation Of Glucose Metabolism Research Articles

The effects of sleep deprivation on insulin, resistin and visfatin levels in healthy humans

The Effects of Sleep Deprivation on Insulin, Resistin and Visfatin Levels in Healthy Humans ABSTRACT Background: Sleep deprivation is known to affect circulating insulin and glucose levels which in turn modulate glucose metabolism. However, the mechanism of alterations in glucose homeostasis during sleep deprivation is not known. In this study, we investigated circulating resistin and visfatin levels in response to 40 hours of sleep loss in order to shed light on the above-mentioned mechanism. Methods: This study included 12 healthy young adult subjects (aged between 18-32 years). All participants underwent polysomnographic evaluation and oral glucose tolerance test and then fasting venous blood samples were collected in morning hours. Then, subjects remained awake for 40 hours under actigraphic monitorization. At the end of sleep deprivation, blood samples were collected again. Serum insulin, resistin and visfatin levels were measured in all blood samples. Insulin was determined by chemical immune assay method, whereas resistin and visfatin levels assayed by ELISA. Results: Compared to baseline, 40-hour total sleep deprivation resulted in a significant increase in serum insulin levels (10.75±7.75 vs 35.98±27.96 IU; p=0.002) and a significant decrease in resistin levels (21.94±7.65 vs 11.71±5.31 IU; p=0.002). Visfatin levels remained unchanged (6.29±3.31 vs 5.43±5.08 IU; p>0.05). Conclusion: These results suggested that short-term total sleep deprivation may lead to insulin resistance which was evidenced by a significant increase insulin levels independent of resistin. This may contribute to pathophysiology of type 2 diabetes mellitus under conditions of chronic sleep deprivation.

Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis

Public health studies indicate that artificial light is a high-risk factor for metabolic disorders. However, the neural mechanism underlying metabolic modulation by light remains elusive. Here, we found that light can acutely decrease glucose tolerance (GT) in mice by activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) innervating the hypothalamic supraoptic nucleus (SON). Vasopressin neurons in the SON project to the paraventricular nucleus, then to the GABAergic neurons in the solitary tract nucleus, and eventually to brown adipose tissue (BAT). Light activation of this neural circuit directly blocks adaptive thermogenesis in BAT, thereby decreasing GT. In humans, light also modulates GT at the temperature where BAT is active. Thus, our work unveils a retina-SON-BAT axis that mediates the effect of light on glucose metabolism, which may explain the connection between artificial light and metabolic dysregulation, suggesting a potential prevention and treatment strategy for managing glucose metabolic disorders.

Celecoxib promotes the efficacy of STING-targeted therapy by increasing antitumor CD8+ T-cell functions via modulating glucose metabolism of CD11b+ Ly6G+ cells.

Recent studies have shown that activation of the cGAS-STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX-2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX-2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD-1 expression on tumor-infiltrating T-cells and enhanced T-cell activation in tumor-draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4+ CD25+ Foxp3+ regulatory T-cells, it enhanced the expression of costimulatory molecules and glycolysis-associated genes in tumor-infiltrating CD11b+ Ly6G+ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN-γ- and TNF-α-producing CD8+ T-cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists.

Treatment optimization of the age-related cardiovascular and neurological pathology using known metabolic, cytoprotective, vasodilatory action substances. Review

