Treatment Of Insulin Resistance Research Articles

Cynomorium songaricum: UHPLC/ESI-LTQ-Orbitrap-MS analysis and mechanistic study on insulin sensitivity of a flavonoid-enriched fraction

BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, posing a significant global health concern due to its increasing prevalence. Insulin resistance (IR) plays a major role in the development of T2DM and is often linked to factors such as obesity, physical inactivity, and a sedentary lifestyle. Recently, there has been growing interest in exploring the potential of natural products for improving insulin sensitivity and glucose metabolism. Among these, Cynomorium songaricum Rupr., an edible parasitic plant, has shown promising antidiabetic effects. However, research on its beneficial effects on IR is still nascent. Therefore, this study aims to investigate the application of a Cynomorium songaricum flavonoid-enriched fraction (CSF) in the treatment of IR in T2DM, along with elucidating the chemical and biochemical mechanisms involved. MethodFirst, UHPLC/ESI-LTQ-Orbitrap-MS was utilized to perform a chemical profiling of Cynomorium songaricum extract (CSF). Subsequently, glycogen synthesis, gluconeogenesis and glucose consumption assays were conducted on HepG2 cells with a high glucose high insulin -induced IR model to illustrate the favorable impacts of CSF on IR. Then, an innovative network pharmacology analysis was executed to predict the potential chemical components and hub genes contributing to CSF's protective effect against IR. To further elucidate molecular interactions, molecular docking studies were performed, focusing on the binding interactions between active constituents of CSF and crucial targets. Additionally, an RNA-sequencing assay was employed to uncover the underlying biochemical signaling pathway responsible for CSF's beneficial effects. To validate these findings, western blot and qPCR assays were employed to verify the pathways related to IR and the potential signaling cascades leading to the amelioration of IR. ResultsThe UHPLC/ESI-LTQ-Orbitrap-MS analysis successfully identified a total of thirty-six flavonoids derived from CSF. Moreover, CSF was shown to significantly improve glycogen synthesis and glucose consumption as well as inhibit gluconeogenesis in HepG2 cells of IR. An innovative network pharmacology analysis unveiled key hub genes—AKT1 and PI3K—integral to metabolic syndrome-related signaling pathways, which contribute to the favorable impact of CSF against IR. Noteworthy active ingredients including quercetin, ellagic acid and naringenin were identified as potential contributors to these effects. The results of western blot and qPCR assays provided compelling evidence that CSF improved insulin sensitivity by modulating the PI3K-Akt signaling pathway. Subsequent RNA-sequencing analysis, in tandem with western blot assays, delved deeper into the potential mechanisms underlying CSF's advantageous effects against IR, potentially associated with the enhancement of endoplasmic reticulum (ER) proteostasis. ConclusionCSF exhibited a remarkable ability to enhance insulin sensitivity in the IR model of HepG2 cells. This was evident through enhancements in glycogen synthesis and glucose consumption, along with its inhibitory impact on gluconeogenesis. Furthermore, CSF demonstrated an improvement in the insulin-mediated PI3K-Akt signaling pathway. The potential active constituents were identified as quercetin, ellagic acid and naringenin. The underlying biochemical mechanisms responsible for CSF's beneficial effects against IR were closely linked to its capacity to mitigate ER stress, thereby offering a comprehensive understanding of its protective action.

Beta2-agonist impairs muscle insulin sensitivity in persons with insulin resistance.

Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and non-diabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance. To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects. In a cross-over design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-h hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, two hours into and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques. We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. While both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen. Our findings suggest that beta2-agonist inhibits glycogenesis while intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist.

The combination of berberine and isoliquiritigenin synergistically improved adipose inflammation and obesity-induced insulin resistance.

