Muscle Insulin Sensitivity Research Articles

Hypolipidemic and insulin sensitizing effects of salsalate beyond suppressing inflammation in a prediabetic rat model.

Background and aims: Low-grade chronic inflammation plays an important role in the pathogenesis of metabolic syndrome, type 2 diabetes and their complications. In this study, we investigated the effects of salsalate, a non-steroidal anti-inflammatory drug, on metabolic disturbances in an animal model of prediabetes-a strain of non-obese hereditary hypertriglyceridemic (HHTg) rats. Materials and Methods: Adult male HHTg and Wistar control rats were fed a standard diet without or with salsalate delivering a daily dose of 200mg/kg of body weight for 6weeks. Tissue sensitivity to insulin action was measured ex vivo according to basal and insulin-stimulated 14C-U-glucose incorporation into muscle glycogen or adipose tissue lipids. The concentration of methylglyoxal and glutathione was determined using the HPLC-method. Gene expression was measured by quantitative RT-PCR. Results: Salsalate treatment of HHTg rats when compared to their untreated controls was associated with significant amelioration of inflammation, dyslipidemia and insulin resistance. Specificaly, salsalate treatment was associated with reduced inflammation, oxidative and dicarbonyl stress when inflammatory markers, lipoperoxidation products and methylglyoxal levels were significantly decreased in serum and tissues. In addition, salsalate ameliorated glycaemia and reduced serum lipid concentrations. Insulin sensitivity in visceral adipose tissue and skeletal muscle was significantly increased after salsalate administration. Further, salsalate markedly reduced hepatic lipid accumulation (triglycerides -29% and cholesterol -14%). Hypolipidemic effects of salsalate were associated with differential expression of genes coding for enzymes and transcription factors involved in lipid synthesis (Fas, Hmgcr), oxidation (Pparα) and transport (Ldlr, Abc transporters), as well as changes in gene expression of cytochrome P450 proteins, in particular decreased Cyp7a and increased Cyp4a isoforms. Conclusion: These results demonstrate important anti-inflammatory and anti-oxidative effects of salsalate that were associated with reduced dyslipidemia and insulin resistance in HHTg rats. Hypolipidemic effects of salsalate were associated with differential expression of genes regulating lipid metabolism in the liver. These results suggest potential beneficial use of salsalate in prediabetic patients with NAFLD symptoms.

Circulating and adipose tissue immune cells in tissue-specific insulin resistance in humans with overweight and obesity.

A proinflammatory adipose tissue (AT) microenvironment and systemic low-grade inflammation may differentially affect tissue-specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity. Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n=219) and the Maastricht Study (replication cohort; n=1256) underwent a seven-point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity.

Rare Sugar Metabolism and Impact on Insulin Sensitivity along the Gut-Liver-Muscle Axis In Vitro.

Rare sugars have recently attracted attention as potential sugar replacers. Understanding the biochemical and biological behavior of these sugars is of importance in (novel) food formulations and prevention of type 2 diabetes. In this study, we investigated whether rare sugars may positively affect intestinal and liver metabolism, as well as muscle insulin sensitivity, compared to conventional sugars. Rare disaccharide digestibility, hepatic metabolism of monosaccharides (respirometry) and the effects of sugars on skeletal muscle insulin sensitivity (impaired glucose uptake) were investigated in, respectively, Caco-2, HepG2 and L6 cells or a triple coculture model with these cells. Glucose and fructose, but not l-arabinose, acutely increased extracellular acidification rate (ECAR) responses in HepG2 cells and impaired glucose uptake in L6 cells following a 24 h exposure at 28 mM. Cellular bioenergetics and digestion experiments with Caco-2 cells indicate that especially trehalose (α1-1α), D-Glc-α1,2-D-Gal, D-Glc-α1,2-D-Rib and D-Glc-α1,3-L-Ara experience delayed digestion and reduced cellular impact compared to maltose (α1-4), without differences on insulin-stimulated glucose uptake in a short-term setup with a Caco-2/HepG2/L6 triple coculture. These results suggest a potential for l-arabinose and specific rare disaccharides to improve metabolic health; however, additional in vivo research with longer sugar exposures should confirm their beneficial impact on insulin sensitivity in humans.

Gestational low dietary protein induces intrauterine inflammation and alters the programming of adiposity and insulin sensitivity in the adult offspring

Malnutrition associated with low dietary protein can induce gestational inflammation and sets a long-lasting metabolic impact on the offspring even after replenishment. The work investigated whether a low-protein diet (LPD) during pregnancy and lactation induces intrauterine inflammation and predisposes offspring to adiposity and insulin resistance in their adult life. Female Golden Syrian hamsters were fed LPD (10.0% energy from protein) or a control diet (CD, 20.0 % energy from protein) from preconception until lactation. All pups were switched to CD after lactation and continued until the end. Maternal LPD increased intrauterine inflammation by enhancing neutrophil infiltration, amniotic hsCRP, oxidative stress, and mRNA expression of NFκβ, IL8, COX2, and TGFβ in the chorioamniotic membrane (P<.05). The prepregnancy body weight, placental, and fetal weights, serum AST and ALT were decreased, while blood platelets, lymphocytes, insulin, and HDL were significantly increased in LPD-fed dams (P<.05). A postnatal switch to an adequate protein could not prevent hyperlipidemia in the 6-months LPD/CD offspring. The lipid profile and liver functions were restored over 10 months of protein feeding but failed to normalize fasting glucose and body fat accumulation compared to CD/CD. LPD/CD showed elevated GLUT4 expression & activated pIRS1 in the skeletal muscle and increased expression of IL6, IL1β, and p65-NFκB proteins in the liver (P<.05). In conclusion, present data suggest that maternal protein restriction may induce intrauterine inflammation and affect liver inflammation in the adult offspring by an influx of fats from adipose that may alter lipid metabolism and reduce insulin sensitivity in skeletal muscle.

White-skinned sweet potato (Ipomoea batatas L.) acutely suppresses postprandial blood glucose elevation by improving insulin sensitivity in normal rats

Long-term administration of Ipomoea batatas L. (white-skinned sweet potato, WSSP) has been reported to help manage type 2 diabetes mellitus (T2DM) in humans and animals; however, the mechanisms of blood glucose regulation by WSSP remain unclear. Therefore, we aimed to investigate the acute effects of WSSP on blood glucose homeostasis under normal conditions and the underlying mechanisms. Three fractions of WSSP (≤10, 10–50, and >50 kDa) were obtained via ultracentrifugation. Rats were subjected to an oral glucose tolerance test (OGTT) after a single administration of WSSP. The insulin tolerance test (ITT) and pyruvate tolerance test (PTT) were performed to evaluate insulin sensitivity and gluconeogenesis, respectively. Single WSSP administration markedly reduced blood glucose levels as revealed by the OGTT. Serum insulin levels were not increased by WSSP treatment. Blood glucose levels during ITT were significantly reduced due to WSSP treatment. WSSP treatment activated the phosphorylation of Akt, thereby activating insulin signaling in the skeletal muscles and liver. The ≤10 kDa fraction considerably reduced blood glucose levels per the OGTT and ITT. In contrast, gluconeogenesis in PTT and the expression of key enzymes in hepatocytes were suppressed by the >50 kDa fraction. This study demonstrated that WSSP acutely reduced postprandial blood glucose levels by improving insulin sensitivity in skeletal muscles in normal rats, which was attributed to constituents with a molecular weight of ≤10 kDa. Moreover, WSSP treatment suppressed gluconeogenesis in the liver, for which constituents of >50 kDa were responsible. Thus, WSSP can acutely regulate blood glucose homeostasis via multiple mechanisms. Since postprandial hyperglycemia leads to the onset of T2DM, WSSP, as a functional food, may possess potential active compounds that prevent T2DM.

An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice.

Exercise intervention at the early stage of type 2 diabetes mellitus (T2DM) can aid in the maintenance of blood glucose homeostasis and prevent the development of macrovascular and microvascular complications. However, the exercise-regulated pathways that prevent the development of T2DM remain largely unclear. In this study, two forms of exercise intervention, treadmill training and voluntary wheel running, were conducted for high-fat diet (HFD)-induced obese mice. We observed that both forms of exercise intervention alleviated HFD-induced insulin resistance and glucose intolerance. Skeletal muscle is recognized as the primary site for postprandial glucose uptake and for responsive alteration beyond exercise training. Metabolomic profiling of the plasma and skeletal muscle in Chow, HFD, and HFD-exercise groups revealed robust alterations in metabolic pathways by exercise intervention in both cases. Overlapping analysis identified nine metabolites, including beta-alanine, leucine, valine, and tryptophan, which were reversed by exercise treatment in both the plasma and skeletal muscle. Transcriptomic analysis of gene expression profiles in the skeletal muscle revealed several key pathways involved in the beneficial effects of exercise on metabolic homeostasis. In addition, integrative transcriptomic and metabolomic analyses uncovered strong correlations between the concentrations of bioactive metabolites and the expression levels of genes involved in energy metabolism, insulin sensitivity, and immune response in the skeletal muscle. This work established two models of exercise intervention in obese mice and provided mechanistic insights into the beneficial effects of exercise intervention on systemic energy homeostasis.

Skeletal muscle mechanisms contributing to improved glycemic control following intense interval exercise and training

High-intensity and sprint interval training (HIIT and SIT, respectively) enhance insulin sensitivity and glycemic control in both healthy adults and those with cardiometabolic diseases. The beneficial effects of intense interval training on glycemic control include both improvements seen in the hours to days following a single session of HIIT/SIT and those which accrue with chronic training. Skeletal muscle is the largest site of insulin-stimulated glucose uptake and plays an integral role in the beneficial effects of exercise on glycemic control. Here we summarize the skeletal muscle responses that contribute to improved glycemic control during and following a single session of interval exercise and evaluate the relationship between skeletal muscle remodelling and improved insulin sensitivity following HIIT/SIT training interventions. Recent evidence suggests that targeting skeletal muscle mechanisms via nutritional interventions around exercise, particularly with carbohydrate manipulation, can enhance the acute glycemic benefits of HIIT. There is also some evidence of sex-based differences in the glycemic benefits of intense interval exercise, with blunted responses observed after training in females relative to males. Differences in skeletal muscle metabolism between males and females may contribute to sex differences in insulin sensitivity following HIIT/SIT, but well-controlled studies evaluating purported muscle mechanisms alongside measurement of insulin sensitivity are needed. Given the greater representation of males in muscle physiology literature, there is also a need for more research involving female-only cohorts to enhance our basic understanding of how intense interval training influences muscle insulin sensitivity in females across the lifespan.

Physical activity and sedentary behavior show distinct associations with tissue-specific insulin sensitivity in adults with overweight.

The aim of this study is to investigate associations between the physical activity (PA) spectrum (sedentary behavior to exercise) and tissue-specific insulin resistance (IR). We included 219 participants for analysis (median [IQR]: 61 [55; 67] years, BMI 29.6 [26.9; 32.0] kg/m2 ; 60% female) with predominant muscle or liver IR, as determined using a 7-point oral glucose tolerance test (OGTT). PA and sedentary behavior were measured objectively (ActivPAL) across 7 days. Context-specific PA was assessed with the Baecke questionnaire. Multiple linear regression models (adjustments include age, sex, BMI, site, season, retirement, and dietary intake) were used to determine associations between the PA spectrum and hepatic insulin resistance index (HIRI), muscle insulin sensitivity index (MISI) and whole-body IR (HOMA-IR, Matsuda index). In fully adjusted models, objectively measured total PA (standardized regression coefficient β=0.17, p=0.020), light-intensity PA (β=0.15, p=0.045) and moderate-to-vigorous intensity PA (β=0.13, p=0.048) were independently associated with Matsuda index, but not HOMA-IR (p > 0.05). A higher questionnaire-derived sport index and leisure index were associated with significantly lower whole-body IR (Matsuda, HOMA-IR) in men but not in women. Results varied across tissues: more time spent sedentary (β=-0.24, p=0.045) and a higher leisure index (β=0.14, p=0.034) were respectively negatively and positively associated with MISI, but not HIRI. A higher sport index was associated with lower HIRI (β=-0.30, p=0.007, in men only). While we confirm a beneficial association between PA and whole-body IR, our findings indicate that associations between the PA spectrum and IR seem distinct depending on the primary site of insulin resistance (muscle or liver).

Postprandial secretion of follistatin after gastric bypass surgery and sleeve gastrectomy

Follistatin is secreted from the liver and may regulate muscle growth and insulin sensitivity. Protein intake stimulates follistatin secretion, which may be mediated by increased glucagon in the context of low insulin concentrations. We investigated circulating follistatin after mixed-meals in two cohorts of patients who were part of previously published studies and had undergone bariatric surgery with either simultaneous assessment of amino acid absorption or administration of the GLP-1 receptor antagonist exendin-(9−39), which increased glucagon concentrations and impaired insulin secretion. Study 1 comprised obese matched subjects with previous Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery and unoperated controls who underwent 6-hour mixed-meal tests with intravenous and oral tracers including intrinsically labelled caseinate in the meal. Study 2 comprised obese subjects with previous RYGB who underwent two 5-hour mixed-meal tests with concomitant exendin-(9−39) or saline infusion. In study 1, the secretion of follistatin as well as the amino acid absorption was accelerated after RYGB compared with SG and controls, but the glucagon-to-C-peptide ratios did not differ between the groups. In study 2, exendin-(9−39) administration increased postprandial glucagon concentrations and lowered insulin secretion, whereas the concentration of follistatin was unchanged. In conclusion, postprandial follistatin secretion is accelerated in patients after RYGB which might be explained by an accelerated protein absorption rate rather than the glucagon-to-insulin ratio.

Chronic cortisol elevation restricts glucose uptake but not insulin responsiveness in zebrafish skeletal muscle

Although teleosts show an elevated insulin response to hyperglycemia, the circulating glucose levels are not normalized as rapidly as in mammals. While this may suggest a lack of target tissue insulin responsiveness, the underlying mechanisms are unclear. We investigated whether changes in skeletal muscle insulin sensitivity and glucose uptake underlie the cortisol-mediated elevated blood glucose levels. Adult zebrafish (Danio rerio) were exposed to water-borne cortisol for 3 days followed by an intraperitoneal injection of glucose with or without insulin. Cortisol treatment resulted in a temporal delay in the reduction in blood glucose levels, and this corresponded with a reduced glucose uptake capacity and lower glycogen content in the skeletal muscle. The transcript abundance of slc2a1b (which encodes for GLUT1b) and a suite of genes encoding enzymes involved in muscle glycogenesis and glycolysis were upregulated in the cortisol group. Both the control and cortisol groups showed higher whole body insulin expression in response to blood glucose elevation, which also resulted in enhanced insulin-stimulated phosphorylation of AKT in the skeletal muscle. The insulin-mediated phosphorylation of S6 kinase was lower in the cortisol group. Altogether, chronic cortisol stimulation restricts glucose uptake and enhances the glycolytic capacity without affecting insulin responsiveness in zebrafish skeletal muscle.

Investigating the effect of Resistance Training on the Axis / IGF-1 PI3K in Skeletal Muscle and Insulin Sensitivity in Type 2 Diabetic Rats

Introduction: IGF-1 is a polypeptide hormone that plays a vital role in the development and regeneration of skeletal muscles.&#x0D; IGF-1 activates anabolic pathways such as PI3K and IRS-1/2 to activate a series of intracellular anabolic signals. The purpose of this study was to investigate the effect of 8 weeks resistance training on IGF1, PI3K and insulin sensitivity in neural muscle in type 2 diabetic rats.&#x0D; Methods: In this experimental study, 14 male Wistar mice aged 8 to 10 weeks and induction of type 2 diabetes (type 2 diabetes was induced by intraperitoneal injection of nicotinamide and STZ in diabetic groups) and were divided into two groups of resistance training and control groups. The mice in the control group did not exercise during the study, while the resistance group performed 8 weeks of training for 5 sessions per week. Resistance exercises in each session were performed in the form of 10 repetitions with 90-second rest intervals in the form of climbing a 26-step ladder to a height of one meter with a vertical slope of 85%, and weight was applied to the base of the rat's tail. 48 hours after the last training session, blood samples were taken from the heart and neural muscle tissue was extracted. Real Time-PCR method was used to determine the genes and one-way ANOVA test was used to compare the variables. All statistical studies were done using SPSS version 16 software.&#x0D; Results: The results of this study showed that expression of IGF-1 and PI3K in the duodenal axis of diabetic rats in resistance training group was significantly higher than that of the control group (P = 0.001) (P = 0.11). Serum insulin sensitivity in diabetic rats was not significantly different in diabetic rats compared to the diabetic rats (P=0.778).&#x0D; Conclusion: It seems that eight weeks of resistance training can be a strong stimulus on IGF-1 and PI3K gene expression and no change in insulin sensitivity in neural muscle in type 2 diabetic rats.

Impact of tyrosine kinase inhibitors on glucose control and insulin regulation in patients with chronic myeloid leukemia.

Treatment with tyrosine kinase inhibitors (TKIs), especially nilotinib, often results in hyperglycemia, which may further increase cardiovascular disease risk in patients with chronic myeloid leukemia (CML). The mechanism underlying the TKI-induced glucose dysregulation is not clear. TKIs are suggested to affect insulin secretion but also insulin sensitivity of peripheral tissue has been proposed to play a role in the pathogenesis of TKI-induced hyperglycemia. Here, we aimed to assess whether skeletal muscle glucose uptake and insulin responses are altered in nondiabetic patients with CML receiving TKI treatment. After a glycogen-depleted exercise bout, an intravenous glucose bolus (0.3 g/kg body weight) was administered to monitor 2-h glucose tolerance and insulin response in 14 patients with CML receiving nilotinib, 14 patients with CML receiving imatinib, and 14 non-CML age- and gender-matched controls. A dynamic [18F]-FDG PET scan during a hyperinsulinemic-euglycemic clamp was performed in a subgroup of 12 male patients with CML to assess m. quadriceps glucose uptake. We showed that patients with CML treated with nilotinib have an increased insulin response to intravenous glucose administration after muscle glycogen-depleted exercise. Despite the increased insulin response to glucose administration in patients with CML receiving nilotinib, glucose disappearance rates were significantly slower in nilotinib-treated patients when compared with controls in the first 15 min after glucose administration. Although [18F]-FDG uptake in m. quadriceps was not different, patients receiving nilotinib showed a trend toward decreased glucose infusion rates during euglycemic clamping when compared with patients receiving imatinib. Together, these findings indicate disturbed skeletal muscle glucose handling in patients with CML receiving nilotinib therapy.NEW & NOTEWORTHY In this study, we have shown that non-diabetic patients with CML receiving nilotinib therapy show early signs of disturbed skeletal muscle glucose handling, which was not observed in imatinib-treated patients. These observations in nilotinib users may reflect decreased muscle insulin sensitivity, which could serve as a potential target to counteract glycemic dysregulation, and is of clinical importance since these patients have an increased cardiovascular disease risk.

Low serum creatinine, a surrogate marker of muscle mass, correlates with insulin sensitivity in nonhuman primates.

Decreased serum creatinine levels are associated with increased risk of type 2 diabetes (T2DM) in humans, however, its association with muscle mass and insulin sensitivity have not been studied in NHPs. Retrospective data of 229 adult NHPs were studied for association of serum creatinine levels with muscle mass and onset of T2DM. Serum creatinine levels were positively correlated with lean muscle mass in nondiabetic (non-DM), male and female NHPs. Aged NHPs had significantly reduced lean muscle mass and corresponding creatinine levels compared to young age groups (p < .001). Creatinine was positively correlated with insulin sensitivity in nonDM male NHPs and significant decrease in creatinine was observed in T2DM (p < .001) compared to same age group nonDM NHPs. The pathophysiology of T2DM in NHPs is similar to humans, low creatinine further provides utility of surrogate biomarkers of lower muscle mass and risk factor for T2DM NHPs.

Exploring the Potential Benefits and Risks of 2,4-Thiazolidinediones (TZDs) in the Management of Diabetes and Related Conditions

TZDs have been demonstrated to enhance insulin sensitivity and glucose absorption in muscle and adipose tissues, resulting in better glycemic control in type 2 diabetes patients. TZDs have also been demonstrated to have potential benefits in terms of lowering the risk of cardiovascular disease and improving lipid profiles. The potential benefits and hazards of a class of medications known as 2,4-thiazolidinediones (TZDs) in the treatment of diabetes and related disorders are discussed in this article. According to recent research, cardiovascular toxicity with rosiglitazone and a rise in bladder cancer with pioglitazone is no longer serious concerns. TZD use is also connected with major hazards, such as an increased risk of bone fractures, edema, and weight gain. Furthermore, TZDs have been linked to an increased risk of bladder cancer, and long-term use may result in liver damage. Overall, TZDs can be an effective tool in the treatment of diabetes and related disorders, but doctors must carefully balance the potential advantages with the hazards associated with their usage. Patients should be constantly monitored for side effects, and alternate treatment options should be sought when necessary.

Triterpenoid CDDO-EA inhibits lipopolysaccharide-induced inflammatory responses in skeletal muscle cells through suppression of NF-κB.

Chronic inflammation is a major contributor to the development of obesity-induced insulin resistance, which then can lead to the development of type 2 diabetes (T2D). Skeletal muscle plays a pivotal role in insulin-stimulated whole-body glucose disposal. Therefore, dysregulation of glucose metabolism by inflammation in skeletal muscle can adversely affect skeletal muscle insulin sensitivity and contribute to the pathogenesis of T2D. The mechanism underlying insulin resistance is not well known; however, macrophages are important initiators in the development of the chronic inflammatory state leading to insulin resistance. Skeletal muscle consists of resident macrophages which can be activated by lipopolysaccharide (LPS). These activated macrophages affect myocytes via a paracrine action of pro-inflammatory mediators resulting in secretion of myokines that contribute to inflammation and ultimately skeletal muscle insulin resistance. Therefore, knowing that synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acids (CDDOs) can attenuate macrophage pro-inflammatory responses in chronic disorders, such as cancer and obesity, and that macrophage pro-inflammatory responses can modulate skeletal muscle inflammation, we first examined whether CDDO-ethyl amide (CDDO-EA) inhibited chemokine and cytokine production in macrophages since this had not been reported for CDDO-EA. CDDO-EA blocked LPS-induced tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukine-1beta (IL-1β), and interleukine-6 (IL-6) production in RAW 264.7 mouse and THP-1 human macrophages. Although many studies show that CDDOs have anti-inflammatory properties in several tissues and cells, little is known about the anti-inflammatory effects of CDDOs on skeletal muscle. We hypothesized that CDDO-EA protects skeletal muscle from LPS-induced inflammation by blocking nuclear factor kappa B (NF-κB) signaling. Our studies demonstrate that CDDO-EA prevented LPS-induced TNF-α and MCP-1 gene expression by inhibiting the NF-κB signaling pathway in L6-GLUT4myc rat myotubes. Our findings suggest that CDDO-EA suppresses LPS-induced inflammation in macrophages and myocytes and that CDDO-EA is a promising compound as a therapeutic agent for protecting skeletal muscle from inflammation.

CLINICAL TRIAL OF METFORMIN FOR FRAILTY PREVENTION IN COMMUNITY-DWELLING OLDER ADULTS WITH PRE-DIABETES

Abstract Background Metformin may reduce frailty through improving insulin resistance and inflammation, aging mechanisms known to increase frailty risk. We describe a randomized clinical trial of metformin for frailty prevention in community-dwelling older adults with pre-diabetes and provide baseline characteristics of randomized participants. Methods Older adults (65+ years) are studied in this randomized, double-blind, placebo-controlled trial of metformin (max 2,000 mg/day). Pre-diabetes, required for inclusion, is assessed by 2-hour oral glucose tolerance test (OGTT). Individuals with glomerular filtration rate &amp;lt; 45 mL/min and frail individuals (Fried criteria) are excluded. The primary outcome, frailty, is assessed by both Fried criteria and frailty index. Secondary outcomes are physical function (short physical performance battery), lower extremity strength (Biodex), 6-minute walk, inflammation (systemic and skeletal muscle tissue), muscle insulin signaling, insulin sensitivity (insulin clamp), glucose tolerance (OGTT), and body composition (dual-energy x-ray absorptiometry). Subjects are followed for 2 years with safety assessments every 3 months and frailty assessment and OGTT every 6 months. Results 145 participants (49% female, 35% Hispanic) are randomized. Mean age is 71.8 ± 5.4 years (range: 65-88), body mass index is 30.8 ±6 kg/m2, and Hemoglobin A1c is 5.6 ±0.4%. Using Fried criteria, 63.4% have frailty score of 0, 30.3% a score of 1, and 6.2% a score of 2. Conclusion Metformin is being examined as a potential therapeutic agent to prevent frailty in older adults with pre-diabetes. Findings from this trial may have future implications for screening and treatment of pre-diabetes in older adults for the prevention of frailty.

NINJ2 deficiency inhibits preadipocyte differentiation and promotes insulin resistance through regulating insulin signaling.

