Glucose Utilization In Skeletal Muscle Research Articles

Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes.

Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship. C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups. Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios. Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia.

Metabolite profiles of diabetes mellitus and response to intervention in anti-hyperglycemic drugs.

Type 2 diabetes mellitus (T2DM) has become a major health problem, threatening the quality of life of nearly 500 million patients worldwide. As a typical multifactorial metabolic disease, T2DM involves the changes and interactions of various metabolic pathways such as carbohydrates, amino acid, and lipids. It has been suggested that metabolites are not only the endpoints of upstream biochemical processes, but also play a critical role as regulators of disease progression. For example, excess free fatty acids can lead to reduced glucose utilization in skeletal muscle and induce insulin resistance; metabolism disorder of branched-chain amino acids contributes to the accumulation of toxic metabolic intermediates, and promotes the dysfunction of β-cell mitochondria, stress signal transduction, and apoptosis. In this paper, we discuss the role of metabolites in the pathogenesis of T2DM and their potential as biomarkers. Finally, we list the effects of anti-hyperglycemic drugs on serum/plasma metabolic profiles.

O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function

Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.

Microbiota influences host exercise capacity via modulation of skeletal muscle glucose metabolism in mice

The microbiota enhances exercise performance and regulates host physiology and energy metabolism by producing beneficial metabolites via bacterial fermentation. In this study, we discovered that germ-free (GF) mice had a reduced capacity for aerobic exercise as well as low oxygen consumption rates and glucose availability. Surprisingly, GF mice showed lower body weight gain and lower fat mass than specific pathogen-free (SPF) mice. Therefore, we hypothesized that these paradoxical phenotypes could be mediated by a compensatory increase in lipolysis in adipose tissues owing to impaired glucose utilization in skeletal muscle. Our data revealed that gut microbiota depletion impairs host aerobic exercise capacity via the deterioration of glucose storage and utilization. The improved browning ability of GF mice may have contributed to the lean phenotype and negatively affected energy generation. These adaptations limit obesity in GF mice but impede their immediate fuel supply during exercise, resulting in decreased exercise performance.

Tinosporaside from Tinospora cordifolia Encourages Skeletal Muscle Glucose Transport through Both PI-3-Kinase- and AMPK-Dependent Mechanisms.

The stem of Tinospora cordifolia has been traditionally used in traditional Indian systems of medicine for blood sugar control, without the knowledge of the underlying mechanism and chemical constitution responsible for the observed anti-diabetic effect. In the present study, Tinosporaside, a diterpenoid isolated from the stem of T. cordifolia, was investigated for its effects on glucose utilization in skeletal muscle cells, which was followed by determining the anti-hyperglycemic efficacy in our diabetic db/db mice model. We found that tinosporaside augmented glucose uptake by increasing the translocation of GLUT4 to the plasma membrane in L6 myotubes, upon prolonged exposure for 16 h. Moreover, tinosporaside treatment significantly increased the phosphorylation of protein kinase B/AKT (Ser-473) and 5' AMP-activated protein kinase (AMPK, Thr-172). These effects were abolished in the presence of the wortmannin and compound C. Administration of tinosporaside to db/db mice improved glucose tolerance and peripheral insulin sensitivity associated with increased gene expression and phosphorylation of the markers of phosphoinositide 3-kinases (PI3Ks) and AMPK signaling in skeletal muscle tissue. The findings revealed that tinosporaside exerted its antidiabetic efficacy by enhancing the rate of glucose utilization in skeletal muscle, mediated by PI3K- and AMPK-dependent signaling mechanisms.

Exercise, Physical Activity, and Cardiometabolic Health: Pathophysiologic Insights.

Physical activity and its sustained and purposeful performance-exercise-promote a broad and diverse set of metabolic and cardiovascular health benefits. Regular exercise is the most effective way to improve cardiorespiratory fitness, a measure of one's global cardiovascular, pulmonary and metabolic health, and one of the strongest predictors of future health risk. Here, we describe how exercise affects individual organ systems related to cardiometabolic health, including the promotion of insulin and glucose homeostasis through improved efficiency in skeletal muscle glucose utilization and enhanced insulin sensitivity; beneficial changes in body composition and adiposity; and improved cardiac mechanics and vascular health. We subsequently identify knowledge gaps that remain in exercise science, including heterogeneity in exercise responsiveness. While the application of molecular profiling technologies in exercise science has begun to illuminate the biochemical pathways that govern exercise-induced health promotion, much of this work has focused on individual organ systems and applied single platforms. New insights into exercise-induced secreted small molecules and proteins that impart their effects in distant organs ("exerkines") highlight the need for an integrated approach towards the study of exercise and its global effects; efforts that are ongoing.

