Muscle Insulin Sensitivity Research Articles

Maternal Apical Periodontitis Increases Insulin Resistance and Modulates the Antioxidant Defense System in the Gastrocnemius Muscle of Adult Offspring

IntroductionMaternal apical periodontitis (AP) is associated with insulin resistance (IR) in adult offspring. Oxidative stress has been linked to IR. This study investigated insulin sensitivity (IS) and oxidative stress in the gastrocnemius muscle (GM) of adult offspring of rats with AP. MethodsFifteen female Wistar rats were distributed into a control group, a group with 1 tooth with AP, and a group with 4 teeth with AP. Thirty days after AP induction, female rats were mated with healthy male rats. When male offspring reached 75 days of age, glycemia, insulinemia, and IS were determined. In the GM, the oxidative damage products (thiobarbituric acid reactive substances and carbonyl protein) and activities of enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) and nonenzymatic (glutathione and total antioxidant capacity) antioxidants were quantified. Analysis of variance was performed followed by the Tukey post hoc test (P < .05). ResultsMaternal AP was associated with decreased IS and changes in antioxidant activities (reduced superoxide dismutase and increased catalase, glutathione peroxidase, and glutathione) and decreased thiobarbituric acid reactive substance concentration in the GM of their adult offspring. However, maternal AP does not appear to affect glycemia, carbonyl protein concentration, and the nonenzymatic total antioxidant capacity in the GM of this offspring. ConclusionsMaternal AP modulates the antioxidant defense system in the GM of their adult offspring, attenuating lipid peroxidation in this tissue. This reflects part of an adaptive response of the offspring to the stimulation of the maternal chronic oral inflammatory process in which the organism acts by decreasing oxidative tissue damage in the postnatal stage. The present study improves knowledge about the impact of maternal oral inflammation on healthy offspring.

Insulin resistance in type 1 diabetes managed with metformin (INTIMET): Study protocol of a double-blind placebo-controlled, randomised trial.

Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. We will study 40 adults aged 20-55years with Type 1 diabetes (HbA1c 80mmol/mol [9.5%], fasting C-peptide <0.3nmol/L) and 20 age-, gender- and body mass index (BMI)-matched controls. Insulin sensitivity will be determined by the two-step hyperinsulinaemic-euglycaemic clamp method with deuterated glucose to document liver, muscle and adipose insulin sensitivity. Subjects with Type 1 diabetes will be randomised to metformin extended-release 1500mg daily or matched placebo for 26weeks. The primary outcome is change in hepatic insulin sensitivity, assessed by change in basal rate of appearance (Ra) of glucose and suppression of endogenous glucose production (EGP) during the low-dose stage of the clamp. The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an individual's response to metformin in Type 1 diabetes. ACTRN12619001440112.

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Remodeling glycerophospholipids affects obesity-related insulin signaling in skeletal muscle.

It has long been known that fatty acids can either adversely or positively affect insulin signaling in skeletal muscle, depending on chain length or saturation, and can therefore be primary drivers of systemic insulin sensitivity. However, the detailed mechanisms linking fatty acids to insulin signaling in skeletal muscle have been elusive. In this issue of the JCI, Ferrara et al. suggest a model whereby membrane lipid remodeling mediates skeletal muscle insulin sensitivity. The authors demonstrate that membrane glycerophospholipid fatty acid remodeling by lysophosphatidylcholine acyltransferase 3 (LPCAT3) in skeletal muscle from subjects with obesity was induced, suppressing insulin signaling and glucose tolerance. Loss or gain of LPCAT3 function in mouse models showed that Lpcat3 was both required and sufficient for high-fat diet-induced muscle insulin resistance. These results suggest that the physiochemical properties of muscle cell membranes may drive insulin sensitivity and, therefore, systemic glucose intolerance.

