Similar Metabolic Effects Research Articles

Sex Differences in the Energy System Contribution during Sprint Exercise in Speed-Power and Endurance Athletes.

Background/Objectives: A high level of specific metabolic capacity is essential for maximal sprinting in both male and female athletes. Various factors dictate sex differences in maximal power production and energy utilization. This study aims to compare the contribution of energy systems between male and female athletes with similar sport-specific physiological adaptations during a 15-s sprint exercise. Methods: The endurance group consisted of 17 males (23 ± 7 y) and 17 females (20 ± 2 y). The speed-power group included 14 males (21.1 ± 2.6 y) and 14 females (20 ± 3 y). The contribution of phosphagen, glycolytic, and aerobic systems was determined using the three-component PCr-LA-O2 method. Results: Significant differences were observed in the energy expenditure for all systems and total energy expenditure between males and females in both groups (p = 0.001-0.013). The energy expenditure in kJ for individual systems (phosphagen-glycolytic-aerobic) was 35:25:7 vs. 20:16:5 in endurance males vs. female athletes, respectively. In the speed-power group, male athletes expended 33:37:6 kJ and female athletes expended 21:25:4 kJ, respectively. The percentage proportions did not differ between males and females in any system. The contribution of the phosphagen-glycolytic-aerobic systems was 52:37:11 vs. 48:39:13 in endurance male and female athletes, respectively. For speed-power males vs. female athletes, the proportions were 42:50:8 vs. 41:50:9, respectively. Conclusions: Despite the differences in body composition, mechanical output, and absolute energy expenditure, the energy system contribution appears to have a similar metabolic effect between male and female athletes engaged in sprint exercises with similar sport-related adaptations. The magnitude and profile of sex differences are related to sports discipline.

Research Progress on the Efficacy and Safety of Different Basal Insulins in the Treatment of Type 2 Diabetes Mellitus

Objective: To evaluate the efficacy and safety of different basal insulins in the treatment of type 2 diabetes mellitus (T2DM). Methods: The current research progress on different basal insulins was evaluated, with efficacy indicators including fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), and safety indicators focusing mainly on weight change and the incidence of hypoglycemia. Results: Several different basal insulins showed similar metabolic control effects in terms of fasting plasma glucose and glycated hemoglobin. However, the risk of hypoglycemia was lower with insulin glargine 300 (Glar-300), insulin degludec 100 (Deg-100), and insulin degludec 200 (Deg-200) compared to insulin glargine 100 (Glar-100). Additionally, Glar-300 had the least impact on weight. Conclusion: For the treatment of T2DM, different basal insulins have similar therapeutic effects, but there are differences in the incidence of hypoglycemic events and their impact on weight. Rational insulin selection and dosage adjustments should be made based on the different patient groups.

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice.

The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in male and female transgenic GluCreERT2/Rosa26-eYFP mice. Mice received five daily doses of STZ (50 mg/kg, i.p.) or 10 daily doses of HC (70 mg/kg, i.p.), with parameters assessed on day 11. STZ-induced hyperglycaemia was evident in both sexes, alongside impaired glucose tolerance and reduced insulin concentrations. HC also had similar metabolic effects in male and female mice resulting in classical increases of circulating insulin indicative of insulin resistance. Control male mice had larger pancreatic islets than females and displayed a greater reduction of islet and beta-cell area in response to STZ insult. In addition, female STZ mice had lower levels of beta-cell apoptosis than male counterparts. Following HC administration, female mouse islets contained a greater proportion of alpha cells when compared to males. All HC mice presented with relatively comparable increases in beta- and alpha-cell turnover rates, with female mice being slightly more susceptible to HC-induced beta-cell apoptosis. Interestingly, healthy control female mice had inherently increased alpha-to-beta-cell transdifferentiation rates, which was decreased by HC treatment. The number of glucagon-positive alpha cells altering their lineage to insulin-positive beta cells was increased in male, but not female, STZ mice. Taken together, although there was no obvious sex-specific alteration of metabolic profile in STZ or HC mice, subtle differences in pancreatic islet morphology emphasises the impact of sex hormones on islets and importance of taking care when interpreting observations between males and females.