Skeletal Muscle Uncoupling Proteins in Mice Models of Obesity.

Obesity and accompanying type 2 diabetes are among major and increasing worldwide problems that occur fundamentally due to excessive energy intake during its expenditure. Endotherms continuously consume a certain amount of energy to maintain core body temperature via thermogenic processes, mainly in brown adipose tissue and skeletal muscle. Skeletal muscle glucose utilization and heat production are significant and directly linked to body glucose homeostasis at rest, and especially during physical activity. However, this glucose balance is impaired in diabetic and obese states in humans and mice, and manifests as glucose resistance and altered muscle cell metabolism. Uncoupling proteins have a significant role in converting electrochemical energy into thermal energy without ATP generation. Different homologs of uncoupling proteins were identified, and their roles were linked to antioxidative activity and boosting glucose and lipid metabolism. From this perspective, uncoupling proteins were studied in correlation to the pathogenesis of diabetes and obesity and their possible treatments. Mice were extensively used as model organisms to study the physiology and pathophysiology of energy homeostasis. However, we should be aware of interstrain differences in mice models of obesity regarding thermogenesis and insulin resistance in skeletal muscles. Therefore, in this review, we gathered up-to-date knowledge on skeletal muscle uncoupling proteins and their effect on insulin sensitivity in mouse models of obesity and diabetes.

Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.

MiR-183 and miR-96 orchestrate both glucose and fat utilization in skeletal muscle.

Our knowledge of the coordination of fuel usage in skeletal muscle is incomplete. Whether and how microRNAs are involved in the substrate selection for oxidation is largely unknown. Here we show that mice lacking miR-183 and miR-96 have enhanced muscle oxidative phenotype and altered glucose/lipid homeostasis. Moreover, loss of miR-183 and miR-96 results in a shift in substrate utilization toward fat relative to carbohydrates in mice. Mechanistically, loss of miR-183 and miR-96 suppresses glucose utilization in skeletal muscle by increasing PDHA1 phosphorylation via targeting FoxO1 and PDK4. On the other hand, loss of miR-183 and miR-96 promotes fat usage in skeletal muscle by enhancing intramuscular lipolysis via targeting FoxO1 and ATGL. Thus, our study establishes miR-183 and miR-96 as master coordinators of fuel selection and metabolic homeostasis owing to their capability of modulating both glucose utilization and fat catabolism. Lastly, weshow that loss of miR-183 and miR-96 can alleviate obesity andimprove glucose metabolism in high-fat diet-induced mice, suggesting that miR-183 and miR-96 may serve as therapeutic targets for metabolic diseases.

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.

Growth hormone receptor disrupts glucose homeostasis via promoting and stabilizing retinol binding protein 4.

Rationale: The molecular mechanisms underlying the pathogenesis of systemic insulin resistance in type 2 diabetes remain elusive. Growth hormone receptor (GHR) deficiency has long been known to improved insulin sensitivity. However, whether hepatic GHR overexpression or activation is a cause of insulin resistance is still unknown. The aim of this study was to identify the new role of GHR in systemic insulin resistance and explore the underlying mechanism.Method: Different samples obtained from obese humans, ob/ob mice, db/db mice, high-fat diet (HFD)-fed mice and primary mouse hepatocytes were used to evaluate the correlations between GHR and metabolic disorders. Recombinant adeno-associated viruses encoding GHR and STAT5 and GHR knockout mice were used to investigate the roles of hepatic GHR in glucose homeostasis. Tissue H&E, Oil Red O and PAS staining were performed for histomorphological analysis. Gel filtration chromatography was employed for the separation of serum RBP4-TTR complexes. Plasmids (related to GHR, STAT5 and HIF1α), siRNA oligos (siGHR and siSTAT5), luciferase activity and ChIP assays were used to explore the potential mechanism of hepatic GHR.Results: Here, we found that hepatic GHR expression was elevated during metabolic disorder. Accordingly, hepatic GHR overexpression disrupted systemic glucose homeostasis by promoting gluconeogenesis and disturbing insulin responsiveness in the liver. Meanwhile, hepatic GHR overexpression promoted lipolysis in white adipose tissue and repressed glucose utilization in skeletal muscle by promoting the circulating level of RBP4, which contributed to impaired systemic insulin action. A mechanistic study revealed that hepatic GHR disrupted systemic insulin sensitivity by increasing RBP4 transcription by activating STAT5. Additionally, overexpression of hepatic GHR promoted TTR transcriptional levels by enhancing the expression of HIF1α, which not only increased the protein stability of RBP4 but also inhibited renal clearance of RBP4 in serum.Conclusions: Hepatic GHR overexpression and activation accelerated systemic insulin resistance by increasing hepatic RBP4 production and maintaining circulating RBP4 homeostasis. Our current study provides novel insights into the pathogenesis of type 2 diabetes and its associated metabolic complications.