Genetic variants in ninjurin-2 (NINJ2; nerve injury-induced protein 2) confer risk of ischemic strokes and coronary artery disease as well as endothelial activation and inflammation. However, little is known about NINJ2's in vivo functions and underlying mechanisms. The phenotypes of NINJ2 knockout mice were analyzed, and mechanisms of NINJ2 that regulate body weight, insulin resistance, and glucose homeostasis and lipogenesis were investigated in vivo and in vitro. This study found that mice lacking NINJ2 showed impaired adipogenesis, increased insulin resistance, and abnormal glucose homeostasis, all of which are risk factors for strokes and coronary artery disease. Mechanistically, NINJ2 directly interacts with insulin receptor/insulin-like growth factor 1 receptor (INSR/IGF1R), and NINJ2 knockdown can block insulin-induced mitotic clonal expansion during preadipocyte differentiation by inhibiting protein kinase B/extracellular signal-regulated kinase (AKT/ERK) signaling and by decreasing the expression of key adipocyte transcriptional regulators CCAAT/enhancer-binding protein β (C/EBP-β), C/EBP-α, and peroxisome proliferator-activated receptor γ (PPAR-γ). Furthermore, the interaction between NINJ2 and INSR/IGF1R is needed for maintaining insulin sensitivity in adipocytes and muscle via AKT and glucose transporter type 4. Notably, adenovirus-mediated NINJ2 overexpression can ameliorate diet-induced insulin resistance in mice. In conclusion, these findings reveal NINJ2 as an important new facilitator of insulin receptors, and the authors propose a unique regulatory mechanism between insulin signaling, adipogenesis, and insulin resistance.

Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.

Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content. C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle. We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine1150 on the insulin receptor kinase (IRKT1150), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively. These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.

Muscle Function, Body Composition, Insulin Sensitivity and Physical Activity in Adolescents Born Preterm: Impact of Gestation and Vitamin D Status.

Whilst several studies have explored adolescent metabolic and cognitive function after preterm birth, few have explored muscle function and physical activity. We set out to examine the relationship between gestational age and muscle metabolism in a cohort of adolescents who were born preterm. Participants were recruited from the Newcastle preterm birth growth study cohort. They did not have severe neurological disease and were not on daily medication. Participants underwent an assessment of oxidative muscle function using phosphorus magnetic resonance spectroscopy that included the half-time for recovery of equilibrium of phosphocreatine, τ½PCr. In addition, we measured key variables that might affect muscle function including physical activity levels determined by 3-day accelerometry, body composition using air displacement plethysmography, insulin sensitivity using the homeostatic model assessment/Matsuda index and serum vitamin D concentrations. 60 adolescents (35F) median age 15.6 years (range 12.1−18.8) with a median gestation of 31 weeks (range 24 to 34 weeks) underwent a single assessment. Males were more active and spent less time in sedentary mode. Time spent in light activity was associated with insulin sensitivity (IS) (Matsuda Index; p < 0.05) but there were no strong correlations between activity levels and gestational age. Greater fat mass, waist circumference and body mass index were all associated with lower IS. Gestational age was negatively associated with adjusted measures of oxidative muscle function (τ½PCr). In a stepwise multivariate linear regression model, gestational age at birth was the most significant predictor of oxidative muscle function (p = 0.005). Higher serum vitamin D levels were also associated with faster phosphocreatine recovery time (p = 0.045). Oxidative function in the skeletal muscle of adolescents born preterm is associated with gestational age and vitamin D concentrations. Our study suggests that being born preterm may have a long-term impact on muscle metabolism.

Skeletal muscle HSF1 prevents insulin resistance by improving glucose utilization.

The regulation of muscle glucose utilization has significant potential for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Heat shock factor 1 (HSF1) is involved in cellular metabolism and regulation of muscle metabolism. However, it is unclear how HSF1 regulates muscle glucose metabolism. In the present study, the development of obesity in mice was associated with HSF1 downregulation. Serum samples and muscle biopsies were obtained from obese and healthy humans. Fasting glucose and insulin levels and the homeostasis model assessment of insulin resistance value showed that obesity was associated with insulin resistance. The skeletal muscle level of HSF1 was decreased in obese and ob/ob mice. HSF1 was selectively over-expressed in the skeletal muscles of high fat diet (HFD)-fed mice. Muscle HSF1 over-expression successfully triggered glycolytic-to-oxidative myofiber switch and increased fatty acid metabolism and insulin sensitivity in the skeletal muscles of HFD-fed mice. Moreover, HSF1 improved energy expenditure and blocked muscle accumulation of triglycerides in HFD-fed mice. Consequently, muscle HSF1 mitigated the impaired muscle insulin signaling and insulin resistance in HFD-fed mice. In conclusion, T2DM and obesity in HFD-fed mice may be treated with selective HSF1-directed programming of exercise-like effects in skeletal muscle. These findings may aid the development of a new therapeutic approach for obesity and T2DM.