White adipose tissue accumulation and inflammation contribute to obesity by inducing insulin resistance. Herein, we aimed to screen the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for the treatment of insulin resistance and explore the potential synergistic mechanisms. Enzyme-linked immunosorbent assay and quantitative PCR were used to detect expression levels of inflammatory genes in vitro and in vivo. Western blotting and immunohistochemistry were performed to detect protein levels of the insulin signaling pathway and macrophage markers. The effects on obesity-induced insulin resistance were verified using a diet-induced obesity (DIO) mouse model. Interactions between macrophage and adipocyte were assessed using a cellular supernatant transfer assay. Berberine (BBR) and isoliquiritigenin (ISL) alleviated mRNA levels and secretion of inflammatory genes in vitro and in vivo. Furthermore, BBR acted synergistically with ISL to ameliorate obesity and dyslipidemia in DIO mice. Meanwhile, the combination treatment significantly improved glucose intolerance and insulin resistance and decreased M1-macrophage accumulation and infiltration in the adipose tissue. Mechanistically, co-treatment with BBR and ISL upregulated the protein expression of the IRS1-PI3K-Akt insulin signaling pathway, enhanced glucose uptake in adipocyte, and suppressed the interaction between macrophage and adipocyte. BBR and ISL were identified as the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for treating insulin resistance. The synergistic combination of BBR with ISL can be a promising and effective strategy for improving obesity-induced adipose inflammation and insulin resistance.

1Comprehensive multi-omics analysis reveals the mechanism of loganin from Corni Fructus in improving insulin resistance in mice

Corni Fructus (CF) has great potential as a food product in the treatment of T2DM (thirst-quenching). As the main active ingredient of CF, loganin (LOG) possesses multiple pharmacological propertiesincluding hypoglycemic, hypolipidemic, anti-inflammatory and antibacterial. In this study, we firstly verified the efficacy of LOG in improving the disordered glycolipid metabolism and liver damages in a murine insulin resistance (IR) model, and then determined the ameliorative effect of LOG on IR-HepG2 cell model. To clarify the mechanism of LOG on IR, a series of differentially expressed metabolites (DEM) and genes (DEG) were screened out through non-targeted metabolomics and transcriptomics techniques. In addition, integrative metabolomics and transcriptomics analyses revealed a few key pathways (foxO signaling pathway, glycine serine and threonine metabolism, glutamatergic synapse, cocaine addiction, amphetamine addiction, and valine leucine and isoleucine biosynthesis), important DEM (l-Glutamate), and DEGs (Sgk2, Grin3b, Acadsb, Grik1) were reversely regulated by LOG as compared with the IR model. It is hypothesized that LOG may exert the anti-IR effect via finely tuning amino acid metabolism. Taken together, our data may shine light on the screening of new intervention targets and developing of new LOG-related agents for IR treatment.

Hypoglycemic effects of propolis extract on polycystic ovarian syndrome in Wistar rats

Background: Polycystic ovarian syndrome (PCOS) is an endocrinopathy that causes various metabolic syndromes, including insulin resistance in 20-40% of patients. The treatment of the condition is often carried out using metformin, but it has been reported to have different gastrointestinal side effects. Consequently, several studies have recommended the use of propolis as an alternative, which has proven effective in improving insulin resistance in diabetic-induced rats and causes fewer side effects. Objective: This study aimed to compare the effects of propolis and metformin in treating insulin resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) value. Materials and Methods: This study used post-test-only randomized control trial design and the sample population comprised 30 Wistar rats. The animals were divided into 5 groups: control (C), PCOS (PCO), PCOS with metformin (PCO+M), PCOS with propolis extract (PCO+P), and PCOS with metformin and propolis extract (PCO+MP). Subsequently, blood sampling, ovarian tissue sampling, and vaginal smearing were performed after 28 days of treatment. Results: PCO+P and PCO+M groups experienced a significant decrease in testosterone concentration and preantral follicle count compared to PCOS group but the anovulation cycle was similar. Fasting blood glucose concentration in PCO+MP group showed a significant decrease compared to others. However, fasting insulin concentration and HOMA-IR value in treatment groups did not show any reduction compared to PCOS group. Conclusion: Based on the results, propolis extract and metformin could not improve insulin resistance based on HOMA-IR value. However, propolis extract had better hypoglycaemic effects compared to metformin. The combination of both treatments had the potential to lower fasting glucose concentration.