Nutraceutical characteristics of the brown seaweed carotenoid fucoxanthin

Fucoxanthin (Fx), a major carotenoid found in brown seaweed, is known to show a unique and wide variety of biological activities. Upon absorption, Fx is metabolized to fucoxanthinol and amarouciaxanthin, and these metabolites mainly accumulate in visceral white adipose tissue (WAT). As seen in other carotenoids, Fx can quench singlet oxygen and scavenge a wide range of free radicals. The antioxidant activity is related to the neuroprotective, photoprotective, and hepatoprotective effects of Fx. Fx is also reported to show anti-cancer activity through the regulation of several biomolecules and signaling pathways that are involved in either cell cycle arrest, apoptosis, or metastasis suppression. Among the biological activities of Fx, anti-obesity is the most well-studied and most promising effect. This effect is primarily based on the upregulation of thermogenesis by uncoupling protein 1 expression and the increase in the metabolic rate induced by mitochondrial activation. In addition, Fx shows anti-diabetic effects by improving insulin resistance and promoting glucose utilization in skeletal muscle.

Psoas muscle fluorine-18-labelled fluoro-2-deoxy-d-glucose uptake associated with the incidence of existing and incipient metabolic derangement.

BackgroundSkeletal muscle glucose utilization is an important component of whole‐body glucose consumption in normal humans. Fluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) is a non‐invasive molecular imaging probe for evaluating tissue glucose utilization. It remains unclear whether or not 18F‐FDG uptake by skeletal muscle has utility as a biomarker for metabolic derangement. We investigated the utility of measurement of muscle 18F‐FDG positron emission tomography/computed tomography uptake as a surrogate marker for existing and incipient metabolic abnormalities.MethodsFluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) uptakes of insulin‐sensitive organs (liver, pancreas, mesenteric visceral fat, psoas muscle, and abdominal subcutaneous fat) and their association with metabolic abnormalities were evaluated in an experimental group comprising 91 men and 66 women (mean age 49.9 ± 11.1 years). In this cross‐sectional cohort, we assessed the predictive power of the optimal cut‐off 18F‐FDG uptake [maximum standardized uptake value (SUVmax)]. We confirmed its feasibility and reliability for diagnosis of existing and incipient metabolic derangement in the validation group (longitudinal cohort comprising 91 men and 67 women; mean age 52.6 ± 7.9 years).ResultsFluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) uptake (SUVmax) of psoas muscle was strongly correlated with clinical metabolic parameters in the experimental group. It was positively correlated with waist circumference, body mass index, fasting glucose, triglyceride, systolic and diastolic pressure, and negatively correlated with high‐density lipoprotein cholesterol levels (for all, P < 0.05). SUVmax of the psoas muscle also showed the best area under the curve value (0.779) as a predictor of metabolic syndrome (MetS) in the experimental group. Using the optimal cut‐off SUVmax of 1.34, the sensitivity, specificity, accuracy, positive, and negative predictive value for predicting existing MetS in the experimental group were 70.0%, 84.6%, 80.9%, 60.9%, and 89.2%, respectively. In the validation group, corresponding values were 47.6%, 92.3%, 86.1%, 50.0%, and 91.6%, respectively. Existing and incipient MetS were significantly higher in subjects with high 18F‐FDG uptake by the psoas muscle (SUVmax > 1.34). Subjects with higher psoas muscle SUVmax had a 3.3‐fold increased risk of developing MetS (P = 0.017).ConclusionsFluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) uptake of psoas muscle is a promising surrogate marker for existing and incipient metabolic derangement.