The effects of different doses of exercise on pancreatic \u03b2-cell function in patients with newly diagnosed type 2 diabetes: study protocol for and rationale behind the \u201cDOSE-EX\u201d multi-arm parallel-group randomised clinical trial

BackgroundLifestyle intervention, i.e. diet and physical activity, forms the basis for care of type 2 diabetes (T2D). The current physical activity recommendation for T2D is aerobic training for 150 min/week of moderate to vigorous intensity, supplemented with resistance training 2–3 days/week, with no more than two consecutive days without physical activity. The rationale for the recommendations is based on studies showing a reduction in glycated haemoglobin (HbA1c). This reduction is supposed to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge about effects on abnormalities in the liver and pancreas are scarce, with the majority of evidence stemming from in vitro and animal studies. The aim of this study is to investigate the role of the volume of exercise training as an adjunct to dietary therapy in order to improve the pancreatic β-cell function in T2D patients less than 7 years from diagnosis. The objective of this protocol for the DOSE-EX trial is to describe the scientific rationale in detail and to provide explicit information about study procedures and planned analyses.Methods/designIn a parallel-group, 4-arm assessor-blinded randomised clinical trial, 80 patients with T2D will be randomly allocated (1:1:1:1, stratified by sex) to 16 weeks in either of the following groups: (1) no intervention (CON), (2) dietary intervention (DCON), (3) dietary intervention and supervised moderate volume exercise (MED), or (4) dietary intervention and supervised high volume exercise (HED). Enrolment was initiated December 15th, 2018, and will continue until N = 80 or December 1st, 2021. Primary outcome is pancreatic beta-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up assessed by hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors and the effect on subsequent complications related to T2D. The study was approved by The Scientific Ethical Committee at the Capital Region of Denmark (H-18038298). Trial registration: The Effects of Different Doses of Exercise on Pancreatic β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX), NCT03769883, registered 10 December 2018 https://clinicaltrials.gov/ct2/show/NCT03769883). Any modification to the protocol, study design, and changes in written participant information will be approved by The Scientific Ethical Committee at the Capital Region of Denmark before effectuation.DiscussionThe data from this study will add knowledge to which volume of exercise training in combination with a dietary intervention is needed to improve β-cell function in T2D. Secondarily, our results will elucidate mechanisms of physical activity mitigating the development of micro- and macrovascular complications correlated with T2D.

English

Creatine is a sports supplement with high scientific evidence on its effects on performance and with emerging health’s results, including for vegetarian athletes and older adults. The creatine type and effective doses have been well studied, presenting consistent results. However, not many studies have evaluated the ingestion timing in terms of its interaction with the creatine effects. The aim of this review is to analyze the different existing scientific literature on creatine supplementation protocols and their interaction with the timing of ingestion, in order to assess whether there is a greater effect of the ergogenic dose of creatine considered effective when It is ingested before, post workout or at another time of the day. The results of this work presented different types of protocols and doses in creatine supplementation, despite being diverse the protocols shown in the literature, the most effective consisted of a consumption of 0.3 g/kg/d for five days, followed by a consumption of 0.03 g/kg/d, thus achieving a greater reserve of PCr in skeletal muscle. Studies showed greater benefits when creatine intake was carried out in the moments close to workout due to greater blood flow, the studies pointing to significant improvements in post-workout consumption, since creatine can increase the rate of glycogen uptake in muscle and increase insulin sensitivity

Relationship between insulin sensitivity and gene expression in human skeletal muscle

BackgroundInsulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood.MethodsTo explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR).ResultsWe identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g.PPARGC1A.ConclusionsThe muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g.SIRT2, and genes regulating autophagy and mTOR signaling, e.g.FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.

The effects of hydroxychloroquine on insulin sensitivity, insulin clearance and inflammation in insulin-resistant adults: A randomized trial.

