Branched chain amino acids, as essential amino acids, can be used to synthesize nitrogen-containing compounds and also act as signal molecules to regulate substance metabolism. Studies have shown that the elevated level of branched chain amino acids is closely related to insulin resistance and type 2 diabetes. It can affect insulin signal transduction by activating mammalian target of rapamycin (mTOR) signal pathway, and regulate insulin resistance by damaging lipid metabolism and affecting mitochondrial function. In addition, abnormal catabolism of branched amino acids can lead to the accumulation of metabolic intermediates, such as branched chain α-keto acids, 3-hydroxyisobutyrate and β-aminoisobutyric acid. Branched chain α-keto acids and 3-hydroxyisobutyrate can induce insulin resistance by affecting insulin signaling pathway and damaging lipid metabolism. β-aminoisobutyric acid can improve insulin resistance by reducing lipid accumulation and inflammatory reaction and enhancing fatty acid oxidation. This paper systematically reviewed the regulatory effects and mechanisms of branched chain amino acids and their metabolic intermediates on insulin resistance, which will provide a new direction for the prevention and treatment of insulin resistance and type 2 diabetes.
Humans ; Amino Acids, Branched-Chain/metabolism* ; Insulin Resistance/physiology* ; Diabetes Mellitus, Type 2 ; Insulin/pharmacology* ; Keto Acids/metabolism*

To explore the effect and mechanism of Zuogui Pills in promoting neural tissue recovery and functional recovery in mice with ischemic stroke. Male C57BL/6J mice were randomly divided into a sham group, a model group, and low-, medium, and high-dose Zuogui Pills groups(3.5, 7, and 14 g·kg~(-1)), with 15 mice in each group. The ischemic stroke model was established using photochemical embolization. Stiker remove and irregular ladder walking behavioral tests were conducted before modeling and on days 7, 14, 21, and 28 after medication. Triphenyl tetrazolium chloride(TTC) staining was performed on day 3 after modeling, and T2-weighted imaging(T2WI) and diffusion-weighted imaging(DWI) were performed on day 28 after medication to evaluate the extent of brain injury. Hematoxylin-eosin(HE) staining was performed to observe the histology of the cerebral cortex. Axonal marker proteins myelin basic protein(MBP), growth-associated protein 43(GAP43), mammalian target of rapamycin(mTOR), and its downstream phosphorylated s6 ribosomal protein(p-S6), as well as mechanism-related proteins osteopontin(OPN) and insulin-like growth factor 1(IGF-1), were detected using immunofluorescence and Western blot. Zuogui Pills had a certain restorative effect on the neural function impairment caused by ischemic stroke in mice. TTC staining showed white infarct foci in the sensory-motor cortex area, and T2WI imaging revealed cystic necrosis in the sensory-motor cortex area. The Zuogui Pills groups showed less brain tissue damage, fewer scars, and more capillaries. The number of neuronal axons in those groups was higher than that in the model group, and neuronal activity was stronger. The expression of GAP43, OPN, IGF-1, and mTOR proteins in the Zuogui Pills groups was higher than that in the model group. In summary, Zuogui Pills can promote the recovery of neural function and axonal growth in mice with ischemic stroke, and its mechanism may be related to the activation of the OPN/IGF-1/mTOR signaling pathway.
Mice ; Animals ; Male ; Ischemic Stroke ; Recovery of Function/physiology* ; Insulin-Like Growth Factor I/pharmacology* ; Mice, Inbred C57BL ; TOR Serine-Threonine Kinases/metabolism* ; Stroke/drug therapy* ; Brain Ischemia/drug therapy* ; Mammals/metabolism*

Nonalcoholic fatty liver disease (NAFLD) and type 2 Diabetes Mellitus (T2DM) are highly prevalent diseases and are closely associated, with NAFLD being present in the majority of T2DM patients. In Asian traditional medicine, Mori Cortex is widely used for the treatment of diabetes and hyperlipidemia. However, whether it has a therapeutic effect on T2DM associated with NAFLD is still unknown. The present study showed that the oral treatment with Mori Cortex extract (MCE; 10 g·kg·d) lowered the blood lipid levels and reversed insulin resistance (IR) in high fat-diet/streptozotocin-induced type 2 diabetes in rats. The expression levels of sterol receptor element-binding protein-1c (SREBP-1c) and carbohydrate-responsive element binding protein (ChREBP), which are involved in steatosis in NAFLD rats, were measured in the liver samples. MCE decreased the protein and mRNA expression levels of SREBP-1c and ChREBP. In conclusion, down-regulation of SREBP-1c and ChREBP might contribute to the protective effect of MCE on hepatic injury and IR in the rats with T2DM associated with NAFLD.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; genetics ; Diabetes Mellitus, Type 2 ; blood ; chemically induced ; drug therapy ; metabolism ; Diet, High-Fat ; adverse effects ; Disease Models, Animal ; Down-Regulation ; drug effects ; Insulin ; blood ; Insulin Resistance ; physiology ; Lipid Metabolism ; drug effects ; genetics ; Liver ; drug effects ; physiopathology ; Male ; Morus ; Non-alcoholic Fatty Liver Disease ; blood ; chemically induced ; drug therapy ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Streptozocin