Short-term and long-term ketogenic diet therapy and the addition of exercise have differential impacts on metabolic gene expression in the mouse energy-consuming organs heart and skeletal muscle

Although a ketogenic diet (KD) is used to treat various metabolic diseases, the organ-specific metabolic changes that occur in response to a KD remain unclear. Therefore, we tested the hypothesis that duration of KD consumption and regular exercise in addition to KD consumption affect metabolic fuel selection at gene levels in heart and skeletal muscle. Six-week-old male C57BL/6J mice were divided into 2 groups, one fed a standard diet and the other fed a KD, and maintained for either 4 weeks (short term) or 12 weeks (long term). The long-term group was further divided into 2 subgroups, and mice in 1 of the 2 groups had an exercise load 5 days a week. Body weight decreased significantly in the KD groups during the first few weeks only. Plasma ketone levels rose and muscle glycogen levels declined significantly in the KD groups, but these changes were less severe in the KD plus exercise group. KD consumption decreased the expression of genes related to glucose utilization in heart and skeletal muscle; however, this decrease did not occur with KD consumption plus exercise. Long-term but not short-term KD consumption increased the expression of genes related to lipid utilization, regardless of exercise. In the KD groups, the expression of genes related to ketolysis was suppressed, and that of genes related to ketogenesis was increased. These results indicate that KD exposure and pairing a KD with exercise have differential impacts on energy substrate selection at gene expression levels in energy-consuming organs, the heart and skeletal muscle.

Mulberry leaf extract displays antidiabetic activity in db/db mice via Akt and AMP-activated protein kinase phosphorylation.

BackgroundAugmenting glucose utilization in skeletal muscle via the phosphatidylinositol-3 kinase (PI3 kinase)/protein kinase B (Akt) pathway or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway is necessary to regulate hyperglycemia in patients with type 2 diabetes mellitus.ObjectiveWe investigated the effect of mulberry leaf extract (MLE) on glucose uptake in skeletal muscle cells and explored its in vivo antidiabetic potential.DesignMale db/db mice were treated with either MLE (50 mg/kg, 100 mg/kg, and 250 mg/kg) or metformin (100 mg/kg) for 8 weeks.ResultsMLE treatment stimulated glucose uptake, driven by enhanced translocation of glucose transporter 4 to cell membranes in L6 myotubes. These effects of MLE were synergistic with those of insulin and were abolished in the presence of PI3K inhibitor or AMPK inhibitor. In db/db mice, supplementation with MLE decreased fasting blood glucose and insulin levels and enhanced insulin sensitivity, with increases of p-Akt and p-AMPK in skeletal muscle. Moreover, MLE improved blood lipid parameters and attenuated hepatic steatosis in diabetic db/db mice.DiscussionThese findings suggest that MLE exerts antidiabetic activity through stimulating glucose disposal in skeletal muscle cells via the PI3K/Akt and AMPK pathways.ConclusionsMLE can potentially improve hyperglycemia and hepatic steatosis in patients with type 2 diabetes.

SIRT2 is required for in vivo tissue‐specific and whole body insulin action in mice

High fat (HF) feeding impairs insulin action and, subsequently glucose homeostasis. A reduction in insulin‐mediated skeletal muscle glucose uptake (MGU) in response to HF feeding is a key contributor to dysregulated glucose homeostasis in the insulin resistant state. Increased skeletal muscle lysine acetylation, a post‐translational modification, has been reported to mediate insulin resistance in response to HF feeding. Indeed, skeletal muscle mitochondrial protein hyperacetylation precipitates insulin resistance. However, the impact of hyperacetylation in the cytosolic compartment is unknown.Hyperinsulinemic‐euglycemic (insulin) clamps combined with isotopic tracers were completed to assess the role of cytosolic hyperacetylation on insulin‐stimulated skeletal muscle glucose utilization in the conscious, unrestrained mouse. Genetic and dietary means were used to increase skeletal muscle cytosolic acetylation. Specifically, mice with a whole‐body knockout (KO) of the predominant cytosolic NAD+‐dependent deacetylase, Sirtuin 2 (SIRT2), and wildtype (WT) littermates were fed a low fat (LF) or HF diet. The hypothesis tested was that loss of SIRT2 would induce cytosolic hyperacetylation leading to impaired MGU in the presence of high‐physiological circulating insulin. It was also hypothesized that this impairment in insulin action would be worsened with a HF diet.LF SIRT2 KO mice exhibited higher skeletal muscle protein acetylation compared to LF WT mice, but similar to levels observed in HF WT mice. Skeletal muscle acetylation was increased in HF WT mice compared to LF WT mice, but not HF SIRT2 KO mice in relation to either LF SIRT2 KO or HF WT mice. LF SIRT2 KO mice exhibited a 27% reduction in insulin‐stimulated MGU compared to LF WT mice (gastrocnemius; p&lt;0.05, n=7–9). This impairment was exacerbated in HF SIRT2 KO mice compared to HF‐WT type mice as gastrocnemius glucose uptake was reduced by 43% (p&lt;0.001, n=12–13). While our experiments were designed to probe muscle glucose metabolism, our in vivo approach allowed us to uncover an additional contributor to insulin resistance in HF SIRT2 KO mice. The ability of insulin to suppress endogenous glucose production was significantly impaired in the HF SIRT2 KO mice (n=7–13). This suggests liver glucose formation is not effectively attenuated by insulin in HF SIRT2 KO mice.In summary, the increased lysine acetylation induced by HF feeding has been implicated in promoting insulin resistance. Extensive study has linked mitochondrial hyperacetylation to impaired insulin action. Here we show that increased acetylation in the cytosol compartment profoundly reduces insulin‐stimulated MGU. Furthermore, our in vivo approach identified a regulatory role for cytosolic hyperacetylation in the control of liver glucose production.Support or Funding InformationNIH DK054902, DK050277This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Central regulation of appetite and energy metabolism.

