Increased Glucose Utilization Research Articles

Bioevaluation of glucose-modified liposomes as a potential drug delivery system for cancer treatment using 177-Lu radiotracking

Liposomes are promising drug's delivery systems due to decreased toxicity of the liposome-encapsulated drug, but wider clinical application requires their more efficient tumor targeting with uptake, controlled drug release and higher shelf life. The unique metabolic characteristics of cancer cells based on higher demand for energy and therefore increased glucose utilization were exploited in the design of glucose modified liposomes (GML) with the aim to provide increased tumor targeting via glucose transporters and increased ability of drug delivery into tumor cells. Tumor accumulating potential of GML and non-glucose liposomes (NGL) were investigated on CT26 and LS174T tumor-bearing mice by simple and reliable radiotracer method using 177Lu as radioactive marker. Both liposomes, GML and NGL were radiolabeled in high radiolabeling yield, showing high in vitro stability in biological media, as the main prerequisite for the biodistribution studies. Tumors displayed significantly better accumulation of 177Lu-GML with the maximum uptake 6 h post-injection (5.8 ± 0.2%/g in LS174T tumor and 5.1 ± 0.5%/g in CT26 tumor), compared to negligible uptake of 177Lu-NGL (0.6 ± 0.1%/g in LS174T tumor and 0.9 ± 0.2%/g in CT26 tumor). Results of comparative biodistribution studies of 177Lu-NGL and 177Lu-GML indicate that increased accumulation of GML is enabled by glucose transporters and subsequent endocytosis, resulting in their prolonged retention in tumor tissues (up to 72 h). Direct radiolabeling of liposomes with 177Lu may be used not only for biodistribution studies using radiotracking, but also for cancer treatment.

N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway.

Insulin resistance is one of important factors causing type2 diabetes; therefore, regulating insulin sensitivity is considered a beneficial therapeutic approach against type2 diabetes. The present study aimed to determine the effects of N1‑methylnicotinamide (MNAM) on insulin resistance(IR) in skeletal muscle from a mouse model of type2 diabetes mellitus(T2DM), and to investigate the regulatory mechanisms of the sirtuin1 (SIRT1)/peroxisome proliferator‑activated receptor γcoactivator‑1α (PGC‑1α) signaling pathway. C57BL/6 mice were fed a normal diet with or without 1%MNAM and ob/ob mice were also fed a normal diet with or without 0.3or 1%MNAM. Blood glucose, insulin levels, insulin resistance(IR), sensitivity indices and triglyceride(TG) content were detected using ELISAs. The expression of gluconeogenesis‑related, insulin signaling‑related and SIRT1/PGC‑1α pathway‑related proteins was analyzed using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. Invitro, C2C12 cells were used to establish an IR muscle cell model by 0.75mM palmitic acid (PA) treatment (PAgroup). The IRcell model was subsequently supplemented with 1mM MNAM (PMgroup) or 1mM MNAM+30µM SIRT1 inhibitor, EX527 (PMEgroup). After treatment the glucose levels and insulin signaling‑related proteins were detected by ELISAs and western blotting, respectively. Furthermore, the expression levels of SIRT1/PGC‑1α signaling pathway‑related mRNA and proteins under MNAM treatment were detected by RT‑qPCR and western blotting. MNAM reduced body weight gain in T2DM mice, decreased fasting blood glucose and fasting insulin levels, and inhibited IR. MNAM also regulated insulin signal transduction and promoted glucose utilization in skeletal muscle, and reduced lipid deposition. Thus, MNAM improved IR in the skeletal muscle of T2DM mice. Following application of a SIRT1 inhibitor, the effects of MNAM on the increased glucose utilization in insulin‑resistant myocytes and the insulin signaling pathway were suppressed. The mechanism of action was associated with activation of the SIRT1/PGC‑1α signaling pathway, which promoted the activation of the insulin receptor substrate IRS1/PI3K/AKT pathway.

Reduced fatty acid β-oxidation improves glucose catabolism and liver health in Nile tilapia (Oreochromis niloticus) juveniles fed a high-starch diet

Fish are poor users of dietary carbohydrates and often display prolonged hyperglycemia and fat deposition after feeding high digestible carbohydrate diets. Recently, fatty acid β-oxidation (FAO) inhibition has been reported to increase glucose oxidation in fish. Therefore, this study tested the assumption that the inhibition of FAO with mildronate (MD, a carnitine synthesis inhibitor) might also increase glucose utilization and alleviate adverse effects induced by high starch diet (HSD) in Nile tilapia, Oreochromis niloticus. Nile tilapia juveniles (6.13 ± 0.11 g) were cultured in nine 200-L tanks (30 fish per tank) and divided into three groups (three tanks per group). The fish were fed twice a day (9:00 and 18:30) at 4% body weight by using a normal starch diet (NSD, 30% corn starch), a HSD (45% corn starch), or a HSD supplemented with MD (25 g/kg of diet, HSD + MD) for eight weeks. These three feeds contained approximately 35.8% protein and 6.4% lipid. The fish each tank were weighed every two weeks, and the feeding amount was adjusted accordingly. After the feeding trial, the fish fed on HSD showed higher hepatosomatic index (HSI), visceral somatic index (VSI), serum triglyceride concentration and whole-body and tissue (liver and muscle) lipid contents than those fed on NSD. The fish fed on HSD also had higher relative area of vacuolation in the liver, hepatic malondialdehyde (MDA) content, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in the serum than those fed on NSD. Moreover, the fish fed on HSD increased serum glucose and insulin concentrations, and hepatic lactate, pyruvate and glycogen contents, but reduced whole-body protein content and dietary protein utilization than those fed on NSD, indicating that HSD induced fat deposition, liver damage, glucose intolerance and lowered protein-sparing effect. However, the fish fed on HSD + MD decreased hepatic carnitine content and FAO activity, attenuated the indexes related to fat deposition and liver damage, improved blood glucose clearance and whole-body protein deposition than those fed on HSD, suggesting that the adverse effects caused by HSD were reversed after FAO inhibition. Furthermore, the fish fed on HSD down-regulated the expression of genes associated with glucose uptake, glycolysis, FAO process, and lipolysis compared to those fed on HSD + MD and NSD, yet up-regulated lipogenic and proteolytic genes. These data suggested that inhibition of FAO improved glucose utilization and alleviated the HSD-induced adverse effects in Nile tilapia. This work demonstrates that, modifying mitochondrial FAO activity regulates the ability of fish to adapt to HSD intake through remodeling energy homeostasis. Our study provides new insights into improving carbohydrate utilization in aquatic animals.

Muscle-specific TGR5 overexpression improves glucose clearance in glucose-intolerant mice

TGR5, a G protein–coupled bile acid receptor, is expressed in various tissues and regulates several physiological processes. In the skeletal muscle, TGR5 activation is known to induce muscle hypertrophy; however, the effects on glucose and lipid metabolism are not well understood, despite the fact that the skeletal muscle plays a major role in energy metabolism. Here, we demonstrate that skeletal muscle–specific TGR5 transgenic (Tg) mice exhibit increased glucose utilization, without altering the expression of major genes related to glucose and lipid metabolism. Metabolite profiling analysis by capillary electrophoresis time-of-flight mass spectrometry showed that glycolytic flux was activated in the skeletal muscle of Tg mice, leading to an increase in glucose utilization. Upon long-term, high-fat diet challenge, blood glucose clearance was improved in Tg mice without an accompanying increase in insulin sensitivity in skeletal muscle and a reduction of body weight. Moreover, Tg mice showed improved age-associated glucose intolerance. These results strongly suggest that TGR5 ameliorated glucose metabolism disorder that is caused by diet-induced obesity and aging by enhancing the glucose metabolic capacity of the skeletal muscle. Our study demonstrates that TGR5 activation in the skeletal muscle is effective in improving glucose metabolism and may be beneficial in developing a novel strategy for the prevention or treatment of hyperglycemia.

Phytosteroid 28-homobrassinolide targets cholesterol and glucose homeostasis implicating ABCA1 and SREBP role in regulation

Oxysterols are natural ligands of certain nuclear receptors known as liver X receptors (LXR). LXRs are regulators of fatty acid, cholesterol, and glucose homeostasis. Dietary phyto-oxysterol 28-homobrassinolide (28-HB) has been demonstrated to transactivate rat LXR α and β. In this study we assessed the potential of 28-HB to effect such changes in – (1) human HepG2 cancer cell line, (2) isolated perfused goat liver, and (3) high-fat diet-fed C57BL/6J mice. Serum and perfusate marker levels along with hexokinase activity were determined through enzyme assays. Fat deposition was studied by Oil Red O staining, ATP-binding cassette transporter (ABCA1), and sterol regulatory element-binding transcription factor 2 (SREBP2) protein expression by Western blot and their mRNA expression through real-time PCR. In HepG2 cells, 28-HB (5–20 μM) treatment indicated a 2-fold increase in glucose utilization and ABCA1 and SREBP2 protein expression within 12 h. Tissue glucose and cholesterol levels decreased in 28-HB perfused goat liver within 2 h, whereas cholesterol level increased 54% in the perfusate (p < 0.05) and tissue hexokinase activity increased 23% (p < 0.05). Glucokinase, ABCA1, and SREBF1 gene expression increased 2.6, 5.37, and 2.85 fold respectively in the perfused tissue after 4 h. High-fat diet-fed C57BL/6J mice when treated with 28-HB (1–20 µg/day) for 6 weeks exhibited a marked decrease in aortic fat deposit and serum marker levels. Our study suggests that 28-HB modulates cholesterol and glucose homeostasis in animal cells through activation of LXR involving ABCA1 and SREBP-1 and 2 augmentations.

Molecular identification of FNDC5 and effect of irisin on the glucose metabolism in common carp (Cyprinus carpio L.)

Irisin, encoded by fibronectin type III domain-containing protein 5 (FNDC5) gene, plays a role in energy expenditure and insulin sensitivity in mice. In fish, the function of irisin related to glucose metabolism is less reported. It may increase glucose utilization in fish. The aim of the present study was to characterize the regulatory role of irisin in glucose metabolism in common carp (Cyprinus carpio L.). In this study, FNDC5a and FNDC5b were isolated from common carp. The cDNA of FNDC5a and FNDC5b were 722 bp and 714 bp, encoding 221 and 207 amino acids, respectively. FNDC5a was abundantly expressed in the brain and gonad. FNDC5b was mainly expressed in brain. Different expression pattern of FNDC5a and FNDC5b under fasting/refeeding and OGTT experiment were identified. The recombinant common carp irisinA and irisinB were prepared by prokaryotic expression system. Glucose concentration was decreased in treatment with irisinA or irisinB in the in vitro and in vivo experiments. The mRNA expression levels of gluconeogenesis-related genes were significantly down-regulated, while the mRNA expression of glycolysis-related genes were significantly up-regulated after treatment with recombinant irisinA or irisinB in liver in vivo and in primary hepatocytes in vitro. Our research shows that irisin inhibits hepatic gluconeogenesis and promotes hepatic glycolysis. Taken together, this study for the first time revealed the two subtypes of FNDC5 and explored the function and mechanisms of irisinA and irisinB in fish glucose homeostasis.