Animals ; Cognitive Dysfunction ; metabolism ; Cystatin C ; pharmacology ; Hippocampus ; drug effects ; Insulin Resistance ; physiology ; Neurons ; drug effects ; Rats ; Rodentia

Insulin resistance is the pathophysiological basis of many diseases. Overcoming early insulin resistance highly significant in prevention diabetes, non-alcoholic fatty liver, and atherosclerosis. The present study aimed at evaluating the therapeutic effects of baicalin on insulin resistance and skeletal muscle ectopic fat storage in high fat diet-induced mice, and exploring the potential molecular mechanisms. Insulin resistance in mice was induced with a high fat diet for 16 weeks. Animals were then treated with three different doses of baicalin (100, 200, and 400 mg·kg(-1)·d(-1)) for 14 weeks. Fasting blood glucose, fasting serum insulin, glucose tolerance test (GTT), insulin tolerance test (ITT), and skeletal muscle lipid deposition were measured. Additionally, the AMP-activated protein kinase/acetyl-CoA carboxylase and protein kinase B/Glycogen synthase kinase 3 beta pathways in skeletal muscle were further evaluated. Baicalin significantly reduced the levels of fasting blood glucose and fasting serum insulin and attenuated high fat diet induced glucose tolerance and insulin tolerance. Moreover, insulin resistance was significantly reversed. Pathological analysis revealed baicalin dose-dependently decreased the degree of the ectopic fat storage in skeletal muscle. The properties of baicalin were mediated, at least in part, by inhibition of the AMPK/ACC pathway, a key regulator of de novo lipogenesis and activation of the Akt/GSK-3β pathway, a key regulator of Glycogen synthesis. These data suggest that baicalin, at dose up to 400 mg·kg(-1)·d(-1), is safe and able to attenuate insulin resistance and skeletal muscle ectopic fat storage, through modulating the skeletal muscle AMPK/ACC pathway and Akt/GSK-3β pathway.
AMP-Activated Protein Kinases ; metabolism ; Acetyl-CoA Carboxylase ; metabolism ; Adipose Tissue ; metabolism ; Animals ; Diet, High-Fat ; Flavonoids ; pharmacology ; Glycogen Synthase Kinase 3 beta ; physiology ; Insulin Resistance ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal ; metabolism ; Proto-Oncogene Proteins c-akt ; physiology ; Signal Transduction ; physiology

Mammalian pancreatic β-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in β-cell number leads to type 2 diabetes (T2D). Despite the physiological importance of β-cells, the viability of β-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect β-cell viability is high concentration of free fatty acids (FFAs) such as palmitate. In this work, we demonstrated that Yes-associated protein (Yap1) is activated when β-cells are treated with palmitate. Our loss- and gain-of-function analyses using rodent insulinoma cell lines revealed that Yap1 suppresses palmitate-induced apoptosis in β-cells without regulating their proliferation. We also found that upon palmitate treatment, re-arrangement of F-actin mediates Yap1 activation. Palmitate treatment increases expression of one of the Yap1 target genes, connective tissue growth factor (CTGF). Our gain-of-function analysis with CTGF suggests CTGF may be the downstream factor of Yap1 in the protective mechanism against FFA-induced apoptosis.
Actins ; metabolism ; Adaptor Proteins, Signal Transducing ; antagonists & inhibitors ; genetics ; metabolism ; Animals ; Apoptosis ; drug effects ; physiology ; Bridged Bicyclo Compounds, Heterocyclic ; pharmacology ; Cell Line, Tumor ; Connective Tissue Growth Factor ; genetics ; metabolism ; pharmacology ; Cytochalasin D ; pharmacology ; Fatty Acids, Nonesterified ; pharmacology ; HEK293 Cells ; Humans ; Immunohistochemistry ; Insulin-Secreting Cells ; cytology ; drug effects ; metabolism ; Mice ; Microscopy, Fluorescence ; Palmitic Acid ; pharmacology ; Phosphoproteins ; antagonists & inhibitors ; genetics ; metabolism ; RNA Interference ; RNA, Small Interfering ; metabolism ; Rats ; Recombinant Proteins ; genetics ; metabolism ; pharmacology ; Thiazolidines ; pharmacology

The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer (NSCLC). This study aimed to investigate the effects of IGF-1R and its inhibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues (n=198). Western blotting was used to determine the expressions of IGF-1 and phosphorylated IGF-1R (p-IGF-1R) in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+AG1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-1+AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF-1 and IGF inhibitor AG1024 promotes lung cancer progression.
Adult ; Aged ; Animals ; Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; Cell Proliferation ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Insulin-Like Growth Factor I ; metabolism ; Lung Neoplasms ; metabolism ; pathology ; Male ; Mice ; Middle Aged ; Receptor, IGF Type 1 ; antagonists & inhibitors ; physiology ; Tyrphostins ; pharmacology

The present study was conducted to investigate the effects of resveratrol on the insulin signaling pathway in the liver of obese mice. To accomplish this, we administered resveratrol to high fat diet-induced obese mice and examined the levels of protein phosphorylation in the liver using an antibody array. The phosphorylation levels of 10 proteins were decreased in the high fat diet and resveratrol (HFR) fed group relative to the levels in the high fat diet (HF) fed group. In contrast, the phosphorylation levels of more than 20 proteins were increased in the HFR group when compared with the levels of proteins in the HF group. Specifically, the phosphorylation levels of Akt (The308, Tyr326, Ser473) were restored to normal by resveratrol when compared with the levels in the HF group. In addition, the phosphorylation levels of IRS-1 (Ser636/Ser639), PI-3K p85-subunit alpha/gamma(Tyr467/Tyr199), PDK1 (Ser241), GSK-3alpha (S21) and GSK-3 (Ser9), which are involved in the insulin signaling pathway, were decreased in the HF group, whereas the levels were restored to normal in the HFR group. Overall, the results show that resveratrol restores the phosphorylation levels of proteins involved in the insulin signaling pathway, which were decreased by a high fat diet.
Animals ; Anti-Inflammatory Agents/*pharmacology ; Fluorescent Antibody Technique ; Insulin/*physiology ; Liver/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Phosphorylation ; Proteins/metabolism ; Signal Transduction/*drug effects ; Stilbenes/*pharmacology

OBJECTIVETo observe the effect of the postpone in skeletal muscle aging process of D-galactose rats by weight training and soy polypeptide supplement in 6 weeks, and discuss the initial mechanism.

METHODSixty male SD rats (three month old)were randomly assigned: 6 week control (C6,) and 6 week model (M6) 6 for each group, 12 week model (M12), big load (B12), small load (S12), peptide (P12), peptide + big load (PB12) and peptide + small load group (PS12) 8 for each group, eight fourteen month rats were taken in the natural aging group. The rats were killed by the end of 6th week and 12th week, tested the indicators.

RESULTCompare with group C6, the indicators in group M6 showed aging in different levels; Compare with group M12, weight training or soy polypeptide supplement in all intervention groups could increase the content of skeletal muscle superoxide dismutase (SOD), SOD/MDA, the serum growth hormone(GH), insulin-like growth factor-1 (IGF-I)and skeletal muscle IGF-I mRNA, decreased the malondialdehyde (MDA) content of skeletal muscle, and they had notable interaction.

CONCLUSIONRat skeletal muscle aging model can be copied successfully by D-galactose hypodermic, and go on with 6-week weight training or soy polypeptide supplement, they can postpone the skeletal muscle aging process of D-galactose rats, and the two interference way united can have more obvious effect. Its preliminary mechanism may be related to the reduction of skeletal muscle oxidative stress and lipid peroxidation, the correction of hormones and related factors metabolic disorders, the elevation of skeletal muscle IGF-I mRNA expression and so on.

Aging ; physiology ; Animals ; Galactose ; Growth Hormone ; blood ; Insulin-Like Growth Factor I ; metabolism ; Male ; Malondialdehyde ; metabolism ; Muscle, Skeletal ; drug effects ; physiology ; Physical Conditioning, Animal ; physiology ; Rats ; Rats, Sprague-Dawley ; Soybean Proteins ; pharmacology ; Soybeans ; chemistry ; Superoxide Dismutase ; metabolism

OBJECTIVETo investigate the effect of Jiangtang Yishen Recipe (JTYSR) on high insulin induced cell proliferation of human glomerular mesangial cells (HMCs) and the expression of insulin receptor substrate 1 (IRS-1) and phosphatidylinositol-3-kinase (PI-3K).

METHODSHMCs were divided into 4 groups, i.e., the negative control group, the high insulin model group, the JTYSR group, and the LY294002 group. The concentration of insulin, JTYSR, and LY294002 was respectively confirmed by pre-experiment. Different culture solution was respectively added for different groups. RPMI1640 culture solution was added for HMCs in the negative control group, while HMCs in the rest 3 groups were cultured by 100 nmol/L insulin for 24 h. Meanwhile, HMCs from the JTYSR group and the LY294002 group were exposed to 125 mg/L JTYSR and 80 micromol/L LY294002 respectively for further 48 h. The proliferation of HMCs was detected by MTT and flow cytometry. The protein expression of IRS-1 and PI-3K in HMC was detected by immunohistochemical assay and Western blot. Results The proliferation of HMCs induced by high insulin could be significantly lowered, and the protein expression of IRS-1 and PI-3K could be down-regulated in the JTYSR group and the LY294002 group (P <0.01). Compared with the LY294002 group, the protein expression of IRS-1 and PI-3K could be slightly down-regulated in the JTYSR group (P <0.05).

CONCLUSIONJTYSR could lower high insulin induced proliferation of HMCs, and its mechanism might be related to insulin signaling pathway.

Cell Proliferation ; drug effects ; Chromones ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Insulin Receptor Substrate Proteins ; metabolism ; Mesangial Cells ; physiology ; Morpholines ; Phosphatidylinositol 3-Kinase ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Signal Transduction