Recent advances of neuroscience shed a light in the neural pathway and mechanisms for food intake regulation. The central nervous system(CNS)has also been recognized as a crucial organ to regulate metabolism in peripheral tissues. This includes the increase in glucose and fatty acid utilization in skeletal muscle as well as in brown adipose tissue and the heart, improving type 1 diabetes without change in insulin secretion. CNS regulation for food intake and energy metabolism is important to understand the mechanism for homeostatic regulation in living body.

Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle

O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine (GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated. In this study, we created skeletal muscle-specific Ogt knockout (Ogt-MKO) mice and analyzed their glucose metabolism. During an intraperitoneal glucose tolerance test, blood glucose was slightly lower in Ogt-MKO mice than in control Ogt-flox mice. High fat diet-induced obesity and insulin resistance were reversed in Ogt-MKO mice. In addition, 12-month-old Ogt-MKO mice had lower adipose and body mass. A single bout of exercise significantly reduced blood glucose in Ogt-MKO mice, probably because of higher AMP-activated protein kinase α (AMPKα) protein expression. Furthermore, intraperitoneal injection of 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, resulted in a more marked decrease in blood glucose levels in Ogt-MKO mice than in controls. Finally, Ogt knockdown by siRNA in C2C12 myotubes significantly increased protein expression of AMPKα, glucose uptake and oxidation. In conclusion, loss of O-GlcNAcylation facilitates glucose utilization in skeletal muscle, potentially through AMPK activation. The inhibition of O-GlcNAcylation in skeletal muscle may have an anti-diabetic effect, through an enhancement of glucose utilization during exercise.

Isoalantolactone derivative promotes glucose utilization in skeletal muscle cells and increases energy expenditure in db/db mice via activating AMPK-dependent signaling

Augmenting glucose utilization and energy expenditure in skeletal muscle via AMP-activated protein kinase (AMPK) is an imperative mechanism for the management of type 2 diabetes. Chemical derivatives (2a-2h, 3, 4a-4d, 5) of the isoalantolactone (K007), a bioactive molecule from roots of Inula racemosa were synthesized to optimize the bioactivity profile to stimulate glucose utilization in skeletal muscle cells. Interestingly, 4a augmented glucose uptake, driven by enhanced translocation of glucose transporter 4 (GLUT4) to cell periphery in L6 rat skeletal muscle cells. The effect of 4a was independent to phosphatidylinositide-3-kinase (PI-3-K)/Akt pathway, but mediated through Liver kinase B1 (LKB1)/AMPK-dependent signaling, leading to activation of downstream targets acetyl coenzyme A carboxylase (ACC) and sterol regulatory element binding protein 1c (SREBP-1c). In db/db mice, 4a administration decreased blood glucose level and improved body mass index, lipid parameters and glucose tolerance associated with elevation of GLUT4 expression in skeletal muscle. Moreover, 4a increased energy expenditure via activating substrate utilization and upregulated the expression of thermogenic transcription factors and mitochondrial proteins in skeletal muscle, suggesting the regulation of energy balance. These findings suggest the potential implication of isoalantolactone derivatives for the management of diabetes.

Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues.

The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues.