scholarly journals Ginsenoside Re Reduces Insulin Resistance through Inhibition of c-Jun NH2-Terminal Kinase and Nuclear Factor-κB

2008 ◽  
Vol 22 (1) ◽  
pp. 186-195 ◽  
Author(s):  
Zhiguo Zhang ◽  
Xiaoying Li ◽  
Wenshan Lv ◽  
Yisheng Yang ◽  
Hong Gao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Signaling Cascades ◽  
Glucose Infusion Rate ◽  
Nuclear Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Ginsenoside Re

Abstract Ginsenoside Re (Re), a compound derived from Panax ginseng, shows an antidiabetic effect. However, the molecular basis of its action remains unknown. We investigated insulin signaling and the antiinflammatory effect by Re in 3T3-L1 adipocytes and in high-fat diet (HFD) rats to dissect its anti-hyperglycemic mechanism. Glucose uptake was measured in 3T3-L1 cells and glucose infusion rate determined by clamp in HFD rats. The insulin signaling cascade, including insulin receptor (IR) β-subunit, IR substrate-1, phosphatidylinositol 3-kinase, Akt and Akt substrate of 160 kDa, and glucose transporter-4 translocation are examined. Furthermore, c-Jun NH2-terminal kinase (JNK), MAPK, and nuclear factor (NF)-κB signaling cascades were also assessed. The results show Re increases glucose uptake in 3T3-L1 cells and glucose infusion rate in HFD rats. The activation of insulin signaling by Re is initiated at IR substrate-1 and further passes on through phosphatidylinositol 3-kinase and downstream signaling cascades. Moreover, Re demonstrates an impressive suppression of JNK and NF-κB activation and inhibitor of NF-κBα degradation. In conclusion, Re reduces insulin resistance in 3T3-L1 adipocytes and HFD rats through inhibition of JNK and NF-κB activation.

A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

2007 ◽  
Vol 292 (5) ◽  
pp. E1358-E1363 ◽  
Author(s):  
Arvinder K. Dhalla ◽  
Mei Yee Wong ◽  
Peter J. Voshol ◽  
Luiz Belardinelli ◽  
Gerald M. Reaven
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Adenosine Receptor ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Oral Glucose ◽  
Acute Administration ◽  
High Fat ◽  
Adenosine Receptor Agonist

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A1 adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly ( P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation

2007 ◽  
Vol 293 (5) ◽  
pp. E1358-E1364 ◽  
Author(s):  
Andrew J. Hoy ◽  
Clinton R. Bruce ◽  
Anna Cederberg ◽  
Nigel Turner ◽  
David E. James ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glucose Infusion ◽  
Metabolic Effects ◽  
Synthesis Rate ◽  
Muscle Sample

Hyperglycemia is a defining feature of Type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance, and our group (Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB. Am J Physiol Endocrinol Metab Endocrinol Metab 290: E471–E479, 2006) has recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5 h but not after 3 h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (∼10 mM) was produced in cannulated male Wistar rats for up to 5 h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5 h (by 25%, P < 0.0001 at 5 h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%; P < 0.05) and glycogen synthesis rate (52%; P < 0.001) were reduced after 5 h compared with after 3 h of infusion. Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3β] over the same time course. In isolated soleus strips taken from control or 1- or 5-h glucose-infused animals, insulin-stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5-h muscle sample (68% vs. 1-h sample; P < 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5 h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than to a defect in insulin signaling or glucose transport.

Insulin stimulates laser Doppler signal by rat muscle in vivo, consistent with nutritive flow recruitment

2001 ◽  
Vol 100 (3) ◽  
pp. 283-290 ◽  
Author(s):  
Andrew D. H. CLARK ◽  
Eugene J. BARRETT ◽  
Stephen RATTIGAN ◽  
Michelle G. WALLIS ◽  
Michael G. CLARK
Keyword(s):  
Blood Flow ◽  
Glucose Uptake ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Laser Doppler ◽  
Arterial Blood Flow ◽  
Glucose Infusion Rate ◽  
Limb Blood Flow ◽  
Capillary Recruitment

