scholarly journals Fagopyrum tataricum(Buckwheat) Improved High-Glucose-Induced Insulin Resistance in Mouse Hepatocytes and Diabetes in Fructose-Rich Diet-Induced Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Chia-Chen Lee ◽  
Wei-Hsuan Hsu ◽  
Siou-Ru Shen ◽  
Yu-Hsiang Cheng ◽  
She-Ching Wu
Keyword(s):  
Insulin Resistance ◽  
High Glucose ◽  
Fagopyrum Tataricum ◽  
Akt Phosphorylation ◽  
Mouse Hepatocytes ◽  
Antioxidant Enzymes Activities ◽  
Glucose Induction ◽  
Ethanol Extracts ◽  
Rutin And Quercetin

Fagopyrum tataricum(buckwheat) is used for the treatment of type 2 diabetes mellitus in Taiwan. This study was to evaluate the antihyperglycemic and anti-insulin resistance effects of 75% ethanol extracts of buckwheat (EEB) in FL83B hepatocytes by high-glucose (33 mM) induction and in C57BL/6 mice by fructose-rich diet (FRD; 60%) induction. The active compounds of EEB (100 μg/mL; 50 mg/kg bw), quercetin (6 μg/mL; 3 mg/kg bw), and rutin (23 μg/mL; 11.5 mg/kg bw) were also employed to treat FL83B hepatocytes and animal. Results indicated that EEB, rutin, and quercetin + rutin significantly improved 2-NBDG uptake via promoting Akt phosphorylation and preventing PPARγdegradation caused by high-glucose induction for 48 h in FL83B hepatocytes. We also found that EEB could elevate hepatic antioxidant enzymes activities to attenuate insulin resistance as well as its antioxidation caused by rutin and quercetin. Finally, EEB also inhibited increases in blood glucose and insulin levels of C57BL/6 mice induced by FRD.

scholarly journals CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2324
Author(s):  
Vanessa Castelli ◽  
Laura Brandolini ◽  
Michele d’Angelo ◽  
Cristina Giorgio ◽  
Margherita Alfonsetti ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Harmful Effect ◽  
High Blood Glucose ◽  
Specific Ligand

Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines’ effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.

β-Cell tropin- and glucose-induced hypersecretion of insulin and amylin from perfused fatty rat pancreas

1993 ◽  
Vol 137 (3) ◽  
pp. 375-381 ◽  
Author(s):  
S. J. Dunmore ◽  
M. A. Cawthorne ◽  
D. C. J. Hislop ◽  
J. L. Morton ◽  
A. Beloff-Chain
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Animal Model ◽  
High Glucose ◽  
Perfused Pancreas ◽  
Β Cell ◽  
Rat Pancreas ◽  
Obesity And Diabetes ◽  
High Insulin

ABSTRACT The neurointermediate pituitary peptide β-cell tropin (BCT) has potent insulin-releasing and lipogenic properties and is elevated in obesity and type-2 diabetes. The effects of BCT and glucose on the release of insulin and amylin from the perfused pancreas of obese 'fatty' (fa/fa) rats and lean (Fa/?) controls were measured. Pancreata were perfused, sequentially, with buffer containing: 5·6 mmol glucose/l (basal); basal glucose±0·5 nmol BCT/l; 16·7 mmol glucose/l (high). Insulin and amylin release during basal glucose treatment was eight to nine times greater from pancreata from fatty than from lean rats. BCT induced a fivefold greater monophasic insulin and amylin release from fatty compared with lean pancreata. When not preceded by BCT there was a twofold greater high glucose-induced amylin release from fatty pancreata but no difference in insulin secretion. When preceded by BCT stimulation, high glucose induced twofold greater insulin and fourfold larger amylin release from fatty compared with lean pancreata. Molar secretion ratios of insulin: amylin varied between 30:1 and 50:1. In view of the elevated levels of BCT found in the fatty rat and in the light of the above findings, it is concluded that the peptide may have a role in the development of hyperinsulinaemia, hyperamylinaemia and insulin resistance in this animal model of obesity and diabetes. Journal of Endocrinology (1993) 137, 375–381

Defective Akt activation is associated with glucose- but not glucosamine-induced insulin resistance

2002 ◽  
Vol 282 (3) ◽  
pp. E497-E506 ◽  
Author(s):  
Bryce A. Nelson ◽  
Katherine A. Robinson ◽  
Maria G. Buse
Keyword(s):  
Insulin Resistance ◽  
Glucose Transport ◽  
High Glucose ◽  
Kinase Activity ◽  
Insulin Receptor Substrate ◽  
Insulin Stimulation ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Insulin Resistant ◽  
Low Glucose

3T3-L1 adipocytes develop insulin-resistant glucose transport upon preincubation with high glucose or glucosamine, provided insulin (0.6 nM) is present during preincubation. Insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity is unaffected (30). Total cellular IRS-1, PI 3-kinase, or Akt concentrations were unchanged. Akt activation in subcellular fractions was assessed by immunoblotting with two phospho-Akt-specific antibodies. Upon acute 100 nM insulin stimulation, plasma membrane (PM)-associated phospho-Akt was highest in cells preincubated in low glucose with no insulin, less in high glucose with no insulin, even less in low glucose+insulin, and lowest in high glucose+insulin. Only high glucose+insulin caused insulin-resistant glucose transport. Acute insulin stimulation increased total PM-Akt about twofold after preincubation without insulin in low or high glucose. Preincubation with 0.6 nM insulin decreased Akt PM translocation by ∼25% in low and ∼50% in high glucose. Preincubation with glucosamine did not affect Akt phosphorylation or translocation. Conclusions: chronic exposure to high glucose or insulin downregulates acute insulin-stimulated Akt activation, acting synergistically distal to PI 3-kinase. Maximal insulin activates more Akt than required for maximal glucose transport stimulation. Insulin resistance may ensue when PM-associated phospho-Akt decreases below a threshold. High glucose and glucosamine cause insulin resistance by different mechanisms in 3T3-L1 adipocytes.

scholarly journals TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Chen Liu ◽  
Wu QiNan ◽  
Lei XiaoTian ◽  
Yang MengLiu ◽  
Gan XiaGuang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Leucine Zipper ◽  
Diabetic Mice ◽  
Β Cells ◽  
Akt Phosphorylation ◽  
Key Steps

Islet β cell apoptosis plays an important role in type 2 diabetes. We previously reported that Par-4-mediated islet β cell apoptosis is induced by high-glucose/fatty acid levels. In the present study, we show that Par-4, which is induced by high-glucose/fatty acid levels, interacts with and inhibits TERT in the cytoplasm and then translocates to the nucleus. Par-4 also inhibited Akt phosphorylation, leading to islet β cell apoptosis. We inhibited Par-4 in islet β cells under high-glucose/fatty acid conditions and knocked out Par-4 in diabetic mice, which led to the up-regulation of TERT and an improvement in the apoptosis rate. We inhibited Akt phosphorylation in islet β cells and diabetic mice, which led to aggressive apoptosis. In addition, the biological film interference technique revealed that Par-4 bound to TERT via its NLS and leucine zipper domains. Our research suggests that Par-4 activation and binding to TERT are key steps required for inducing the apoptosis of islet β cells under high-glucose/fatty acid conditions. Inhibiting Akt phosphorylation aggravated apoptosis by activating Par-4 and inhibiting TERT, and Par-4 inhibition may be an attractive target for the treatment of islet β cell apoptosis.

scholarly journals DhHP-6 ameliorates hepatic oxidative stress and insulin resistance in type 2 diabetes mellitus through the PI3K/AKT and AMPK pathway

2020 ◽  
Vol 477 (12) ◽  
pp. 2363-2381
Author(s):  
Kai Wang ◽  
Yuting Liang ◽  
Yu Su ◽  
Liping Wang
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Akt Phosphorylation ◽  
Ampk Pathway ◽  
Ampk Phosphorylation ◽  
Improve Insulin Resistance