Stressful situations that accompany us during military operations provoke a significant increase in the incidence of cardiovascular and psychoneurological pathology, especially among the elderly. Therefore, there is a need for a complex approach to treatment, in particular, with the use of combined drugs. The review presents data from preclinical and clinical studies on drugs with metabolic action - meldonium (trimethylhydrazinium propionate), L-arginine, and inosine. It has been shown that, apart from the general pharmacotherapeutic action, these drugs have a significant clinical effect on various illnesses in the form of adjunctive therapy. Antioxidant, neuroprotective, vasodilatory, and several pleiotropic effects of meldonium have been established. The use of meldonium as part of combined therapy improves the prognosis in cardiovascular and neurological disease treatment. Most reports ascribe the clinical benefits of L-arginine in cardiovascular diseases to the provision of NO. L-arginine is the only precursor for the NO-synthase reaction. NO is produced by all tissues of the body and plays particularly important roles in cardiovascular homeostasis. Very few articles examine the effects of L-arginine supplementation on central nervous system (CNS) function. However, accumulating evidence indicates that NO plays a role in memory formation. The possible role of L-arginine in Alzheimer's disease was investigated, taking into account the known functions of L-arginine in atherosclerosis, redox stress and inflammation, regulation of synaptic plasticity and neurogenesis, as well as modulation of glucose metabolism and insulin activity. Evidence is provided that L-arginine may play a prominent role in protecting against age-related degenerative diseases such as Alzheimer's disease. L-arginine has been demonstrated to improve peripheral circulation, renal function, and immune function. It also possesses anti-stress and adaptogenic capabilities. L-arginine stimulates the release of growth hormone as well as the release of pancreatic insulin and glucagon and pituitary prolactin. The antioxidant property of L-arginine has been well documented in several reports. As well known that inosenhancesance the myocardial energy potential improvesrove coronary circulation. At the same time over the past two decades, inosine has been shown to evoke significant improvements in motor function and visceral organ control in preclinical models of neurologic injury including spinal cord injury, stroke, traumatic brain injury, multiple sclerosis, and Parkinson`s disease through its ability to enhance the growth of axon collaterals from undamaged neurons. The basis of these beneficial effects stems from its antioxidant, anti-inflammatory, anxiogenic and neuroprotective properties. Keywords: age-related pathology; combined drugs; meldonium; L-arginine; inosine, endothelial dysfunction.

Self-reported dietary omega-3 polyunsaturated fatty acids are associated with adipose tissue markers and glucose metabolism in apparently healthy subjects

Background Plasminogen activator inhibitor 1 (PAI-1) and resistin are associated with dysfunctional adipose tissue (AT)-related metabolic complications. The role of dietary eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids in this relationship is unknown. Aim To investigate the association of EPA and DHA with PAI-1 and resistin, as well as the role of this association on the glucose metabolism of apparently healthy subjects. Subjects and methods Thirty-six healthy individuals were included. Validated food frequency questionnaires were used to analyse dietary habits. Inflammatory and glucose metabolism markers were quantified. Subcutaneous AT samples were obtained, and adipocyte number, area, and macrophage content were assessed. Results In 36 subjects aged 56 ± 8 years and with a body mass index of 26 ± 4 kg/m2, logEPA, and logDHA showed significant association with logresistin and a marginal association with PAI-1. Adipocyte number, area, and lognumber of macrophages per adipocyte significantly correlated with PAI-1 but not with logresistin. Although logEPA and logDHA were independently associated with loginsulin, loginsulin resistance, and C-Peptide, the addition of logresistin, but not of PAI-1, into the multivariable model, abolished the associations. Conclusions EPA and DHA could modulate glucose metabolism across AT functional states. Our data indicate that this association is independent of other metabolic risk factors.

Establishment and operation of glucose clamp technique in mice.

Glucose metabolism plays a central role in energy supply and metabolism regulation in various tissues and organs. Besides, insulin is the sole hormone lowering blood glucose in the body, and islet function and insulin sensitivity are the key steps modulating glucose metabolism. Since the development of glucose clamp technology, it has been recognized as the gold standard for evaluating insulin metabolism. The main categories include hyperinsulinemia-euglycemia clamp, hyperglycemia clamp, and hyperinsulinemia-hypoglycemia clamp. These can be done on either anesthetized mice or conscious and unrestricted mice. This protocol focuses on the establishment and operation of the mouse glucose clamp technique, including preparation of instrument consumables, surgical operations, clamping procedures, and precautions, serving as reference and guidance.

Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity

SummaryIntracellular and environmental cues result in heterogeneous cancer cell populations with different metabolic and migratory behaviors. Although glucose metabolism and epithelial-to-mesenchymal transition have previously been linked, we aim to understand how this relationship fuels cancer cell migration. We show that while glycolysis drives single-cell migration in confining microtracks, fast and slow cells display different migratory sensitivities to glycolysis and oxidative phosphorylation inhibition. Phenotypic sorting of highly and weakly migratory subpopulations (MDA+, MDA−) reveals that more mesenchymal, highly migratory MDA+ preferentially use glycolysis while more epithelial, weakly migratory MDA− utilize mitochondrial respiration. These phenotypes are plastic and MDA+ can be made less glycolytic, mesenchymal, and migratory and MDA− can be made more glycolytic, mesenchymal, and migratory via modulation of glucose metabolism or EMT. These findings reveal an intrinsic link between EMT and glucose metabolism that controls migration. Identifying mechanisms fueling phenotypic heterogeneity is essential to develop targeted metastatic therapeutics.

Mutant p53K120R expression enables a partial capacity to modulate metabolism.

The TP53 tumor suppressor gene is one of the most studied gene in virtue of its ability to prevent cancer development by regulating apoptosis, cell cycle arrest, DNA repair, autophagy and senescence. Furthermore, the modulation of metabolism by P53 is fundamental for tumor suppressor activity. Studies in mouse models showed that mice carrying TP53 mutations affecting the acetylation in the DNA binding domain still retain the ability to transactivate genes involved in metabolism. Noteworthy, mice expressing the triple 3KR or the single K117R mutant do not show early on-set tumor development in contrast to TP53 −/− mice. Interestingly, the mouse K117R mutation corresponds to the human tumor-derived K120R modification, which abrogates P53-dependent activation of apoptosis without affecting growth arrest. In this study, we investigated the property of the human P53 K120R mutant in the regulation of metabolism by analyzing the transcriptional specificity in yeast- and mammalian-based reporter assays, the metabolic phenotype associated to its expression in colon cancer HCT116 TP53−/− cells and the induction of P53 targets and proteins involved in the antioxidant response. These properties were analyzed in comparison to wild type P53 protein, the human triple mutant corresponding to mouse 3KR and the cancer hot-spot R273H mutant. We confirm the selective functionality of P53 K120R mutant, which shows a transcriptional activity on cell cycle arrest but not on apoptotic targets. Interestingly, this mutant shows a partial transactivation activity on p53 response element belonging to the metabolic target TIGAR. Moreover, we observe a significant uncoupling between oxygen consumption and ATP production associated with higher lipid peroxidation level in all P53 mutants carrying cells with respect to wild type P53 expressing cells. Noteworthy, in the absence of a pro-oxidative challenge, cells expressing K120R mutant retain a partial capacity to modulate glucose metabolism, limiting lipid peroxidation with respect to the other P53 mutants carrying cells. Lastly, especially in presence of human 3KR mutant, a high expression of proteins involved in the antioxidant response is found. However, this response does not avoid the increased lipid peroxidation, confirming that only wild type P53 is able to completely counteract the oxidative stress and relative damages.

Chemical Modulation of Glucose Metabolism with a Fluorinated CaCO3 Nanoregulator Can Potentiate Radiotherapy by Programming Antitumor Immunity.

Tumor hypoxia and acidity are well-known features in solid tumors that cause immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional fluorinated calcium carbonate (fCaCO3) nanoregulator by coating CaCO3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA2-PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO3-PEG showed high loading efficacy to perfluoro-15-crown-5-ether (PFCE), a type of perfluorocarbon with high oxygen solubility, thereby working as both oxygen nanoshuttles and proton sponges to reverse tumor hypoxia and acidity-induced resistance to radiotherapy. The as-prepared PFCE@fCaCO3-PEG could not only function as long-circulating oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment by restricting the production of lactic acid and reacting with extracellular protons. As a result, treatment with PFCE@fCaCO3-PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO3-PEG-assisted radiotherapy could also collectively inhibit the growth of unirradiated tumors and reject rechallenged tumors by synergistically eliciting protective antitumor immunity. Therefore, our work presents the preparation of fluorinated CaCO3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.

