C-Phycocyanin inhibits hepatic gluconeogenesis and increases glycogen synthesis via activating Akt and AMPK in insulin resistance hepatocytes

2018 ◽  
Vol 9 (5) ◽  
pp. 2829-2839 ◽  
Author(s):  
Zhiheng Ren ◽  
Zhifei Xie ◽  
Danni Cao ◽  
Mufeng Gong ◽  
Lei Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Glycogen Synthesis ◽  
Hepatic Gluconeogenesis ◽  
Ampk Signaling ◽  
Insulin Resistant ◽  
Glucose Homoeostasis

The mechanism of C-PC in improving glucose homoeostasis is to activate the IRS/PI3 K/Akt and SIRT1/LKB1/AMPK signaling pathway in insulin resistant hepatocytes.

scholarly journals Resveratrol metabolites ameliorate insulin resistance in HepG2 hepatocytes by modulating IRS-1/AMPK

RSC Advances ◽  
2018 ◽  
Vol 8 (63) ◽  
pp. 36034-36042 ◽  
Author(s):  
Wendi Teng ◽  
Wenjing Yin ◽  
Liang Zhao ◽  
Changwei Ma ◽  
Jiaqiang Huang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Hepg2 Cell ◽  
Glycogen Synthesis ◽  
Ros Generation ◽  
Ampk Signaling ◽  
Ameliorate Insulin Resistance

RSV metabolites R3G and R4G protected HepG2 cell from insulin resistance by improving glucose uptake and glycogen synthesis, along with inhibiting ROS generation and modulating the RS-1/AMPK signaling pathway.

scholarly journals Four sesquiterpene glycosides from loquat (Eriobotrya japonica) leaf ameliorates palmitic acid-induced insulin resistance and lipid accumulation in HepG2 Cells via AMPK signaling pathway

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10413
Author(s):  
Jiawei Li ◽  
Xiaoqin Ding ◽  
Tunyu Jian ◽  
Han Lü ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Eriobotrya Japonica ◽  
Expression Levels ◽  
Ampk Signaling ◽  
Insulin Resistant ◽  
Compound C

Insulin resistance (IR), caused by impaired insulin signal and decreased insulin sensitivity, is generally responsible for the pathophysiology of type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides (SGs), the exclusive natural products from loquat leaf, have been regarded as potential lead compounds owing to their high efficacy in hypoglycemia and hypolipidemia. Here, we evaluated the beneficial effects of four single SGs isolated from loquat leaf, including SG1, SG2, SG3 and one novel compound SG4 against palmitic acid-induced insulin resistance in HepG2 cells. SG1, SG3 and SG4 could significantly enhance glucose uptake of insulin-resistant HepG2 cells at non-cytotoxic concentration. Meanwhile, Oil Red O staining showed the decrease of both total cholesterol and triglyceride content, suggesting the amelioration of lipid accumulation by SGs in insulin-resistant HepG2 cells. Further investigations found that the expression levels of phosphorylated AMPK, ACC, IRS-1, and Akt were significantly up-regulated after SGs treatment, on the contrary, the expression levels of SREBP-1 and FAS were significantly down-regulated. Notably, AMPK inhibitor Compound C (CC) blocked the regulative effects, while AMPK activator AICAR mimicked the effects of SGs in PA-treated insulin-resistant HepG2 cells. In conclusion, SGs (SG4>SG1≈SG3>SG2) improved lipid accumulation in insulin-resistant HepG2 cells through the AMPK signaling pathway.

Selective in vitro reversal of the insulin resistance of glucose transport in denervated rat skeletal muscle

1989 ◽  
Vol 257 (3) ◽  
pp. E418-E425 ◽  
Author(s):  
M. O. Sowell ◽  
S. L. Dutton ◽  
M. G. Buse
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Glycogen Synthesis ◽  
Insulin Response ◽  
Medium Composition ◽  
Insulin Resistant ◽  
Denervated Muscles

Denervation (24 h) of skeletal muscle causes severe postreceptor insulin resistance of glucose transport and glycogen synthesis that is demonstrable in isolated muscles after short (30 min) preincubations. After longer preincubations (2-4 h), the insulin response of glucose transport increased to normal, whereas glycogen synthesis remained insulin resistant. Basal and insulin-stimulated amino acid transport were significantly lower in denervated muscles than in controls after short or long incubations, although the percentage stimulation of transport by insulin was not significantly different. The development of glucose transport insulin resistance after denervation was not attributable to increased sensitivity to glucocorticoids or adenosine. The selective in vitro reversal of glucose transport insulin resistance was not dependent on medium composition, did not require protein or prostaglandin synthesis, and could not be attributed to release of a positive regulator into the medium. The data suggest 1) the insulin receptor in muscle stimulates glucose transport by a signaling pathway that is not shared by other insulin-sensitive effector systems, and 2) denervation may affect insulin receptor signal transduction at more than one site.

scholarly journals Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

2016 ◽  
Vol 229 (2) ◽  
pp. 133-144 ◽  
Author(s):  
Hong Xu ◽  
Yang Zhou ◽  
Yongxia Liu ◽  
Jian Ping ◽  
Qiyang Shou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Function ◽  
Insulin Receptor ◽  
Glucose Intolerance ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Akt Signaling ◽  
Hepatic Glycogen ◽  
Impaired Liver Function ◽  
Insulin Resistant

Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathwayin vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.

Introduction to the Kinases in Diabetes Biochemical Society focused meeting: are protein kinases good targets for antidiabetic drugs?