Lactate dehydrogenase inhibition affects homologous recombination repair independently of cell metabolic asset; implications for anticancer treatment

BackgroundCancer cells show highly increased glucose utilization which, among other cancer-essential functions, was found to facilitate DNA repair. Lactate dehydrogenase (LDH) activity is pivotal for supporting the high glycolytic flux of cancer cells; to our knowledge, a direct contribution of this enzyme in the control of DNA integrity was never investigated. In this paper, we looked into a possible LDH-mediated regulation of homologous recombination (HR) repair. MethodsWe identified two cancer cell lines with different assets in energy metabolism: either based on glycolytic ATP or on oxidative reactions. In cells with inhibited LDH, we assessed HR function by applying four different procedures. ResultsOur findings revealed an LDH-mediated control of HR, which was observed independently of cell metabolic asset. Since HR inhibition is known to make cancer cells responsive to PARP inhibitors, in both the cellular models we finally explored the effects of a combined inhibition of LDH and PARP. ConclusionsThe obtained results suggest for LDH a central role in cancer cell biology, not merely linked to the control of energy metabolism. The involvement of LDH in the DNA damage response could suggest new drug combinations to obtain improved antineoplastic effects. General significanceSeveral evidences have correlated the metabolic features of cancer cells with drug resistance and LDH inhibition has been repeatedly shown to increase the antineoplastic power of chemotherapeutics. By shedding light on the processes linking cell metabolism to the control of DNA integrity, our findings also give a mechanistic explanation to these data.

Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism.

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

Flavonoids as Potential Therapeutic Agents for the Management of Diabetic Neuropathy.

Flavonoids are secondary metabolites that are widely distributed in plants. These phenolic compounds are classified into various subgroups based on their structures: flavones, flavonols, isoflavones, flavanones, and anthocyanins. They are known to perform various pharmacological actions like antioxidant, anti-inflammatory, anticancer, antimicrobial, antidiabetic and antiallergic, etc. Diabetes is a chronic progressive metabolic disorder that affects several biochemical pathways and leads to secondary complications such as neuropathy, retinopathy, nephropathy, and cardiomyopathy. Among them, the management of diabetic neuropathy is one of the major challenges for physicians as well as the pharmaceutical industries. Naturally occurring flavonoids are extensively used for the treatment of diabetes and its related complications due to their antioxidant properties. Moreover, flavonoids inhibit various pathways that are involved in the progression of diabetic neuropathy like the reduction of oxidative stress, decrease in glycogenolysis, increase glucose utilization, decrease in the formation of advanced glycation end products, and inhibition of the α-glucosidase enzyme. This review entails current updates on the therapeutic perspectives of flavonoids in the treatment of neuropathic pain. This manuscript explains the pathological aspects of neuropathic pain, the chemistry of flavonoids, and their application in amelioration of neuropathic pain through preclinical studies either alone or in combination with other therapeutic agents.

Peroxisomal proliferator-activated receptor α-b deficiency induces the reprogramming of nutrient metabolism in zebrafish.

The pparab subtype in zebrafish is much more highly expressed in tissues with high oxidative activity than pparaa. The pparab deficiency in zebrafish reduces fatty acid β-oxidation both in liver and muscle, illustrating its functional homology as a mammalian peroxisome proliferator-activated receptor α (PPARα). pparab deficiency promotes metabolic reprogramming by increasing glucose utilization and inhibiting amino acid breakdown. The present study brings new insights into the comprehensive regulatory roles of PPARα in the cellular fuel selection and provides a valuable animal model for PPARα studies from a viewpoint of comparative physiology. Dysfunction of lipid metabolism is involved in the pathogenesis of several chronic metabolic diseases. Peroxisome proliferator-activated receptor α (PPARα) is essential for normal metabolic homeostasis and, in particular, for the regulation of fatty acid β-oxidation (FAO). However, little is known about its regulation roles in systemic nutrient metabolism. To explore the underlying modulation role of PPARα in metabolic homeostasis, we generated a pparab-knockout zebrafish (Danio rerio) model. The pparab mutants demonstrated lower expression of key enzymes involved in FAO, as well as lower mitochondrial and peroxisomal FAO in tissues, which was associated with lipid accumulation in liver and visceral mass. Conversely, glucose utilization was higher because they demonstrated lower blood glucose and tissue glycogen concentrations, as well as activation of the phosphoinositide 3-kinase/AKT pathway. In addition, pparab-deficient zebrafish demonstrated activation of AKT/mammalian target of rapamycin signalling and higher protein content, implying greater protein synthesis and/or lower amino acid breakdown. These data clearly revealed that pparab deletion reduces FAO but increases glucose utilization and protein deposition to maintain energy homeostasis. The present study provides new insights into the comprehensive regulatory role of PPARα in systemic energy metabolism in fish, and this pparab-deficient zebrafish also constitutes a valuable model for investigating the functions of PPARα in mammals from comparative physiology aspects.

Clinical Parameters, Fuel Oxidation, and Glucose Kinetics in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin.

To examine the mechanisms responsible for improved glycemia with combined sodium-glucose cotransporter 2 inhibitor (SGLT2i) plus dipeptidyl peptidase 4 inhibitor therapy in type 2 diabetes. Fifty-six patients (HbA1c 8.9 ± 0.2% [74 ± 2 mmol/mol]) were randomized to dapagliflozin (DAPA) 10 mg, DAPA/saxagliptin (SAXA) 10/5 mg, or placebo (PCB) for 16 weeks. Basal endogenous glucose production (EGP) (3-3H-glucose), urinary glucose excretion, glucose/lipid oxidation, HbA1c, and substrate/hormone levels were determined before treatment (Pre-Tx) and after treatment (Post-Tx). At week 16, HbA1c decrease was greater (P < 0.05) in DAPA/SAXA (-2.0 ± 0.3%) vs. DAPA (-1.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (∼2.40 mg/kg/min) decreased by -0.44 ± 0.09 mg/kg/min in PCB (P < 0.05) but only by -0.21 ± 0.02 mg/kg/min in DAPA and DAPA/SAXA (P < 0.05 vs. PCB). At week 16, EGP increased to 2.67 ± 0.09 mg/kg/min (DAPA) and 2.61 ± 0.08 mg/kg/min (DAPA/SAXA), despite reductions in fasting plasma glucose by 47 and 77 mg/dL, respectively, and no changes in PCB. Baseline plasma free fatty acids rose by 40 µmol/L with DAPA but declined by -110 with PCB and -90 µmol/L with DAPA/SAXA (P < 0.05, Pre-Tx vs. Post-Tx). In DAPA, carbohydrate oxidation rates decreased from 1.1 ± 0.1 to 0.7 ± 0.1 mg/kg/min, whereas lipid oxidation rates increased from 0.6 ± 0.1 to 0.8 ± 0.1 mg/kg/min (P < 0.01). In DAPA/SAXA, the shift in carbohydrate (1.1 ± 0.1 to 0.9 ± 0.1 mg/kg/min) and lipid (0.6 ± 0.1 to 0.7 ± 0.1 mg/kg/min) oxidation was attenuated (P < 0.05). The addition of SAXA to DAPA resulted in superior glycemic control compared with DAPA monotherapy partly because of increased glucose utilization and oxidation. Although the decrease in insulin/glucagon ratio was prevented by SAXA, EGP paradoxical elevation persisted, indicating that other factors mediate EGP changes in response to SGLT2i-induced glucosuria.

2084-P: Hepatic Fat Accumulation Underlies the Inability of Glucokinase Activator to Achieve a Sustained Hypoglycemic Effect in db/db Mice