To determine the effect of hydroxychloroquine (HCQ) on skeletal muscle and liver insulin sensitivity, insulin clearance, inflammation and adipokines. Insulin-resistant adults without rheumatic disease were randomized to 13 weeks of HCQ (400 mg/day) versus placebo (double-blinded). Primary outcomes were changes in skeletal muscle and liver insulin sensitivity assessed by hyperinsulinaemic-euglycaemic clamp and stable-isotope tracer methods. Secondary outcomes included insulin clearance, inflammation biomarkers and adipokines. Compared with placebo, HCQ significantly improved skeletal muscle insulin sensitivity by 26% (p = .019) and enhanced systemic glucose clearance (p = .025). By contrast, HCQ had no effect on hepatic insulin sensitivity. HCQ did not affect insulin clearance but decreased circulating IL-6 (p = .01) and increased adiponectin (p = .045). There were no effects on leptin, RBP-4, FGF-21 or C-reactive protein. HCQ selectively enhances insulin sensitivity and glucose disposal in skeletal muscle, without affecting hepatic insulin sensitivity or insulin clearance. These findings offer a mechanistic explanation for the antidiabetic properties of HCQ and suggest that this medication might be useful in conditions linked to insulin resistance such as type 2 diabetes.

Viburnum stellato-tomentosum Extract Suppresses Obesity and Hyperglycemia through Regulation of Lipid Metabolism in High-Fat Diet-Fed Mice.

The potential biological activities of Viburnum stellato-tomentosum (VS), a plant mainly found in Costa Rica, have yet to be reported. Supplementation of VS extract for 17 weeks significantly decreased body weight gain, fat weight, fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride levels in high-fat diet (HFD)-fed C57BL/6J mice. The molecular mechanisms underlying the anti-obesity and glucose-lowering effects of VS extract were investigated. VS extract suppressed adipocyte hypertrophy by regulating lipogenesis-related CCAAT/enhancer-binding protein α (C/EBPα) and insulin sensitivity-related peroxisome proliferator-activated receptor γ (Pparg) expression in adipose tissue (AT) and hepatic steatosis by inhibiting C/EBPα and lipid transport-related fatty acid binding protein 4 (FABP4) expression. VS extract enhanced muscular fatty acid β-oxidation-related AMP-activated protein kinase (AMPK) and PPARα expression with increasing Pparg levels. Furthermore, VS extract contained a much higher content of amentoflavone (AMF) (29.4 mg/g extract) compared to that in other Viburnum species. AMF administration decreased Cebpa and Fabp4 levels in the AT and liver, as well as improved insulin signaling-related insulin receptor substrate 1 (Irs1) and glucose transporter 1 (Glut1) levels in the muscle of HFD-fed mice. This study elucidated the in vivo molecular mechanisms of AMF for the first time. Therefore, VS extract effectively diminished obesity and hyperglycemia by suppressing C/EBPα-mediated lipogenesis in the AT and liver, enhancing PPARα-mediated fatty acid β-oxidation in muscle, and PPARγ-mediated insulin sensitivity in AT and muscle.

Meteorin-like protein (METRNL)/IL-41 improves LPS-induced inflammatory responses via AMPK or PPARδ–mediated signaling pathways

PurposeMeteorin-like protein (METRNL) (also known as IL-41), recently identified as a myokine, is released in response to muscle contraction. It improves the skeletal muscle insulin sensitivity through exerting a beneficial anti-inflammatory effect. However, no independent studies have been published to verify the effects of METRNL on human umbilical vein endothelial cells (HUVECs) and THP-1 human monocytes. Materials and methodsThe levels of NFκB and IκB phosphorylation as well as the expression of adhesion molecules were assessed by Western blotting analysis. Cell adhesion assay demonstrated the interactions between HUVEC and THP-1 ​cells. We used enzyme-linked immunosorbent assay (ELISA) to measure the levels of TNFα and MCP-1 in culture medium. ResultsTreatment with METRNL suppressed the secretion of TNFα and MCP-1 as well as NFκB and IκB phosphorylation and inflammatory markers in lipopolysaccharide (LPS)-treated HUVECs and THP-1 ​cells. Furthermore, treatment with METRNL ameliorated LPS-induced attachment of THP-1 monocytes to HUVECs via inhibition of adhesion molecule expression and apoptosis. Treatment of HUVEC and THP-1 ​cells with METRNL enhanced AMPK phosphorylation and PPARδ expression in a dose-dependent manner. Small interference (si) RNA-mediated suppression of AMPK or PPARδ restored all these changes. ConclusionsIt has therefore been shown that METRNL ameliorates inflammatory responses through AMPK and PPARδ-dependent pathways in LPS-treated HUVEC. In sum, the current study may suggest the suppressive potential of METRNL against endothelial inflammation.