2005 ◽  
Vol 33 (2) ◽  
pp. 339-342 ◽  
Author(s):  
M.P. Coghlan ◽  
D.M. Smith
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Activity ◽  
Whole Body ◽  
Protein Kinase Activity ◽  
Pharmacological Agents ◽  
Insulin Resistant ◽  
Insulin Mimetic ◽  
Glucose Homoeostasis

Insulin regulates whole-body glucose homoeostasis by modulating the activities of protein kinases in its target tissues: muscle, liver and fat. Defects in insulin's ability to modulate protein kinase activity lead to ‘insulin resistance’ or impaired insulin action. Insulin resistance in combination with defective insulin secretion from the pancreas results in the elevated blood glucose levels that are characteristic of diabetes mellitus. Pharmacological agents that selectively modulate protein kinase activities in insulin-resistant tissues may act either as insulin-sensitizing or insulin-mimetic drugs. Consistent with this, small molecule modulators of a number of protein kinases have demonstrated efficacy in animal models of insulin resistance and diabetes. Moreover, emerging data in humans suggest that marketed anti-diabetic agents may also act in part through modulating protein kinase activities. This meeting was convened to consider the potential to treat insulin resistance and Type II diabetes by modulating protein kinase activity.

scholarly journals RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Mei Han ◽  
Lianghui You ◽  
Yanting Wu ◽  
Nan Gu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Rna Sequencing ◽  
Metabolic Diseases ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
C2c12 Myotubes ◽  
Insulin Resistant

Abstract Insulin resistance (IR) has been considered as the common pathological basis and developmental driving force for most metabolic diseases. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators in modulation of glucose and lipid metabolism. However, the comprehensive profile of lncRNAs in skeletal muscle cells under the insulin resistant status and the possible biological effects of them were not fully studied. In this research, using C2C12 myotubes as cell models in vitro, deep RNA-sequencing was performed to profile lncRNAs and mRNAs between palmitic acid-induced IR C2C12 myotubes and control ones. The results revealed that a total of 144 lncRNAs including 70 up-regulated and 74 down-regulated (|fold change| > 2, q < 0.05) were significantly differentially expressed in palmitic acid-induced insulin resistant cells. In addition, functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases revealed that the target genes of the differentially expressed lncRNAs were significantly enriched in fatty acid oxidation, lipid oxidation, PPAR signaling pathway, and insulin signaling pathway. Moreover, Via qPCR, most of selected lncRNAs in myotubes and db/db mice skeletal muscle showed the consistent expression trends with RNA-sequencing. Co-expression analysis also explicated the key lncRNA–mRNA interactions and pointed out a potential regulatory network of candidate lncRNA ENSMUST00000160839. In conclusion, the present study extended the skeletal muscle lncRNA database and provided novel potential regulators for future genetic and molecular studies on insulin resistance, which is helpful for prevention and treatment of the related metabolic diseases.

scholarly journals ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinyu Cao ◽  
Xiaotong Ye ◽  
Shuang Zhang ◽  
Li Wang ◽  
Yanhong Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Liver Tissue ◽  
Hepatic Insulin Resistance ◽  
Indirect Pathway ◽  
Hepatic Gluconeogenesis ◽  
Insulin Tolerance ◽  
Elevated Expression

Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.

scholarly journals MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN

2015 ◽  
Vol 36 (6) ◽  
pp. 2357-2365 ◽  
Author(s):  
Lei Wang ◽  
Ning Zhang ◽  
Hua-ping Pan ◽  
Zun Wang ◽  
Zhen-yu Cao
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Glycogen Synthesis ◽  
Tolerance Test ◽  
Hepatic Insulin Resistance ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Tail Vein Injection ◽  
Insulin Tolerance ◽  
Dual Luciferase Reporter Assay

Background: Type 2 diabetes afflicts 95% of diabetes patients. Recent data suggest that miRNAs play a key role in insulin production, secretion and function. This study aims to explore the specific role of miR-499-5p in hepatic insulin resistance. Methods: The miRNA expression levels in the livers of db/db mice were analyzed using miRNA chips and were verified by real-time PCR. miR-499-5p mimics and an inhibitor were transfected into NCTC1469 cells. Then, the PI3K/AKT signaling pathway and glycogen level were determined. The target genes of miR-499-5p were predicted by bioinformatics and then confirmed by dual luciferase reporter assay and Western blot. To establish an insulin resistance (IR) animal model, C57BL/6 mice were fed a high-fat diet (HFD). The level of miR-499-5p in the livers of HFD-fed mice was upregulated through tail vein injection of adenovirus vectors (ad) containing miR-499-5p mimics. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to determine glucose tolerance and insulin tolerance, respectively. Results: MicroRNA chips and qPCR showed that miR-499-5p was significantly decreased in the livers of db/db mice. Downregulation of miR-499-5p impaired the insulin signaling pathway and glycogen synthesis, whereas upregulation of miR-499-5p promoted the insulin signaling pathway and glycogen synthesis in NCTC1469 cells. The dual luciferase reporter assay and Western blot demonstrated that PTEN was the target gene of miR-499-5p. Compared with the control group, miR-499-5p was increased 2.1-fold in the livers of HFD-fed mice. By tail vein injection of adenovirus vector containing miR-499-5p mimics, GTT and ITT were improved in HFD-fed mice. Conclusion: Downregulation of the miR-499-5p level impaired the PI3K/AKT/GSK signaling pathway and glycogen synthesis by targeting PTEN.

scholarly journals Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

1997 ◽  
Vol 273 (5) ◽  
pp. E859-E867 ◽  
Author(s):  
M. Hettiarachchi ◽  
S. Chalkley ◽  
S. M. Furler ◽  
Y.-S. Choong ◽  
M. Heller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthesis ◽  
Human Growth ◽  
Whole Body ◽  
Nonesterified Fatty Acids ◽  
Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

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