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle.

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide–CoQ–respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.

Parabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a

Gut microbiota plays a key role in insulin resistance (IR). Here we perform a case-control study of Chinese adults (ChiCTR2200065715) and identify that Parabacteroides distasonis is inversely correlated with IR. Treatment with P. distasonis improves IR, strengthens intestinal integrity, and reduces systemic inflammation in mice. We further demonstrate that P. distasonis-derived nicotinic acid (NA) is a vital bioactive molecule that fortifies intestinal barrier function via activating intestinal G-protein-coupled receptor 109a (GPR109a), leading to ameliorating IR. We also conduct a bioactive dietary fiber screening to induce P. distasonis growth. Dendrobium officinale polysaccharide (DOP) shows favorable growth-promoting effects on P. distasonis and protects against IR in mice simultaneously. Finally, the reduced P. distasonis and NA levels were also validated in another human type 2 diabetes mellitus cohort. These findings reveal the unique mechanisms of P. distasonis on IR and provide viable strategies for the treatment and prevention of IR by bioactive dietary fiber.

ß- Caryophyllene Ameliorates Insulin Resistance in Liver of High Fat Diet and Fructose-Induced Type-2 Diabetic Rats

Insulin resistance may impact organs that transmit insulin signals, like skeletal muscle, adipose tissue, and the liver. Hyperglycemia and hypertriglyceridemia in the fasting state of type 2 diabetes mellitus are more significantly impacted by insulin resistance in the liver. Hypertriglyceridemia is the culprit behind beta-cell failure in type 2 diabetes. Treating insulin resistance in liver as a primary mechanism of traditional antidiabetic drugs, but unfortunately traditional drugs has unalterable advisory effect. In the present research, insulin resistance in the liver is addressed with the versatile natural phytonutrient beta-caryophyllene to demonstrate effectiveness in managing diabetes. An effective dose of -Caryophyllene taken by non-parental route (200 mg/kg b.wt) was given for 30 days to experimentally induced (high-fat diet and fructose-fed) type-2 diabetic rats to find out whether β-Caryophyllene regulates the IRS-2/akt pathway of insulin signaling. In the liver of diabetic rats, the data demonstrates that ß-caryophyllene treatment significantly increased the mRNA and protein expression of insulin receptor (IR) and GLUT-2. However, there was a significant variation in the mRNA expression of akt and insulin receptor-substrate-2 (IRS-2) between groups. Taking caryophyllene supplements can be beneficial for the control of type 2 diabetes. Studies conducted with this sesquiterpene could have tremendous potential and benefit for the treatment of type 2 diabetes.

2 A Randomized, Double-blinded, Placebo-controlled Trial of Liraglutide in Patients with Parkinson’s Disease: Neuropsychological Outcomes

Objective:Parkinson’s disease (PD) is associated with metabolic disorders such as insulin resistance. Pharmacological intervention used to treat insulin resistance, like GLP-1 agonists, may have auspicious results in the treatment for PD. The objective of this clinical trial was to assess the therapeutic effect of liraglutide on non-motor symptoms, such as, but not limited to, cognitive function and emotional well-being, and quality of life for individuals with PD.Participants and Methods:In a single-center, randomized, double-blind, placebo-controlled trial, PD patients self-administered liraglutide injections once-daily (1.2 or 1.8 mg, as tolerated) or placebo in a 2:1 study design for 52 weeks after titration. Primary outcomes included adjusted difference in the OFF-state Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) part III, non-motor symptom scale (NMSS) and Mattis Dementia Rating Scale (MDRS-2). Secondary outcomes included quality of life scores (Parkinson Disease Questionnaire, PDQ-39) and other neuropsychological tests, including Delis-Kaplan Executive Function System (DKEFS), Geriatric Depression Scale (GDS), and Parkinson’s Anxiety Scale (PAS) scores.Results:Sixty-three subjects were enrolled and randomized to liraglutide (n=42) or placebo (n=21). Mean age in years was 63.5 (9.8) and 64.2 (6.4) for liraglutide and placebo cohorts, respectively (p=0.78), and mean age at symptom onset was 58.9 (10.5) and 59.3 (7.5) for liraglutide and placebo cohorts, respectively (p=0.86). At 54 weeks, NMSS scores had improved by 6.6 points in the liraglutide group and worsened by 6.5 points in the placebo group, a 13.1 point adjusted mean difference (p<0.05). Further analysis showed all nine NMSS sub-domain changes favoring the liraglutide group, with one (attention/memory) reaching statistical significance (p<0.05). Secondary outcome analyses revealed a significant improvement of PDQ-39 (p<0.001) and Parkinson’s Anxiety Scale - Avoidance Behavior scores (p<0.05) in the treatment group. MDRS-2 sub-scores did not further differentiate study groups, while DKEFS letter fluency scores favored placebo group (p<0.05).Conclusions:Treatment with liraglutide improved self-reported non-motor symptoms of PD, activities of daily living, and quality of life. These results validate similar outcomes reported with other GLP-1 agonists implicating consideration for novel treatment opportunities for individuals with PD. Notably, the absence of significant performance-based cognitive changes over the duration of the trial for the participants in this study has several plausible explanations given participant-related baseline demographic and clinical factors. Implications for neuropsychologists will be discussed.

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

BackgroundMonogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology.MethodsSystematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.Results10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions.ConclusionsThe evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.

Sesamol Alleviates High-Fat Diet-Induced Hepatic Insulin Resistance in C57BL/6J Mice Through AMPK Activation Mediated by Adipose Adiponectin.

Sesamol is the major bioactive constituent isolated from sesame seeds and has a variety of bioactivities. However, its role and mechanism in liver insulin resistance remain unknown. The current study was designed to investigate the underlying adipose-liver crosstalk mechanism of sesamol ameliorating hepatic insulin sensitivity. The therapeutic effect of sesamol was evaluated in high-fat diet (HFD)-fed C57BL/6J mice (100mg/kg for 8weeks, XYGW-2021-75) and the mechanism was further explored in HepG2 cells with/without adiponectin and adenosine 5 '-monophosphate-activated protein kinase (AMPK) inhibitor administration. Our in vivo data showed that sesamol reduced hepatic insulin resistance in HFD-induced mice with obesity by modulating protein expression levels of glycogen synthase (GS), phosphoenolpyruvate carboxykinase (PEPCK) and protein kinase B (AKT). Moreover, sesamol not only increased the serum and adipose tissue adiponectin concentrations but also activated the phosphorylation of AMPK in the liver. Furthermore, in vitro studies using recombinant human adiponectin and an AMPK inhibitor revealed that adiponectin and sesamol have a synergic impact on increasing glycogenesis and reducing gluconeogenesis, of which the effects could be attenuated by the AMPK inhibitor. Taken together, our results suggested that sesamol stimulated adiponectin secretion from adipocytes, whereby exhibited a co-effect on activating the downstream signal of hepatic AMPK, resulting in the alleviation of hepatic insulin resistance. The novel findings of sesamol on hepatic effects provides prospective therapeutic approaches to treat insulin resistance.

Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD.

This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development. SPP1 and T-cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individualswith obesity. The role of SPP1 on T cells was evaluated in Spp1-knockout mice challenged with a high-fat diet. In humanswith obesity, elevated SPP1 expression in AT was parallel to T-cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T-cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T-cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1)polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity-associated liver steatosis and inflammation. Current findings highlight a critical role of SPP1 in the initiation of obesity-driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.

Revisiting Resistin: A Novel Signaling Molecule in the Development of Inflammation, Insulin Resistance, and Type 2 Diabetes Mellitus

Resistin has a role in the development of insulin resistance, occurring through the pathways of glucose regulation, inflammation, and dyslipidemia. The aim of this study was to revisit the topic of resistin and uncover the latest research on this novel molecule. Additionally, another aim was to create a molecular diagram detailing how resistin contributes to the development of insulin resistance in humans through these pathways. This resulting diagram demonstrates that resistin may play an integral role in the development of insulin resistance. Further in vivo studies are needed to investigate the action of resistin within humans. Further research in this area could potentially lead to the development of pharmaceutical therapies that target resistin to treat insulin resistance.

Exercise ameliorates skeletal muscle insulin resistance by modulating GRK4-mediated D1R expression.

Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as fenoldopam, could improve peripheral insulin sensitivity, while antipsychotics, which are dopamine receptor antagonists, increased susceptibility to Type 2 diabetes mellitus (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the up-regulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, the present study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity.

Inhibiting Phosphatidylcholine Remodeling in Adipose Tissue Increases Insulin Sensitivity.

Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.

Low-Calorie Ketogenic Diet: Potential Application in the Treatment of Polycystic Ovary Syndrome in Adolescents.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Hyperandrogenism, hyperinsulinism and insulin resistance (IR) are the main drivers of clinical, metabolic and reproductive phenotypes of PCOS. In adolescence, the cornerstones of PCOS treatment are lifestyle and dietary interventions. In particular, the quality and quantity of carbohydrates introduced with the diet play a crucial role in the benefits of diet on PCOS. Recently, the ketogenic diet (KD) has attracted significant interest for the treatment of IR and for the control of carbohydrate metabolism, which has proven to be beneficial for several dysmetabolic conditions, including PCOS. The goal of the KD is to induce a fasting-like metabolism with production of chetonic bodies. Ketosis is a good regulator of calorie intake and mimics the starvation effect in the body, leading to body weight control and consequent metabolism. Additionally, during ketogenesis, insulin receptor sensitivity is also promoted. We proposed a broad overview of the available literature regarding KD indications and considered its metabolic benefits useful for improving PCOS management. The reported data support that a low-calorie ketogenic diet (LCKD) plays a positive role as a regulator of control weight, IR, glucose and lipid homeostasis and hormonal profile. Unfortunately, the evidence concerning the benefits of the very LCKD in adolescents with PCOS and excessive body weight is still numerically scarce. Further studies are necessary to understand whether these effects are due to weight loss or to the nutritional characteristics of this diet. Considering the long-term consequences of PCOS, it is crucial to detect the prospects of nutritional interventions to protect fertility, starting in adolescence.

Exercise combined with heat treatment improves insulin resistance in diet-induced obese rats

Insulin resistance is a risk factor for various cardiovascular diseases, which seriously threaten human health. Thus, finding a safe, effective and economical strategy to treat insulin resistance is urgently needed. This study aimed to investigate the effects of exercise combined with heat treatment on the insulin sensitivity in skeletal muscle of diet-induced obese (DIO) rats. Obese rats were induced by a 10-week high-fat diet and were randomly divided into normal temperature + control (NC), normal temperature + exercise (NE), heat treatment + control (HC) and heat treatment + exercise (HE) groups for 7 weeks of incremental load endurance exercise and heat treatment (exposure to a high-temperature environment room). At the end of the 7-week intervention, we measured fasting blood glucose, serum fasting insulin, serum leptin, serum adiponectin, protein expression of HSF1/HSP27 and JAK2/STAT3 pathway in soleus (primarily composed of slow-twitch fibres) and extensor digitorum longus (primarily composed of fast-twitch fibres) muscles. The results showed that exercise combined with heat treatment can effectively improve insulin resistance by regulating HSF1/HSP27 and JAK2/STAT3 pathways in the slow-twitch muscle of DIO rats. Importantly, exercise combined with heat treatment is more effective in improving insulin resistance in DIO rats than exercise or heat treatment alone. Low-moderate intensity exercise that stimulates slow-twitch muscle, combined with heat treatment is an effective strategy to treat insulin resistance.

Design, Synthesis, Biological Evaluation and Molecular Docking Studies of Quercetin-Linker-H2 S Donor Conjugates for the Treatment of Diabetes and Wound Healing.

Based on the use of quercetin for treating diabetes and H2 S for promoting wound healing, a series of three quercetin-linker-H2 S donor conjugates was designed, synthesized and characterized by 1 H-NMR, 13 C-NMR and MS. Meanwhile, in vitro evaluation of these compounds was also researched by IR-HepG2 treatment experiment, MTT assay, scratch test and tubule formation experiment. The three compounds could be used to treat insulin resistance induced by high glucose and promote the proliferation of human umbilical vein endothelial cells, wound healing, and the formation of tubules in vitro under a high-glucose environment. Our results illustrate that these compounds could be used to treat diabetes and promote wound healing at the same time. Furthermore, molecular docking study results of the compounds were consistent with the evaluated biological activity. In vivo research of compounds is underway.

849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats

Background: TLC-3595 is a potent (IC50=14nM), selective, small molecule, allosteric inhibitor of acetyl-CoA carboxylase 2 (ACC2). TLC-3595 provides a novel therapeutic approach for type 2 diabetes (T2D), via reduction in intramyocellular lipid (IMCL) content, that is complementary to approved therapies. Reduced IMCL strongly correlates with insulin sensitivity (IS). Here, we demonstrate antidiabetic effects of TLC-3595 in Zucker Diabetic Fatty (ZDF) rats. Methods: IMCL was measured by 1H-MRS. T2D progression and IS by hyperinsulinemic-euglycemic clamp were assessed in 30% diet-restricted ZDF rats treated with TLC-3595 (1.67, 5, or 15mg/kg) or pioglitazone (Pio, 0.75mg/kg) daily for 5-12 weeks. Results: TLC-3595 or an analog caused rapid and sustained IMCL reduction (~50%) in lean and dysmetabolic rodents. TLC-3595 enhanced systemic fatty acid oxidation (increased plasma beta-hydroxybutyrate) and reduced cardiac lipid in ZDF rats. TLC-3595 dose-dependently delayed β-cell failure in ZDF rats and was non-inferior to Pio for reductions in hyperglycemia (15-25% lower glucose AUC) and HbA1c (0.6-1.6% vs. vehicle) (Fig A, B). TLC-3595 improved IS and increased clamp glucose infusion rate by 29%, (Fig C). Conclusion: TLC-3595 reduced IMCL, improved IS, and delayed T2D progression comparable to Pio in ZDF rats. These data provide strong rationale for evaluation of TLC-3595 to treat insulin resistance and T2D. Disclosure A. Vijayakumar: Employee; OrsoBio Inc, Gilead Sciences, Inc. E. Murakami: Employee; OrsoBio. R.S. Huss: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. N. Sroda: None. A. Shimazaki: Employee; Shionogi & Co. Ltd. Y. Kashiwagi: Employee; Shionogi & Co. Ltd. R.P. Myers: Employee; OrsoBio, Inc. Stock/Shareholder; OrsoBio, Inc. M. Subramanian: Other Relationship; OrsoBio Inc. G.I. Shulman: Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC. Consultant; Novo Nordisk. Other Relationship; iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc. Consultant; DiCerna Pharmaceuticals, Inc. Other Relationship; Equator Therapeutics, Inc., Generian Pharmaceuticals. Stock/Shareholder; Levels Health, Inc. Other Relationship; Fortress Biotech, Inc. Consultant; Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc. Other Relationship; OrsoBio, Aro Biotherapeutics Company.