Lupinus albus γ-Conglutin: New Findings about Its Action at the Intestinal Barrier and a Critical Analysis of the State of the Art on Its Postprandial Glycaemic Regulating Activity

γ-Conglutin (γ-C) is the glycoprotein from the edible seed L. albus, studied for long time for its postprandial glycaemic regulating action. It still lacks clear information on what could happen at the meeting point between the protein and the organism: the intestinal barrier. We compared an in vitro system involving Caco-2 and IPEC-J2 cells with an ex vivo system using pig ileum and jejunum segments to study γ-C transport from the apical to the basolateral compartment, and its effects on the D-glucose uptake and glucose transporters protein expression. Finally, we studied its potential in modulating glucose metabolism by assessing the possible inhibition of α-amylase and α-glucosidase. RP-HPLC analyses showed that γ-C may be transported to the basolateral side in the in vitro system but not in the pig intestines. γ-C was also able to promote a decrease in glucose uptake in both cells and jejunum independently from the expression of the SGLT1 and GLUT2 transporters.

The Mineralocorticoid Receptor Functions as a Key Glucose Regulator in the Skeletal Muscle of Zebrafish

Glucocorticoids (GCs) are essential for maintaining energy homeostasis as part of the adaptive stress response. Most work to date has characterized the metabolic role of GCs via the activation of the glucocorticoid receptor (nr3c1; GR), which is activated under high GC conditions. However, GCs also bind to the mineralocorticoid receptor (nr3c2; MR), a high-affinity corticosteroid receptor active under basal GC conditions. Despite the expression of MR in skeletal muscles, almost nothing is known about its physiological role. Here we tested the hypothesis that the MR promotes anabolic processes during resting cortisol levels and curtails the catabolic actions of the GR during high (stressed) levels of cortisol. To determine the effect of MR, a zebrafish line with a ubiquitous MR knockout (MRca402/ca402) was utilized. The GR was activated in the same group by chronically treating fish with exogenous cortisol. In the muscle, MR primarily promoted nutrient storage, and restricted energy substrate mobilization under resting conditions, whereas GR activation resulted in increased nutrient utilization. Interestingly, MR loss improved GR-driven metabolic flexibility, suggesting that the activation state of these receptors is a key determinant of skeletal muscle ability to switch fuel sources. To determine if the anabolism-promoting nature of MR was due to an interaction with insulin, fish were co-injected with insulin and the fluorescent glucose analogue 2-NBDG. A loss of MR abolished insulin-stimulated glucose uptake in the skeletal muscle. Taken together, we postulate that MR acts as a key modulator of glucose metabolism in the musculature during basal and stress conditions.

Growth Hormone and Counterregulation in the Pathogenesis of Diabetes.

Canonical growth hormone (GH)-dependent signaling is essential for growth and counterregulatory responses to hypoglycemia, but also may contribute to glucose homeostasis (even in the absence of hypoglycemia) via its impact on metabolism of carbohydrates, lipids and proteins, body composition, and cardiovascular risk profile. The aim of this review is to summarize recent data implicating GH action in metabolic control, including both IGF-1-dependent and -independent pathways, and its potential role as target for T2D therapy. Experimental blockade of the GHR can modulate glucose metabolism. Moreover, the soluble form of the GH receptor (GHR, or GHBP) was recently identified as a mediator of improvement in glycemic control in patients with T2D randomized to bariatric surgery vs. medical therapy. Reductions in GHR were accompanied by increases in plasma GH, but unchanged levels of both total and free IGF-1. Likewise, hepatic GHR expression is reduced following both RYGB and VSG in rodents. Emerging data indicate that GH signaling is important for regulation of long-term glucose metabolism in T2D. Future studies will be required to dissect tissue-specific GH signaling and sensitivity and their contributions to systemic glucose metabolism.