Potential of Creatine in Glucose Management and Diabetes.

Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and non-athletic populations to improve power, strength, muscle mass and performance. A growing body of evidence has been identified potential therapeutic effects of creatine in a wide variety of clinical conditions, such as cancer, muscle dystrophy and neurodegenerative disorders. Evidence has suggested that creatine supplementation alone, and mainly in combination with exercise training, may improve glucose metabolism in health individuals and insulin-resistant individuals, such as in those with type 2 diabetes mellitus. Creatine itself may stimulate insulin secretion in vitro, improve muscle glycogen stores and ameliorate hyperglycemia in animals. In addition, exercise induces numerous metabolic benefits, including increases in insulin-independent muscle glucose uptake and insulin sensitivity. It has been speculated that creatine supplementation combined with exercise training could result in additional improvements in glucose metabolism when compared with each intervention separately. The possible mechanism underlying the effects of combined exercise and creatine supplementation is an enhanced glucose transport into muscle cell by type 4 glucose transporter (GLUT-4) translocation to sarcolemma. Although preliminary findings from small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of creatine for improving glycemic control is yet to be confirmed. In this review, we aim to explore the possible therapeutic role of creatine supplementation on glucose management and as a potential anti-diabetic intervention, summarizing the current knowledge and highlighting the research gaps.

Adipose Insulin Resistance and Decreased Adiponectin Are Correlated With Metabolic Abnormalities in Nonobese Men

Adipose tissue dysfunction is characterized by decreased adiponectin (AN) levels and impaired adipose tissue insulin sensitivity (ATIS), and is associated with metabolic disorders. While Asians readily develop metabolic disease without obesity, it remains unclear how decreased AN level and impaired ATIS affect metabolic abnormalities in non-obese Asians. To investigate the relationships between decreased AN level, impaired ATIS, and metabolic abnormalities, we studied 94 Japanese men whose body mass index was less than 25kg/m 2. We divided the subjects into four groups based on their median AN level and ATIS, the latter calculated as the degree of insulin-mediated suppression of free fatty acids during hyperinsulinemic euglycemic clamp, and compared the metabolic parameters in the four groups. The High-ATIS/High-AN group (n=29) showed similar anthropometric data to the High-ATIS/Low-AN group (n=18). In contrast, both the Low-ATIS/High-AN (n=18) and Low-ATIS/Low-AN (n=29) groups showed significantly lower muscle insulin sensitivity than the High-ATIS groups. The intrahepatic lipid level in the Low-ATIS/Low-AN group was significantly higher than that in the High-ATIS groups. In addition, the Low-ATIS/Low-AN group had a significantly higher fasting serum triglyceride level and significantly lower high-density lipoprotein cholesterol level than the other three groups. In non-obese Japanese men with high ATIS, the AN level was not associated with metabolic characteristics. On the other hand, subjects with low ATIS showed reduced muscle insulin sensitivity and those with a decreased AN level demonstrated multiple metabolic abnormalities, represented by fatty liver and dyslipidemia.

The association between vitamin D receptor polymorphisms and tissue-specific insulin resistance in human obesity.

To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort. We included 553 adult obese individuals (mean BMI 34.8 kg/m2), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression. None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 ± 0.4 vs. AA 5.6 ± 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 ± 13.4 vs. AA: 547.9 ± 24.7 µmol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters). The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort.

Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.

Countering impaired glucose homeostasis during catch-up growth with essential polyunsaturated fatty acids: is there a major role for improved insulin sensitivity?

Background/ObjectivesCatch-up growth, an important risk factor for later obesity and type 2 diabetes, is often characterized by a high rate of fat deposition associated with hyperinsulinemia and glucose intolerance. We tested here the hypothesis that refeeding on a high-fat diet rich in essential polyunsaturated fatty acids (ePUFA) improves glucose homeostasis primarily by enhancing insulin sensitivity in skeletal muscles and adipose tissues.MethodsRats were caloric restricted for 2 weeks followed by 1–2 weeks of isocaloric refeeding on either a low-fat (LF) diet, a high-fat (HF) diet based on animal fat and high in saturated and monounsaturated fatty acids (HF SMFA diet), or a HF diet based on vegetable oils (1:1 mixture of safflower and linseed oils) and rich in the essential fatty acids linoleic and α-linolenic acids (HF ePUFA diet). In addition to measuring body composition and a test of glucose tolerance, insulin sensitivity was assessed during hyperinsulinemic-euglycemic clamps at the whole-body level and in individual skeletal muscles and adipose tissue depots.ResultsCompared to animals refed the LF diet, those refed the HF-SMFA diet showed a higher rate of fat deposition, higher plasma insulin and glucose responses during the test of glucose tolerance, and markedly lower insulin-stimulated glucose utilization at the whole body level (by a-third to a-half) and in adipose tissue depots (by 2–5 folds) during insulin clamps. While refeeding on the ePUFA diet prevented the increases in fat mass and in plasma insulin and glucose, the results of insulin clamps revealed that insulin-stimulated glucose utilization was not increased in skeletal muscles and only marginally higher in adipose tissues and at the whole-body level.ConclusionsThese results suggest only a minor role for enhanced insulin sensitivity in the mechanisms by which diets high in ePUFA improves glucose homeostasis during catch-up growth.

Skeletal muscle anabolic and insulin sensitivity responses to a mixed meal in adult patients with active Crohn's disease.

We have previously shown reduced protein balance in response to nutrition in paediatric Crohn's disease (CD) in remission, associated with reduced lean mass (sarcopenia) and reduced protein intake in males. We aim to compare skeletal muscle metabolic response to feeding in adult active CD and healthy volunteers. Eight CD participants with active disease (41.3±4.5yrs; BMI 26.9±1.5kg/m2) and eight matched healthy volunteers (Con) (41.2±4.3yrs; BMI 25.1±1.1kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialized hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20mins for 2hrs after the ingestion of a standardized mixed liquid meal. Net balance of branched chain amino acids (BCAA), glucose and free fatty acids across the forearm were derived. No differences in muscle BCAA, glucose or FFA net balance were found between CD and Con. Neither were differences in muscle mass and function, physical activity or diet found. CD did not differ from Con in whole body insulin and lipid responses, or in energy expenditure and fuel oxidation. Skeletal muscle mass, function, dietary protein intake and response to a test meal in an adult CD cohort with active disease is similar to that seen in healthy volunteers. Combining these results with our previous findings in paediatric patients suggests that age of onset and/or disease burden over time, as well as daily protein intake, may be significant in the development of sarcopenia in CD. Longitudinal studies investigating these factors are required.

SENP2 is vital for optimal insulin signaling and insulin-stimulated glycogen synthesis in human skeletal muscle cells

Sentrin-specific protease (SENP) 2 has been suggested as a possible novel drug target for the treatment of obesity and type 2 diabetes mellitus after observations of a palmitate-induced increase in SENP2 that lead to increased fatty acid oxidation and improved insulin sensitivity in skeletal muscle cells from mice. However, no precedent research has examined the role of SENP2 in human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism as well as insulin sensitivity in human skeletal muscle using cultured primary human myotubes. Acute (4 ​h) oleic acid oxidation was reduced in SENP2-knockdown (SENP2-KD) cells compared to control cells, with no difference in uptake. After prelabeling (24 ​h) with oleic acid, total lipid content and incorporation into triacylglycerol was decreased, while incorporation into other lipids, as well as complete oxidation and β-oxidation was increased in SENP2-KD cells. Basal glucose uptake (i.e., not under insulin-stimulated conditions) was higher in SENP2-KD cells, whereas oxidation was similar to control myotubes. Further, basal glycogen synthesis was not different in SENP2-KD myotubes, but both insulin-stimulated glycogen synthesis and AktSer473 phosphorylation was completely blunted in SENP2-KD cells. In conclusion, SENP2 plays an important role in fatty acid and glucose metabolism in human myotubes. Interestingly, it also appears to have a pivotal role in regulating myotube insulin sensitivity. Future studies should examine the role of SENP2 in regulation of insulin sensitivity in other tissues and in vivo, defining the potential for SENP2 as a drug target.

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.

Protective Effect of Jiang Tang Xiao Ke Granules against Skeletal Muscle IR via Activation of the AMPK/SIRT1/PGC-1α Signaling Pathway.

The Jiang Tang Xiao Ke (JTXK) granule is a classic Chinese herbal formula that has been put into clinical use in the treatment of type 2 diabetes mellitus for decades. However, whether its ability to ameliorate skeletal muscle insulin resistance (IR) is through modulation of the AMPK/SIRT1/PGC-1α signaling pathway remains unknown. Therefore, we aimed to investigate the effects of JTXK granules on IR in skeletal muscle of high-fat diet-induced diabetic mice and C2C12 cells and analyze the underlying mechanisms. In the present study, we showed that JTXK granules attenuated body weight gain, reduced body fat mass, improved body lean mass, and enhanced muscle performance of diabetic mice. JTXK granules also improved glucose metabolism and skeletal muscle insulin sensitivity and partially reversed abnormal serum lipid levels, which might be related to the regulation of the AMPK/SIRT1/PGC-1α pathway, both in skeletal muscle tissue of diabetic mice and in C2C12 cells. Furthermore, drug-containing serum of JTXK granules was capable of enhancing glucose uptake and mitochondrial respiration in C2C12 cells, and AMPKα was proven to be closely involved in this process. Taken together, these results suggest that the JTXK granule ameliorates skeletal muscle IR through activation of the AMPK/SIRT1/PGC-1α signaling pathway, which offers a novel perspective of this formula to combat IR-related metabolic diseases.

Ca2+/calmodulin-dependent protein kinase IV attenuates inflammation and mitochondrial dysfunction under insulin resistance in C2C12 cells

CaMKIV has been reported involved in the improvement of whole-body insulin sensitivity and mitochondrial biogenesis of skeletal muscle. Here, we first investigate the effects of CaMKIV on glucose metabolism, cell viability, inflammatory function, and mitochondrial function in palmitate-induced C2C12 cells of insulin resistance. Then we explored the potential mechanism of these effects. Differentiated C2C12 cells were treated with or without 100 ng/ml of CaMKIV under palmitate-induced insulin resistance. The results suggest palmitate induced insulin sensitivity, reduced glucose uptake, decreased cell viability, increased inflammatory factors, and caused mitochondrial dysfunction in C2C12 cells. Of note, CaMKIV reversed palmitate-induced insulin resistance, increased the reduction of glucose uptake, inhibited inflammatory response, and mitochondrial dysfunction, despite of no change in cells viabilities. However, these beneficial effects of CaMKIV were blocked by the downregulation of CREB1. Taken together, our data demonstrated CaMKIV prevents palmitate-induced insulin resistance, inflammatory response, and mitochondrial dysfunction through phosphorylated CREB1 in differentiated C2C12 cells.