Background: Previous clinical trials have demonstrated that glucokinase activators (GKAs) do not achieve a sustained hypoglycemic effect; however, the mechanism for this has not been determined. Aims: We aimed to clarify the mechanisms for the loss of GKA hypoglycemic effect. Method: Six-week-old db/db mice were fed standard chow and divided into three groups as follows: Untreated (UT), 0.04% GKA (G), or 0.005% ipragliflozin, a sodium-glucose cotransporter 2 inhibitor that has a long-term hypoglycemic effect in db/db mice (S). After measuring body weight (BW) and blood glucose (BG) for 28 days, pancreatic beta-cell mass and hepatic triglyceride (TG) content were analyzed. Results: The three groups did not differ in BW. A hypoglycemic effect persisted until Day 28 in S; however, in G it lasted only 6 days (Day 6: UT 454 ± 84 mg/dL, G 257 ± 85 mg/dL, S 224 ± 55 mg/dL, Day 28: UT 588 ± 102 mg/dL, G 508 ± 129 mg/dL, S 217 ± 30 mg/dL). Insulin sensitivity on insulin tolerance testing did not differ between Days 9 and 23. Glucose tolerance was improved in G and S on Days 4 and 11; however, this improvement had disappeared by Day 25. Only S exhibited increased fasting insulin-to-BG ratio on Days 11 and 25. On Day 28, pancreatic beta-cell mass and proliferation were increased in S, but not in G. Although the three groups did not differ in visceral or subcutaneous fat weight, liver weight was increased in G on Days 6 and 28. Hepatic TG content was increased in G on Day 6 (UT 130 ± 18 mg/g liver, G 226 ± 20 mg/g liver, S 39 ± 7 mg/g liver), and mRNA expression related to lipogenesis, including Fas, Elovl6 and Scd1, was upregulated in G. Conclusion: Our results indicate that GKA does not increase insulin secretion or pancreatic beta-cell mass in db/db mice. However, GKA does increase hepatic TG in db/db mice, suggesting that GKA increases glucose utilization in the liver. However, it might also promote lipogenesis and hepatic fat accumulation, leading to its hypoglycemic effect being unsustained. Disclosure S. Kawata: None. A. Nakamura: None. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk Inc., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., MDS CO. LTD., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. K. Tsuchida: None. K. Omori: None. K. Takahashi: None. H. Nomoto: None. H. Kameda: None. K. Cho: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk A/S, Sanofi. Consultant; Self; Astellas Pharma Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Medscape, Medtronic, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. T. Atsumi: Consultant; Self; Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline plc., Pfizer Inc., UCB Japan Co. Ltd. Speaker’s Bureau; Self; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB Japan Co. Ltd.

Trace element nanoparticles improved diabetes mellitus; a brief report

BackgroundDiabetes mellitus is a chronic metabolic disease that induces several complications in various organs such as the liver, kidney, and reproductive system. Trace elements such as copper, zinc, selenium, and magnesium play an essential role in the management or treatment of diabetes mellitus. Aimthe aim of the present study was conducted to investigate the effect of these trace elements nanoparticles and their probable mechanism of action on diabetes and its complications. MethodsThe present brief report was conducted with a search of articles published in several databases including PubMed, ScienceDirect, Google Scholar, and Scopus. The articles were selected from 2011 to 2018 using the keywords “zinc,” “copper,” “selenium,” “magnesium,” and “diabetes.” Following the eligibility criteria were selected 16 articles and 1 book. ResultsThe scientific results of the presented brief report show that zinc, copper, selenium, and magnesium have antidiabetic effects. Also, they improved the diabetes-induced complications through increase antioxidant enzyme level, glucose utilization, and insulin sensitivity. ConclusionWhile zinc, copper, selenium, and magnesium revealed antidiabetic effects, but their nanoparticles were more potent for the treatment of this disease.

Relationship between white matter glucose metabolism and fractional anisotropy in healthy and schizophrenia subjects

Decreased fractional anisotropy and increased glucose utilization in the white matter have been reported in schizophrenia. These findings may be indicative of an inverse relationship between these measures of white matter integrity and metabolism. We used 18F-fluorodeoxyglucose positron emission tomography and diffusion-tensor imaging in 19 healthy and 25 schizophrenia subjects to assess and compare coterritorial correlation patterns between glucose utilization and fractional anisotropy on a voxel-by-voxel basis and across a range of automatically placed representative white matter regions of interest. We found a pattern of predominantly negative correlations between white matter metabolism and fractional anisotropy in both healthy and schizophrenia subjects. The overall strength of the relationship was attenuated in subjects with schizophrenia, who displayed significantly fewer and weaker correlations in all regions assessed with the exception of the corpus callosum. This attenuation was most prominent in the left prefrontal white matter and this region also best predicted the diagnosis of schizophrenia. There exists an inverse relationship between the measures of white matter integrity and metabolism, which may therefore be physiologically linked. In subjects with schizophrenia, hypermetabolism in the white matter may be a function of lower white matter integrity, with lower efficiency and increased energetic cost of task-related computations.

Sleeve gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss.

Sleeve gastrectomy (SG) induces weight loss-independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements. Nonobese C57BL/6J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-fluorodeoxyglucose (18-FDG) PET/computed tomography, and RNA sequencing was used for gene-expression analysis. In this model, SG induced durable improvements in glucose tolerance in the absence of changes in weight, body composition, or food intake. Indirect calorimetry revealed that SG increased the average respiratory exchange ratio toward 1.0, indicating a weight-independent, systemic shift to carbohydrate utilization. Following SG, orally administered 18-FDG preferentially localized to white adipose depots, showing tissue-specific increases in glucose utilization induced by surgery. Transcriptional analysis with RNA sequencing demonstrated that increased glucose uptake in the visceral adipose tissue was associated with upregulation in transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation. SG induces a rapid, weight loss-independent shift toward glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue. Continued study of this early post-SG physiology may lead to a better understanding of the anti-diabetic mechanisms of bariatric surgery.

Metabolic Modulation to Treat Cardiac Diseases: Role for Membrane Substrate Transporters

There is growing recognition of the importance and multiple roles of substrate energy metabolism in both cardiac health and disease. Cardiac diseases are frequently accompanied by altered myocardial metabolism, while chronic changes in the type of myocardial substrate utilization are found to elicit cardiac contractile dysfunction. Examples are the increased glucose utilization, at the expense of fatty acids, in cardiac hypertrophy and ischemic heart failure, and the increased fatty acid utilization, at the expense of glucose, in obesity and diabetes-related cardiac dysfunction. Modulation of cardiac metabolism has emerged as a suitable therapeutic intervention in cardiac disease. Insights obtained during the past decade have revealed sarcolemmal substrate transport, facilitated by CD36 for fatty acids and by GLUT4 for glucose, to represent the main rate-governing kinetic step of substrate utilization, over-ruling intracellular sites of flux regulation. This suggests that manipulating the presence of substrate transporters in the sarcolemma may be an effective approach for metabolic modulation therapy. The present mini-review provides a short summary of the functioning of substrate transporters CD36 and GLUT4 in the heart, and discusses their application as targets for metabolic intervention.

CD4 T Cell Metabolism Is a Major Contributor of HIV Infectivity and Reservoir Persistence.

HIV infection is characterized by elevated glycolytic metabolism in CD4 T cells. In their recent study, Valle-Casuso et al. demonstrated that both increased glucose utilization and glutamine metabolism are essential for HIV infectivity and replication in CD4 T cells. Here, we discuss the broader implications of immunometabolism in studies of HIV persistence and their potential to inform new treatment and curative strategies.

Lipid accumulation and oxidation in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite the multimodal standard treatments for GBM, the median survival is still about one year. Analysis of brain tissues from GBM patients shows that lipid droplets are highly enriched in tumor tissues while undetectable in normal brain tissues, yet the identity and functions of lipid species in GBM are not well understood. The aims of the present work are to determine how GBM utilizes fatty acids, and assess their roles in GBM proliferation. Treatment of U138 GBM cells with a monounsaturated fatty acid, oleic acid, induces accumulation of perilipin 2-coated lipid droplets containing triglycerides enriched in C18:1 fatty acid, and increases fatty acid oxidation. Interestingly, oleic acid also increases glucose utilization and proliferation of GBM cells. In contrast, pharmacologic inhibition of monoacylglycerol lipase attenuates GBM proliferation. Our findings demonstrate that monounsaturated fatty acids promote GBM proliferation via triglyceride metabolism, suggesting a novel lipid droplet-mediated pathway which may be targeted for GBM treatment.

Insights Into GLP-1 and GIP Actions Emerging From Vildagliptin Mechanism Studies in Man.

Vildagliptin blocks glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) inactivation of the meal induced increases in GLP-1 and GIP so that elevated GLP-1 and GIP levels are maintained over 24 h. The primary insulin secretion effect of vildagliptin is to improve the impaired sensitivity of the β-cells to glucose in subjects with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and in patients with type 2 diabetes mellitus (T2DM); this effect was seen acutely and maintained over at least 2 years in patients with T2DM. Vildagliptin was also associated with improved β-cell function that is likely secondary to the improved metabolic state. Although there was no evidence of restoration of β-cell mass, the preponderance of the vildagliptin data does indicate that for at least 2 years β-cell function was maintained in vildagliptin treated patients but not in the untreated patients. Vildagliptin suppressed an inappropriate glucagon response to an oral glucose challenge in patients with T2DM, to a mixed meal challenge in patients with T2DM and type 1 diabetes mellitus, and to a mixed meal challenge in subjects with IGT and IFG. The improved glucagon response was maintained for at least 2 years in patients with T2DM and there was no change in the glucagon response in normoglycemic individuals. Vildagliptin lowered glucose levels into the normal range without increasing hypoglycemia. These hypoglycemic benefits appear to be secondary in large part to the improved sensitivity of both the β and α-cell to glucose. In the case of the α-cell, if glucose levels are high, GLP-1 attenuates the glucagon levels and if glucose levels are low, GIP increases glucagon levels. Vildagliptin reduces fatty acid flux from the adipocyte leading to reduced liver fat which in turn leads to increased glucose utilization. The reduced glycosuria and reduced lipo-toxicity associated with vildagliptin therapy does not lead to weight gain presumably due to increased fat mobilization and oxidation during meals and to reduced fat extraction from the gut.

Design and in silico modeling of Indoloquinoxaline incorporated keratin nanoparticles for modulation of glucose metabolism in 3T3-L1 adipocytes.

The following study was done to assess the glucose utilizing efficiency of Indoloquinoxaline derivative incorporated keratin nanoparticles (NPs) in 3T3-L1 adipocytes. Indoloquinoxaline derivative had wide range of biological activities including antidiabetic activity. In this view, Indoloquinoxaline moiety containing N, N-dimethyl (3-fluoro-6H-indolo [3,2-b] quinoxalin-6-yl) methanamine compound was designed and synthesized, and further it is incorporated into keratin nanoparticles. The formulated NPs, drug entrapment efficiency, releasing capacity, stability, and physicochemical properties were characterized by various spectral analyzer and obtained results of characterizations were confirmed the properties of NPs. The analysis of mechanism underlying the glucose utilization of NPs was examined through molecular docking with identified target, and observed in silico study reports shown strong interaction of NPs in the binding pockets of AMPK and PTP1B. Based on the in silico screening, the formulated NPs was performed for in vitro cellular viability and glucose uptake studies on 3T3-L1 adipocytes. Interestingly, 40 μg of NPs displayed 78.2 ± 2.76% cellular viability, and no cell death was observed at lower concentrations. Further, the concentration dependent glucose utilization was observed at different concentrations of NPs in 3T3-L1 adipocytes. The results of NPs (40 μg) on glucose utilization have revealed eminent result 58.56 ± 4.54% compared to that of Metformin (10 μM) and Insulin (10 μM). The identified results clearly indicated that Indoloquinoxaline derivative incorporated keratin NPs significantly increased glucose utilization efficiency and protect the cells against the insulin resistance.