Long noncoding RNA CERS6-AS1 modulates glucose metabolism and tumor progression in hepatocellular carcinoma by promoting the MDM2/p53 signaling pathway

Hepatocellular carcinoma (HCC) is one of the most serious malignant cancers and has a high fatality rate. However, clinical strategies for the effective treatment of HCC remain lacking. Long non-coding RNAs (lncRNAs) with aberrant expression have been closely correlated with the occurrence and development of HCC. Here we investigated the underlying mechanism of the lncRNA CERS6-AS1 in HCC progression. The expression and prognosis of CERS6-AS1 in HCC patients was explored using The Cancer Genome Atlas. PCR analysis was utilized to measure the expression of CERS6-AS1 in tissues and cell lines. Transwell, wound healing, proliferation and glycolysis assays were conducted to evaluate the function of CERS6-AS1 on HCC cell functions. Bioinformation methods and luciferase assays were used to screen and verify potential target miRNAs and genes. A subcutaneous tumorigenesis model was constructed in nude mice to assess the effect of CERS6-AS1 on tumorigenesis in vivo. CERS6-AS1 was highly expressed in HCC tissues and cell lines. Upregulated CERS6-AS1 expression was remarkably correlated with poor prognosis of HCC patients. High CERS6-AS1 expression facilitated cell growth, invasion and glycolysis of HCC cells. Bioinformatics analyses combining with PCR analysis identified miR-30b-3p as the potential target of CERS6-AS1, and MDM2 mRNA was verified as the target of miR-30b-3p. The expression of miR-30b-3p was negatively correlated with CERS6-AS1, whereas MDM2 was positively associated with CERS6-AS1. Mechanistic studies showed that CERS6-AS1 may sponge miR-30b-3p to elevate MDM2, thus promoting the MDM2-mediated ubiquitin-dependent degradation of the p53 tumor suppressor. MDM2 overexpression or miR-30b-3p inhibitors blocked the inhibitory effect of CERS6-AS1 knockdown on proliferation, migration and glycolysis. CERS6-AS1 depletion reduced tumor formation in the in vivo mouse model. The CERS6-AS1/miR-30b-3p/MDM2/p53 signaling axis may play key roles in regulating HCC progression. CERS6-AS1 may exert as a novel biomarker or therapeutic target for HCC.

LncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance inSCLC:Potentialmolecular panel for targeted therapy

lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance inSCLC:Potentialmolecular panel for targeted therapy

Abstract 1547: LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer

Abstract Colorectal cancer (CRC) is the primary cause of cancer-related deaths worldwide. According to the American Cancer Society, it is the third most common cancer diagnosed in adults in the United States. It will have an estimated 149,500 new cases of colon cancer in 2021. In addition, studies show CRC has increased morbidity with obesity and obesity-related diseases such as diabetes. In a geographical area of The Rio Grande Valley which has a high incidence of diabetes, understanding the connection between CRC and diabetes is essential. Our lab identified LncRNA UCA1, a poor prognosis marker in CRC, responsible for increased proliferation and upregulating glucose metabolic pathway. First, we investigated the possible role of UCA1 in glucose metabolism, finding that UCA1 overexpressing cells (SW480+UCA1) showed a higher glucose consumption than their vector. The inverse of this trend was established when we knockdown UCA1 (SW620+shUCA1). Further, we found that overexpressing UCA1 increases the migration, invasion, and proliferation of SW480 cells. A vital aspect of the metastatic progression is when the cell survives detachment from the extracellular matrix. A route in which they overcome apoptosis is through modulation of the metabolic pathways, upregulating such markers as GLUT1, FDFT1, SGK1, and HIF1α. At 36hrs of anchorage-independent stimulation, we found an uptick in glucose consumption and lactate production and an increase in the expression of GLUT1, FDFT1, SGK1, and HIF1α compared to 0hrs. The Warburg effect is when glycolysis is no longer connected to the tricarboxylic acid cycle or oxidative phosphorylation. The increase in expression of the markers GLUT1, FDFT1, SGK1, and HIF1α indicates aerobic metabolic activity during anchorage-independent growth with UCA1 expression. This relationship needs to be further examined and could lead to understanding the increased morbidity associated with diabetes and CRC. Citation Format: Sophia Leslie, Kyle Doxtater, Samantha Lopez, Adithya Anilkumar, Meena Jaggi, Subhash Chauhan, Manish Tripathi. LncRNA UCA1 modulates glucose metabolism proteins in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1547.

Exposure to per- and polyfluoroalkyl substances as a risk factor for gestational diabetes mellitus through interference with glucose homeostasis

Per- and polyfluoroalkyl substances (PFASs) are hypothesized to trigger gestational diabetes mellitus (GDM) through modulation of glucose metabolism. However, studies investigating links between joint PFASs to GDM are limited and led to discrepant conclusions. This study included 171 women with GDM development in pregnancy and 169 healthy controls from Hangzhou, China between October 2020 and September 2021. By using the solid-phase extraction (SPE)-ultra performance liquid chromatography-tandem-mass-spectrometry (UPLC/MS-MS), 15 PFASs were detected to be widely distributed in maternal serum, with highest median concentrations of 7.43, 4.23, and 3.64 ng/mL for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and 6:2 chlorinated polyfluorinated ether sulfonates (6:2 Cl-PFESA). Multivariable logistic regressions suggested that the adjusted odds ratios (ORs) with 95% confidence intervals (CI) of GDM for second and highest tertiles of PFOA were 2.57 (1.24, 4.86), p = 0.001 and 1.98 (1.06, 3.65), p = 0.023. Compared with the reference tertile, the ORs of GDM were also significantly increased at the highest tertile of perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoA), PFOS and 6:2Cl-PFESA. Multiple linear regressions further indicated that exposure to these PFASs congeners were positively associated with continuous glycemic outcomes of fasting blood glucose (FBG), 1-h, and 2-h glucose after 75 g oral glucose tolerance (OGTT) test as well as glycohemoglobin (HbA1c). Nevertheless, perfluorohexane sulfonic acid (PFHxS), 4:2 fluorotelomer sulfonates (FTSs), and 3H-perfluoro-3-[(3-methoxy-propoxy) propanoic acid] (ADONA) exhibited protective effects on some of these glycemic outcomes. When assessing the PFASs as mixtures by conducting the Bayesian kernel machine regression (BKMR), the risks of GDM and values of glycemic outcomes increased significantly as the concentrations of the PFASs mixture increased, with PFOA being the largest contributor. We therefore propose that although the effects on glucose homeostasis varied between different PFAS congeners, the elevated combined exposures to PFASs may be associated with substantially increased GDM risks by altering glucose metabolism.

Bioactive spermidine nanoparticles for effective cardiovascular recovery and diabetic therapy

Cardiovascular complications account for more than 80% of type II diabetes (T2D)-related mortality every year. Although glucagon-like peptide 1 receptor agonists (GLP-1RA) can effectively maintain the glycemic level, their efficacy and related cardiovascular benefits are significantly limited owing to their short half-life. Hence, in this study, on the basis of calorie restriction theory, spermidine containing bioactive polymers have been developed to deliver liraglutide with sustained release kinetics. Calorie restrictive and cardiovascular beneficial spermidine (SPM) was conjugated to oxidized dextran to synthesize bioactive SPM-DEX polymer and the SPM-DEX/Liraglutide nanoparticles were successfully prepared using the flash nanocomplexation (FNC) technique via electrostatic polyelectrolyte complexation. Single administration of these sub-100 nm liraglutide nanoparticles efficiently prolonged the hypoglycemic efficacy of liraglutide for more than 4 days. Moreover, through modulating glucose metabolism dysfunction and excessive lipid metabolism, these long-acting liraglutide and SPM containing nanoparticles efficiently maintained a stable blood glucose level (BGL) and body weight in 30 days as biochemical indices, such as HbA1c and triglycerides, were all reduced to the normal range. In addition, by downregulating the Wnt/β-catenin signaling pathway, SPM containing nanoparticles effectively postponed the progression of myocardial fibrosis and systemically improved the systolic function of the cardiac left ventricle. We believe this highly biocompatible, bioactive and calorie restrictive spermidine-containing liraglutide nanoparticles with long-term hypoglycemic efficacy and cardiovascular benefits may hold great clinical potentials.

Ganoderma lucidum Modulates Glucose, Lipid Peroxidation and Hepatic Metabolism in Streptozotocin-Induced Diabetic Pregnant Rats.

The consumption of functional foods, such as mushrooms, apparently influences Gestational Diabetes Mellitus (GDM), and brings benefits to maternal-fetal health. Ganoderma lucidum contains a variety of bioactive compounds, such as polysaccharides, proteins and polyphenols that are able to control blood glucose and be used in anti-cancer therapy. We aimed to evaluate the effects of the consumption of Ganoderma lucidum (Gl) on maternal-fetal outcomes in streptozotocin-induced GDM (GDM-STZ). Pregnant rats were exposed to Gl (100 mg/kg/day) before and after the induction of GDM-STZ (single dose 40 mg/kg) on the eighth pregnancy day. Biochemical and oxidative stress parameters, reproductive performance and morphometry of fetuses were assessed. Gl reduced the glycemic response in the oral glucose tolerance test. Moreover, Gl decreased AST and ALT activities. GDM increased lipid peroxidation, which was reverted by Gl. Catalase and glutathione peroxidase activities were decreased in GDM and the administered Gl after the fetus implantation increased catalase activity. Measurements of the fetal head, thorax, craniocaudal and tail showed greater values in fetuses from rats exposed to Gl compared to GDM. Ganoderma lucidum has an encouraging nutritional and medicinal potential against GDM, since it modifies glucose metabolism, reduces lipid peroxidation, and has protective effects in fetuses born from GDM dams.

Cortisol modulates glucose metabolism and oxidative response after acute high temperature stress in Pacific oyster Crassostrea gigas

Cortisol is the main stress hormone that plays crucial roles in energy metabolism and immune response in vertebrates. In the present study, the homologues of 11β-hydroxysteroid dehydrogenase type 1 (designated Cg11β-HSD1) and 5α-reductase 1 (designated Cg5αR1), the key enzymes related to cortisol metabolism, were identified from Pacific oyster Crassostrea gigas. The Cg11β-HSD1 harbored a conserved SDR domain, and Cg5αR1 contained a Steroid_dh domain and three transmembrane domains. The mRNA transcripts of Cg11β-HSD1 and Cg5αR1 were constitutively expressed in all the examined tissues of oysters, with the highest expression level in haemocytes and labial palp, respectively. After acute high temperature stress (28 °C), the mRNA expression level of Cg11β-HSD1 in hepatopancreas significantly up-regulated at 6 h and 12 h, and that of Cg5αR1 significantly up-regulated at 6 h, compared with the Blank group (11 °C). The concentration of cortisol and glucose, as well as the activities of superoxide dismutase (SOD) and catalase (CAT) in hepatopancreas all significantly up-regulated after acute high temperature stress, while the glycogen concentration in adductor muscle decreased significantly at 6 h and 12 h. After the blockage of Cg11β-HSD1 with metyrapone, the cortisol concentration and the activities of SOD and CAT significantly decreased after acute high temperature stress, the glucose concentration in hepatopancreas significantly increased at 24 h, and the glycogen concentration in adductor muscle significantly increased at 6 h. These results collectively suggested that cortisol played a crucial role in regulating glucose metabolism and oxidative response in oysters upon acute high temperature stress.

Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies.

Diabetic retinopathy (DR) is undoubtedly one of the most prominent causes of blindness worldwide. This pathology is the most frequent microvascular complication arising from diabetes, and its incidence is increasing at a constant pace. To date, the insurgence of DR is thought to be the consequence of the intricate complex of relations connecting inflammation, the generation of free oxygen species, and the consequent oxidative stress determined by protracted hyperglycemia. The sirtuin (SIRT) family comprises 7 histone and non-histone protein deacetylases and mono (ADP-ribosyl) transferases regulating different processes, including metabolism, senescence, DNA maintenance, and cell cycle regulation. These enzymes are involved in the development of various diseases such as neurodegeneration, cardiovascular pathologies, metabolic disorders, and cancer. SIRT1, 3, 5, and 6 are key enzymes in DR since they modulate glucose metabolism, insulin sensitivity, and inflammation. Currently, indirect and direct activators of SIRTs (such as antagomir, glycyrrhizin, and resveratrol) are being developed to modulate the inflammation response arising during DR. In this review, we aim to illustrate the most important inflammatory and metabolic pathways connecting SIRT activity to DR, and to describe the most relevant SIRT activators that might be proposed as new therapeutics to treat DR.