Insulin resistance is one major features of type 2 diabetes mellitus (T2DM). Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6), a novel microperoxidase mimetic designed and synthesized based on microperoxidase 11 (MP-11), can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we showed that oral DhHP-6 could reduce blood glucose and improve insulin resistance. To investigate the mechanisms of how DhHP-6 ameliorates oxidative stress and insulin resistance, we established T2DM mouse models and glucosamine-induced HepG2 cell insulin resistance models. The results suggested that DhHP-6 decreased blood glucose, increased antioxidant enzyme activity, and inhibited glycogen synthesis in T2DM mice. In addition, DhHP-6 improved insulin resistance by activating phosphatidylinositol 3-kinase (PI3K)/AKT, and AMP-activated protein kinase (AMPK) pathway in T2DM mice. Furthermore, DhHP-6 also activated PI3K/AKT and AMPK pathway in glucosamine-induced HepG2 cells. However, LY294002 did not completely inhibit AKT phosphorylation, and partially inhibited AMPK phosphorylation, whilst compound C only partially reduced AMPK phosphorylation, and also partially inhibited AKT phosphorylation, suggesting that AKT and AMPK interact to improve insulin resistance. Thus, these data suggest that DhHP-6 attenuates insulin resistance via the PI3K/AKT and AMPK pathway.

scholarly journals The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance

2020 ◽  
Author(s):  
Gustavo W. Fernandes ◽  
Barbara M. L. C. Bocco ◽  
Tatiana L. Fonseca ◽  
Federico Salas-Lucia ◽  
Olivia Nickel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Transcriptional Repressor ◽  
Acid Oxidation ◽  
Allosteric Activation ◽  
Methyl Transferase ◽  
Hepatic Energy Metabolism ◽  
Mouse Hepatocytes ◽  
Histone Methyl Transferase ◽  
Glucose Output

SummaryZfp125 is a transcriptional repressor that inhibits hepatic VLDL secretion. Here we show that mice with liver-specific Zfp125 knockdown exhibited lower respiratory quotient, reduced glycemia and pyruvate-stimulated liver glucose output, and higher levels of β-hydroxyl-butyrate. Microarray and ChIP-seq studies identified Zfp125 peaks in the promoter of 135 metabolically relevant genes, including genes involved in fatty acid oxidation and ketogenesis, e.g. Ppara, Cpt1a, Bdh1 and Hmgcs2. Repression by Zfp125 involved recruitment of the corepressors Kap1 and the histone methyl transferase Setdb1, increasing the levels of H3K9me3, a heterochromatin marker of gene silencing. The resulting increase in acetyl-CoA levels accelerated gluconeogenesis through allosteric activation of pyruvate carboxylase. Zfp125 knockdown in isolated mouse hepatocytes amplified the induction of ketogenesis by glucagon or insulin resistance, whereas the expression of key gluconeogenic genes Pck1 and G6pc was amplified by Zfp125. These findings place Zfp125 at the center of fuel dysregulation of type 2 diabetes.

scholarly journals Is “fat-induced” muscle insulin resistance rapidly reversible?

2009 ◽  
Vol 297 (1) ◽  
pp. E236-E241 ◽  
Author(s):  
Dong-Ho Han ◽  
Chad Hancock ◽  
Su-Ryun Jung ◽  
John O. Holloszy
Keyword(s):  
Insulin Resistance ◽  
High Glucose ◽  
High Fat Diet ◽  
Exercise Bout ◽  
Experimental Models ◽  
Adaptive Responses ◽  
High Fat ◽  
The Metabolic Syndrome

Elevated plasma free fatty acids (FFA) cause insulin resistance and are thought to play a key role in mediating insulin resistance in patients with the metabolic syndrome (MTS) and type 2 diabetes mellitus (DM). Two experimental models used to study the mechanisms responsible for insulin resistance in patients are high-fat diet-fed rodents and administration of triglycerides and heparin to raise plasma FFA. As evidence that insulin resistance in high-fat diet-fed rats is due to high FFA, it has been reported that the insulin resistance is rapidly reversed by an overnight fast, a high-glucose meal, and an exercise bout. If true, these findings would invalidate the high-fat diet-fed rodent as a model for MTS or type 2 DM, because insulin resistance is not rapidly reversed by these treatments in patients. The purpose of this study was to determine whether diet-induced insulin resistance is, in fact, rapidly reversible. Incubation of muscles in vitro rapidly reversed insulin resistance induced by administration of triglycerides and heparin, but not by a high-fat diet. An overnight fast and a high-glucose meal were followed by a large increase in insulin-stimulated muscle glucose transport. However, these are adaptive responses, rather than reversals of insulin resistance, because they also occurred in muscles of insulin-sensitive, chow-fed control rats. Our results show that insulin resistance induced by high FFA, i.e., Randle glucose-fatty acid cycle, is transient. In contrast, the insulin resistance induced by a high-fat diet does not reverse rapidly.