Beta-blockers used in cardiac failure and blood glucose level impairment - a literature review

Introduction: Blood sugar level impairment, especially diabetes mellitus (DM) is a significant problem. DM leads to many serious complications. Patients suffering from cardiac failure (HF) and diabetes have a risk of hospitalization increased 1.5 times compared to the control group without DM. That is why it is very important to keep appropriate glycemic control. β-blockers, are considered to cause a blood glucose level impairment. The relationship between the use of β-blockers and the development of DM is one of the most interesting and controversial issues in diabetology. Despite many benefits, some doctors are reluctant to prescribe β-blockers because of perceived negative metabolic effects.Aim of study: The purpose of the study was to review the literature describing oral β-blockers, used in HF, influence on glucose metabolism and to discover the best β-blocker treatment for cardiac failured diabetics and prediabetics.
 Methods: A systemic review was conducted using PubMed, ScienceDirect, Google Scholar databases. The search strategy was based on the following terms: beta-blocker, blood glucose level, metoprolol, nebivolol, carvedilol, bisoprolol.
 Results: β-blockers differ in terms of their mechanism of action and their effects on glucose metabolism. Metoprolol is associated with a worsening of glucose and lipid control. Bisoprolol have a neutral impact on glucose metabolism. Vasodilating β-blockers may improve glycemic profile.Conclusions: All four β-blockers used in HF have similar blood pressure lowering effect but different metabolic effect. Metoprolol should not be used as a drug of choice in patients with impaired glucose metabolism. Bisoprolol, nebivolol or carvedilol may be recommended as a drug of choice in patients with cardiac failure and impaired carbohydrate metabolism. The choice between bisoprolol and vasodilating β-blockers in patients with glycemic disorders is still an unresolved issue.

Oral and Vaginal Hormonal Contraceptives Induce Similar Unfavorable Metabolic Effects in Women with PCOS: A Randomized Controlled Trial.

This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased (p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min (p = 0.011) and AUCglucose (p = 0.018) increased in the CVC group. Fasting insulin levels (p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride (p < 0.001) and hs-CRP (p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS.

The role of daylight exposure on body mass in male mice

Physiology and behavior are synchronized to the external environment by endogenous circadian rhythms that are set to precisely 24 h by exposure to bright light early in the day. Exposure to artificial light outside of the typical solar day, such as during the night, may impair aspects of physiology and behavior in human and non-human animals. Both the intensity and the wavelength of light are important in mediating these effects. The present report is the result of an unplanned change in our vivarium lighting conditions, which led to the observation that dim light during the daytime affects body mass similarly to dim nighttime light exposure in male Swiss Webster mice. Mice exposed to bright days (≥125 lux) with dark nights (0 lux) gained significantly less weight than those exposed to bright days with dim light at night (5 lux) or dim days (≤60 lux) with either dark nights or dim light at night. Notably, among the mice exposed to dim daytime light, no weight gain differences were observed between dark nights and dim light at night exposure; however dim light at night exposure shifted food intake to the inactive phase as previously reported. The mechanisms mediating these effects remain unspecified, but it appears that dimly illuminated days may have similar adverse metabolic effects as exposure to artificial light at night.

Gut immune cells-A novel therapeutical target for cardiovascular disease?

Despite scientific and clinical advances during the last 50 years cardiovascular disease continues to be the main cause of death worldwide. Especially patients with diabetes display a massive increased cardiovascular risk compared to patients without diabetes. Over the last two decades we have learned that cardiometabolic and cardiovascular diseases are driven by inflammation. Despite the fact that the gastrointestinal tract is one of the largest leukocyte reservoirs of our bodies, the relevance of gut immune cells for cardiovascular disease is largely unknown. First experimental evidence suggests an important relevance of immune cells in the intestinal tract for the development of metabolic and cardiovascular disease in mice. Mice specifically lacking gut immune cells are protected against obesity, diabetes, hypertension and atherosclerosis. Importantly antibody mediated inhibition of leukocyte homing into the gut showed similar protective metabolic and cardiovascular effects. Targeting gut immune cells might open novel therapeutic approaches for the treatment of cardiometabolic and cardiovascular diseases.

The RALF1-FERONIA complex interacts with and activates TOR signaling in response to low nutrients

Target of rapamycin (TOR) kinase is an evolutionarily conserved major regulator of nutrient metabolism and organismal growth in eukaryotes. In plants, nutrients are remobilized and reallocated between shoots and roots under low-nutrient conditions, and nitrogen and nitrogen-related nutrients (e.g., amino acids) are key upstream signals leading to TOR activation in shoots under low-nutrient conditions. However, how these forms of nitrogen can be sensed to activate TOR in plants is still poorly understood. Here we report that the Arabidopsis receptor kinase FERONIA (FER) interacts with the TOR pathway to regulate nutrient (nitrogen and amino acid) signaling under low-nutrient conditions and exerts similar metabolic effects in response to nitrogen deficiency. We found that FER and its partner, RPM1-induced protein kinase (RIPK), interact with the TOR/RAPTOR complex to positively modulate TOR signaling activity. During this process, the receptor complex FER/RIPK phosphorylates the TOR complex component RAPTOR1B. The RALF1 peptide, a ligand of the FER/RIPK receptor complex, increases TOR activation in the young leaf by enhancing FER-TOR interactions, leading to promotion of true leaf growth in Arabidopsis under low-nutrient conditions. Furthermore, we showed that specific amino acids (e.g., Gln, Asp, and Gly) promote true leaf growth under nitrogen-deficient conditions via the FER-TOR axis. Collectively, our study reveals a mechanism by which the RALF1-FER pathway activates TOR in the plant adaptive response to low nutrients and suggests that plants prioritize nutritional stress response over RALF1-mediated inhibition of cell growth under low-nutrient conditions.

Intermittent methionine restriction reduces IGF-1 levels and produces similar healthspan benefits to continuous methionine restriction.

A sustained state of methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, continuously methionine‐restricted rodents have less age‐related pathology and are up to 45% longer‐lived than controls. Promisingly, MR is feasible for humans, and studies have suggested that methionine‐restricted individuals may receive similar benefits to rodents. However, long‐term adherence to a methionine‐restricted diet is likely to be challenging for many individuals. Prompted by this, and the fact that intermittent variants of other healthspan‐extending interventions (i.e., intermittent fasting and the cyclic ketogenic diet) are just as effective, if not more, than their continuous counterparts, we hypothesized that an intermittent form of MR might produce similar healthspan benefits to continuous MR. Accordingly, we developed two increasingly stringent forms of intermittent MR (IMR) and assessed whether mice maintained on these diets demonstrate the beneficial metabolic changes typically observed for continuous MR. To the best of our knowledge, we show for the first time that IMR produces similar beneficial metabolic effects to continuous MR, including improved glucose homeostasis and protection against diet‐induced obesity and hepatosteatosis. In addition, like continuous MR, IMR confers beneficial changes in the plasma levels of the hormones IGF‐1, FGF‐21, leptin, and adiponectin. Together, our findings demonstrate that the more practicable intermittent form of MR produces similar healthspan benefits to continuous MR, and thus may represent a more appealing alternative to the classical intervention.

Contrasting Metabolic Profiles of TGFβ2 and TNFα in the Induction of Retinal Epithelial‐Mesenchymal Transition (EMT)

Epithelial‐mesenchymal‐transition (EMT) is a process whereby epithelial cells transdifferentiate into matrix‐producing mesenchymal cells. EMT of retinal pigment epithelial cells (RPE) plays a crucial role in severe ocular pathologies including retinal fibrosis. Emerging evidence implicates metabolic and mitochondrial dysfunction as key drivers of EMT. Both transforming growth factor‐beta 2 (TGFβ2) and tumor necrosis factor‐alpha (TNFα) have the capacity to induce EMT in RPE; however, little is known about their impact on mitochondrial metabolism. We hypothesized that TGFβ2 and TNFα should share similar metabolic effects, i.e. repressed mitochondrial function and enhanced glycolysis, to support EMT of RPE. Matured human primary RPE (H‐RPE) were treated with TGFβ2 or TNFα (both at 10 ng/ml) for up to 5 days for Seahorse metabolic assays (Mito and Glycolytic Stress Tests), qPCR and untargeted metabolomics analysis (West Coast Metabolomics Center) analyzed using MetaboAnalyst. Both TGFβ2 and TNFα induced the upregulation of mesenchymal genes (fibronectin and matrix metalloproteinase‐2) in H‐RPE. While TNFα significantly upregulated inflammatory genes (IL‐6, IL‐8, IL‐1β, MCP‐1), no changes were evident in TGFβ2‐treated cells. Metabolically, TGFβ2 induced the “Warburg effect” in H‐RPE with enhanced glycolysis and a suppression of oxidative phosphorylation capacity. Surprisingly, TNFα showed the opposite effect with enhanced oxidative phosphorylation (higher basal levels of oxygen consumption and maximal respiration) and reduced glycolysis and glycolytic capacity. Metabolomics profiling showed distinct metabolomics signatures associated with TGFβ2‐ and TNFα‐treated primary RPE cells. Of the 188 metabolites tested, 7 metabolites were significantly changed in TGFβ2‐treated cells and 26 in TNFα‐treated cells. Enrichment analysis depicted altered glutathione metabolism, proline metabolism, aminoacyl‐tRNA synthesis, nicotinamide metabolism, pentose phosphate pathway and arachidonic acid metabolism in TNFα‐treated cells whereas TGFβ2‐treated cells showed perturbations in the biosynthesis of fatty acids, tryptophan metabolism, linoleic acid metabolism and arachidonic acid metabolism. The divergent bioenergetic rewiring governing TGFβ2 and TNFα in their induction of EMT may be linked to their differential effect on inflammation. Elucidating the contributions of TGFβ2 and TNFα and their mechanistic differences will enable the development of more effective drug targets for combating retinal fibrosis.

Hinokitiol Dysregulates Metabolism of Carcinoma Cell Lines and Induces Downregulation of HPV16E6 and E7 Oncogenes and p21 Upregulation in HPV Positive Cell Lines

Background: Hinokitiol (β-thujaplicin), isolated from the wood of Chamaecyparis taiwanensis, has a wide variety of biological properties including anti-inflammatory, anti-microbial, and anti-tumor effects. Therefore, hinokitiol has become a frequent additive in oral and other healthcare products. Objectives: Our goal was to determine the anti-tumor activity of hinokitiol on human papillomavirus (HPV) positive (n = 3) and negative (n = 2) cell lines derived from cervical or head and neck squamous cell carcinoma (HNSCC) and keratinocyte cell lines (n = 3) transformed spontaneously or with HPV16E6 and E7 oncogenes. Methods: The cell-lines were exposed to hinokitiol at different concentrations (0–200 µM) for 24 h. Cell metabolism, proliferation, and the cell cycle distribution were assessed by MTT- and 3H-thymidine incorporation and flow cytometry. Expressions of p21 and on HPV16E6 and E7 oncogenes were assessed by qPCR. Results: In all carcinoma cell lines, hinokitiol treatment declined the metabolic activity irrespective of the HPV status. This decline was statistically significant, however, only in HPV-positive cell lines CaSki and UD-SCC-2 when exposed to hinokitiol concentrations at 100 and 200 µM, respectively (p &lt; 0.05). Immortalized cell lines, HMK and HPV-positive IHGK, were more sensitive as a similar metabolic effect was achieved at lower hinokitiol concentrations of 3.1, 6.25, and 50 µM, respectively. Hinokitiol blocked DNA synthesis of all carcinoma cell lines without evident association with HPV status. G1 cell cycle arrest and p21 upregulation was found in all cell lines after hinokitiol treatment at higher concentration. However, when the p21 results of all HPV-positive cells were pooled together, the increase in p21 expression was statistically significantly higher in HPV-positive than in HPV-negative cell lines (p = 0.03), but only at the highest hinokitiol concentration (200 µM). In HPV-positive cell lines hinokitiol declined the expression of HPV16E7 and E6 along the increase of p21 expression. The dose-dependent inverse correlation between p21 and E7 was statistically significant in SiHa cells (r = −0.975, p-value = 0.03) and borderline in UD-SCC-2 cells (r = −0.944, p-value = 0.06), in which p21 and E6 were also inversely correlated (r = −0.989). Conclusions: Our results indicate that hinokitiol might have potential in preventing the progress of immortalized cells toward malignancy and the growth of malignant lesions. Hinokitiol can also influence on the progression of HPV-associated lesions by downregulating the E6 and E7 expression.

Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.

It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.

Peculiarities of neuroendocrine and metabolic effects of sulfate-chloride sodium-magnesium mineral waters "Myroslava" and "Khrystyna" of Truskavets’ spa in healthy female rats

Background. Earlier we found that the newly created sulfate-chloride sodium-magnesium drinking mineral waters of Truskavets’ spa have similar neuroendocrine and metabolic effects on healthy old female rats significantly different from daily water. The aim of this study is to elucidate the effects of these mineral waters on the neuroendocrine status and metabolism of these animals. Materials and Methods. Experiment was performed on 50 healthy female Wistar rats. Animals of the first group remained intact, using tap water from drinking ad libitum. Rats of the control group for 6 days injected a tap water through the tube at a dose of 1,5 mL/100 g of body mass. The rats of the main groups received the water "Myroslava" and "Khrystyna". The day after the completion of the drinking course in all rats, at first, assessed the state of autonomous regulation by parameters of the HRV. The plasma levels of the hormones of adaptation were determined: corticosterone, triiodothyronine and testosterone (by the ELISA) as well as electrolytes: calcium, magnesium, phosphates, chloride, sodium and potassium; nitric metabolites: creatinine, urea, uric acid, medium molecular polypeptides, bilirubin; lipid peroxidation products and antioxidant enzymes, as well as cholesterol, amylase and glucose. Most of the listed parameters of metabolism were also determined in daily urine. In the adrenals the thickness of glomerular, fascicular, reticular and medullar zones was measured. Results. To identify exactly those parameters, the set of which all four groups of animals differ significantly from each other, the information field of the registered parameters was subjected to discriminant analysis. The program included in the model 8 endocrine and 16 metabolic parameters, information about which is condensed into three roots. The first root reflects directly the SOD and corticosterone and inversely the reticular zone as well as plasma uric acid and glucose. The second root contains information about Nap/Kp ratio, natrihistia, amylasemia, magnesiumuria as well as inversely about kaliemia. The third root reflects directly the triiodothyronine, parathyroid activity, plasma Ca, natriuria and chloriduria as well as urine malondyaldehide. Inversely displays the root information about the testosterone, Ku/Nau ratio, glomerular zone, plasma katalase and Na as well as uricosuria and amylasuria. In the information space of the three discriminant roots, all four groups are quite clearly distinguished. Classification accuracy is 94% (three errors). Conclusion. The newly created sulfate-chloride sodium-magnesium drinking mineral waters of Truskavets resort have specific endocrine and metabolic effects on healthy old female rats with weekly use. This provides a basis for preclinical studies.

Similar neuroendocrine and metabolic effects of sulfate-chloride sodium-magnesium mineral waters "Myroslava" and "Khrystyna" of Truskavets’ spa in healthy female rats

Background. In order to expand the hydro-mineral base of Truskavets’ spa by diluting brine (130 g/L), two new sulphate-chloride sodium-magnesium mineral waters "Myroslava" (5 g/L) and "Khrystyna" (10 g/L) were created. This report is the first in a series of experimental studies of their physiological activity in line with the concepts of neuroendocrine-immune complex and functional-metabolic continuum. Materials and Methods. Experiment was performed on 50 healthy female Wistar rats 220-300 g divided into 4 groups. Animals of the first group remained intact, using tap water from drinking ad libitum. Rats of the control group for 6 days administered a single tap water through the tube at a dose of 1,5 mL/100 g of body mass. The rats of the main groups received the water "Myroslava" and "Khrystyna". The day after the completion of the drinking course in all rats assessed the state of autonomous regulation by parameters of the HRV. The plasma levels of the hormones of adaptation were determined: corticosterone, triiodothyronine and testosterone (by the ELISA); as well as electrolytes, nitric metabolites, lipid peroxidation products and antioxidant enzymes as well as cholesterol, glucose, amylase and middle mass molecules. Most of the listed parameters of metabolism as well as 17-ketosteroids were determined in daily urine. In the adrenal glands the thickness of glomerular, fascicular, reticular and medullar zones was measured. Results. To identify exactly those parameters, the set of which three groups of animals differ significantly from each other, the information field of the registered parameters was subjected to discriminant analysis. The program included in the model 6 endocrine and 11 metabolic parameters, as well as glomerular filtration. Conclusion. The newly created sulfate-chloride sodium-magnesium drinking mineral waters of Truskavets’ spa have similar neuroendocrine and metabolic effects on healthy old female rats significantly different from daily water.

32-OR: Receptor-Mediated Gq Signaling in Adipocytes as a Critical Modulator of Systemic Glucose and Lipid Homeostasis

Objective: In obesity, decreased insulin action leads to the accelerated breakdown of triglycerides stored in adipocytes, causing peripheral insulin resistance, a hallmark of type 2 diabetes. In this study, we investigated whether selective activation of Gq signaling in adipocytes might cause similar metabolic effects as insulin. Methods: We generated a novel mutant mouse strain that expressed a CNO-sensitive, Gq-coupled designer G protein-coupled receptor (Gq DREADD = QGD) selectively in adipocytes (adipo-GqD mice). DREADDs are stimulated by an exogenous agent (e.g., CNO) that is otherwise pharmacologically inactive. We also made another mouse strain that selectively lacked Galpha-q and -11 in adipocytes (adipo-Gq/11 KO mice). Both mutant mouse strains underwent a series of metabolic tests. Results: CNO-mediated activation of adipocyte Gq signaling in the adipo-GqD mice significantly improved glucose homeostasis and suppressed lipolysis. In contrast, adipo-Gq/11 KO mice showed the opposite metabolic phenotypes, impaired glucose metabolism and enhanced lipolysis. Consistent with these findings, in vitro studies with cultured adipocytes demonstrated that activation of Gq signaling enhanced glucose uptake and inhibited lipolysis in an AMPK-dependent manner. To test the hypothesis that activation of adipocyte Gq signaling might counteract impaired insulin signaling in adipocytes, we generated adipo-GqD mice that carried only one copy of the insulin receptor (IR) gene in adipocytes (adipo-GqD-IR+/- mice). Interestingly, activation of adipocyte Gq signaling by CNO ameliorated the metabolic deficits displayed by adipo-GqD-IR+/- mice maintained on a high-fat diet. Conclusion: Our data indicate that adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis. This finding is likely to stimulate the development of novel drugs that can mimic the actions of insulin in the insulin-resistant state. Disclosure T. Kimura: None. S. Pydi: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.

Consistency evaluation of Chaihuang granules based on pharmacokinetics and metabolomics

Consistency evaluation of Traditional Chinese Medicinal preparations (TCMPs) with complex chemical composition is challenging. Chaihuang granules (CHG), as a well-known TCMP, consists of Chaihu (Bupleuri Radix) and Huangqin (Scutellariae Radix) extract. In this work, we used pharmacokinetics and metabolomics to evaluate consistency of CHG products from two different manufacturers. In the pharmacokinetic study, a liquid chromatography tandem mass spectrometry (LC–MS/MS) method was applied to determine the plasma concentration-time profiles of baicalin in rat plasma. Pharmacokinetic parameters, including the maximum concentration in blood (Cmax), area under the curve (AUC), the time to reach Cmax (Tmax), and half-life (T1/2), were calculated to assess the consistency preliminarily. And there was no significant difference in these pharmacokinetic parameters between the two CHG. In LC–MS-based metabolomics, the metabolic response profiles changes based on relative distance values (RDV) to different CHG products were compared. Meanwhile, the kinetic process of 31 differential endogenous metabolites that altered by CHG were determined. Metabolomics data showed the similar metabolic regulation effects to rats of the two formulations. Both pharmacokinetic and metabolomics results indicated there was no significant difference between CHG products. Furthermore, metabolic pathways significantly altered by CHG were elucidated, including phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, and sphingolipid metabolism. Pharmacokinetics combined with metabolomics could provide a comprehensive perspective for consistency evaluation of CHG.

Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes.

The aim of this study was to identify the molecular mechanism for hyperglycaemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes. Hyperglycaemia induces increased nuclear factor-κB (NF-κB) signalling, up-regulation of miR-27a-3p, down-regulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signalling, down-regulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-κB signalling, down-regulating miR-27a-3p, up-regulating NRF2 expression, reducing TGF-β signalling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin-induced diabetic mice, whereas insulin alone does not improve cardiac function. Our data indicate that disruption of hyperglycaemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signalling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT involved in metabolic memory.

Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis

ABSTRACT The gut bacterium Akkermansia muciniphila has been increasingly recognized for its therapeutic potential in treating metabolic disorders, including obesity, diabetes, and metabolicdysfunction-associated fatty liver disease (MAFLD). However, its underlying mechanism involved in its well-known metabolic actions needs further evaluation. The present study explored the therapeutic effect and mechanism of A. muciniphila in intervening MAFLD by using a high-fat and high-cholesterol (HFC) diet induced obese mice model. Mice treated with A. muciniphila efficiently reversed MAFLD in the liver, such as hepatic steatosis, inflammatory, and liver injury. These therapeutic effects persisted after long-term drug withdrawal and were slightly weakened in the antibiotics-treated obese mice. A. muciniphila treatment efficiently increased mitochondrial oxidation and bile acid metabolism in the gut-liver axis, ameliorated oxidative stress-induced cell apoptosis in gut, leading to the reshaping of the gut microbiota composition. These metabolic improvements occurred with increased L-aspartate levels in the liver that transported from the gut. The administration of L-aspartate in vitro or in mice displayed the similar beneficial metabolic effects mentioned above and efficiently ameliorated MAFLD. Together, these data indicate that the anti-MAFLD activity of A. muciniphila correlated with lipid oxidation and improved gut–liver interactions through regulating the metabolism of L-aspartate. A. muciniphila could be a potential agent for clinical intervention in MAFLD.

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.

Aims Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.Methods and results Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.Conclusions Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.

Fasting in diabetes treatment (FIT) trial: study protocol for a randomised, controlled, assessor-blinded intervention trial on the effects of intermittent use of a fasting-mimicking diet in patients with type 2 diabetes

BackgroundCaloric restriction is an effective way to treat Type 2 diabetes (T2D). However, chronic and severe restriction of food intake is difficult to sustain and is known to promote slower metabolism. Intermittent and frequent fasting can exert similar metabolic effects, but may be even more challenging for most patients. A fasting-mimicking diet (FMD) is low in calories, sugars and proteins, but includes relatively high levels of plant based complex carbohydrates and healthy fats. The metabolic effects of such a diet mimic the benefits of water-only fasting. The effects of a FMD applied periodically in T2D patients are still unknown. The Fasting In diabetes Treatment (FIT) trial was designed to determine the effect of intermittent use (5 consecutive days a month during a year) of a FMD in T2D patients on metabolic parameters and T2D medication use compared to usual care.MethodsOne hundred T2D patients from general practices in the Netherlands with a BMI ≥ 27 kg/m2, treated with lifestyle advice only or lifestyle advice plus metformin, will be randomised to receive the FMD plus usual care or usual care only. Primary outcomes are HbA1c and T2D medication dosage. Secondary outcomes are anthropometrics, blood pressure, plasma lipid profiles, quality of life, treatment satisfaction, metabolomics, microbiome composition, MRI data including cardiac function, fat distribution and ectopic fat storage, cost-effectiveness, and feasibility in clinical practice.DiscussionThis study will establish whether monthly 5-day cycles of a FMD during a year improve metabolic parameters and/or reduce the need for medication in T2D. Furthermore, additional health benefits and the feasibility in clinical practice will be measured and a cost-effectiveness evaluation will be performed.Trial registrationThe trial was registered on ClinicalTrials.gov. Identifier: NCT03811587. Registered 21th of January, 2019; retrospectively registered.