TRIB3 is highly expressed in the adipose tissue of obese patients and is associated with insulin resistance

2021 ◽  
Author(s):  
Seul Ki Lee ◽  
Chan Yoon Park ◽  
Jimin Kim ◽  
Donguk Kim ◽  
Han Choe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Human Adipose Tissue ◽  
Normal Weight ◽  
Bioactive Molecules ◽  
Human Adipocytes ◽  
Akt Phosphorylation ◽  
Fat Depots

Abstract Context The up-regulation of TRIB3, a stress-inducible gene encoding a pseudokinase, has been implicated in the development of insulin resistance in the skeletal muscle and liver of patients with obesity and type 2 diabetes. However, there is little information regarding TRIB3 expression in human adipose tissue. Objectives To investigate whether TRIB3 expression is dysregulated in human adipose tissue in the context of obesity and type 2 diabetes and whether TRIB3 expression in adipose tissues is associated with insulin resistance. Methods We measured metabolic parameters and TRIB3 expression in the abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Regulation of TRIB3 expression was studied in human adipocytes. Results TRIB3 expression in both fat depots was higher in patients with obesity and/or type 2 diabetes; in addition, the expression level was significantly associated with insulin resistance. Incubating adipocytes under the conditions mimicking the microenvironment of obese adipose tissue, including increased endoplasmic reticulum (ER) stress, induced TRIB3 expression. In human adipocytes, the overexpression of TRIB3 impaired the insulin-stimulated AKT phosphorylation and caused dysregulation of the transcription of genes encoding the bioactive molecules released from adipocytes, such as proinflammatory cytokines, adiponectin, and leptin. Pioglitazone, an insulin-sensitizing agent, reduced both these effects of TRIB3 and the ER stressor-induced expression of TRB3. Conclusions Our data indicate that TRIB3 expression in adipose tissue is enhanced in patients with obesity and suggest that the increased TRIB3 dysregulates adipocyte function, which may contribute to the development of insulin resistance.

scholarly journals Renal Protective Effects of Toll-like Receptor 4 Signaling Blockade in Type 2 Diabetic Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2144-2155 ◽  
Author(s):  
J. J. Cha ◽  
Y. Y. Hyun ◽  
M. H. Lee ◽  
J. E. Kim ◽  
D. H. Nam ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Glucose ◽  
Proinflammatory Cytokine ◽  
Leptin Resistance ◽  
Diabetic Mice ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Cytokine Synthesis ◽  
Type 2 Diabetic

Abstract Chronic inflammation caused by high glucose and high free fatty acid (FFA) concentrations is a major contributor to the pathogenesis of type 2 diabetes. Recent evidence suggests that activation of Toll-like receptor (TLR) signaling induces peripheral insulin resistance and mediates central insulin and leptin resistance. In this study, we investigated the renal effects of TLR4 signaling blockade in type 2 diabetic mice. Eight-week-old db/db mice were treated for 12 weeks with (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (GIT27), which targets macrophages through the inhibition of TLR4- and TLR2/6-mediated signaling pathways. Although GIT27 treatment improved glycemic control and insulin tolerance, which is associated with a lower lipid profile, it did not impact body weight or food consumption. GIT27 treatment also markedly decreased urinary albumin excretion, decreased proinflammatory cytokine synthesis, improved tissue lipid metabolism, induced oxidative stress, and improved glomerulosclerosis compared with the control db/db group. In cultured podocytes and adipocytes, high glucose levels with FFA stimulation increased TLR4 expression and proinflammatory cytokine synthesis, but the effects were abolished by GIT27 treatment. In addition, knockdown of TLR4 expression by stealth small interfering RNA abolished FFA-induced proinflammatory cytokine synthesis in cultured podocytes. In conclusion, our results suggest that GIT27 treatment improves insulin resistance and protects against the renal injury that occurs in type 2 diabetic nephropathy through both metabolic and antiglomerulosclerotic mechanisms. These results suggest that TLR pathway inhibition might play a direct protective role in diabetic kidney disease.

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