Insulin-mediated increases in limb blood flow are thought to enhance glucose uptake by skeletal muscle. Using the perfused rat hindlimb, we report that macro laser Doppler flowmetry (LDF) probes positioned on the surface of muscle detect changes in muscle capillary (nutritive) flow. With this as background, we examined the effects of insulin and adrenaline (epinephrine), which are both known to increase total leg blood flow, on the LDF signals from scanning and stationary probes on the muscle surface in vivo. The aim is to assess the relationship between capillary recruitment, total limb blood flow and glucose metabolism. Glucose infusion rate, femoral arterial blood flow (FBF) and muscle LDF, using either scanning or a stationary probe positioned over the biceps femoris muscle, were measured. With scanning LDF, animals received insulin (10 m-units·min-1·kg-1), adrenaline (0.125 µg·min-1·kg-1) or saline. By 1 h, insulin had increased the glucose infusion rate from 0 to 128 µmol·min-1·kg-1 and the scanning LDF had increased by 62±8% (P < 0.05), but FBF was unaffected. Adrenaline increased FBF by 49% at 15 min, but LDF was unchanged. With saline at 1 h, neither FBF nor LDF had changed. With the stationary LDF surface probe, insulin at 1 h had increased FBF by 47% (P < 0.05) and LDF by 47% (P < 0.05) relative to saline controls. Adrenaline increased FBF (39%), but LDF was unaltered. The stimulation of LDF by insulin is consistent with capillary recruitment (nutritive flow) as part of the action of this hormone in vivo. The recruitment may be independent of changes in total flow, as adrenaline, which also increased FBF, did not increase LDF. The time of onset suggests that LDF closely parallels glucose uptake. Thus, depending on probe design, measurement of muscle haemodynamic effects mediated by insulin in normally responsive and insulin-resistant patients should be possible.

scholarly journals Oxidative Stress Is Associated with Adiposity and Insulin Resistance in Men

2003 ◽  
Vol 88 (10) ◽  
pp. 4673-4676 ◽  
Author(s):  
Hideki Urakawa ◽  
Akira Katsuki ◽  
Yasuhiro Sumida ◽  
Esteban C. Gabazza ◽  
Shuichi Murashima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Body Mass Index ◽  
Body Mass ◽  
Body Fat ◽  
Plasma Levels ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Total Fat

Abstract To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2α (PGF2α) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2α than nonobese men (P &lt; 0.05). The plasma levels of 8-epi-PGF2α were significantly correlated with body mass index (r = 0.408; P &lt; 0.05), body fat weight (r = 0.467; P &lt; 0.05), visceral (r = 0.387; P &lt; 0.05) and total fat area (r = 0.359; P &lt; 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2α and glucose infusion rate in obese men (r = −0.552; P &lt; 0.05) and all men (r = −0.668; P &lt; 0.01). In all subjects, the plasma levels of 8-epi-PGF2α were significantly correlated with fasting serum levels of insulin (r = 0.487; P &lt; 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2α are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.

scholarly journals Insulin-Stimulated Glucose Uptake Occurs in Specialized Cells within the Cumulus Oocyte Complex

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2444-2454 ◽  
Author(s):  
Scott H. Purcell ◽  
Maggie M. Chi ◽  
Kelle H. Moley
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Kinase Inhibitor ◽  
Polycystic Ovary ◽  
Cumulus Cell ◽  
Cumulus Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Cumulus Oocyte Complex ◽  
Phosphatidylinositol 3

The oocyte exists within the mammalian follicle surrounded by somatic cumulus cells. These cumulus cells metabolize the majority of the glucose within the cumulus oocyte complex and provide energy substrates and intermediates such as pyruvate to the oocyte. The insulin receptor is present in cumulus cells and oocytes; however, it is unknown whether insulin-stimulated glucose uptake occurs in either cell type. Insulin-stimulated glucose uptake is thought to be unique to adipocytes, skeletal and cardiac muscle, and the blastocyst. Here, we show for the first time that many of the components required for insulin signaling are present in both cumulus cells and oocytes. We performed a set of experiments on mouse cumulus cells and oocytes and human cumulus cells using the nonmetabolizable glucose analog 2-deoxy-d-glucose to measure basal and insulin-stimulated glucose uptake. We show that insulin-stimulated glucose uptake occurs in both compact and expanded cumulus cells of mice, as well as in human cumulus cells. Oocytes, however, do not display insulin-stimulated glucose uptake. Insulin-stimulated glucose uptake in cumulus cells is mediated through phosphatidylinositol 3-kinase signaling as shown by inhibition of insulin-stimulated glucose uptake and Akt phosphorylation with the specific phosphatidylinositol 3-kinase inhibitor, LY294002. To test the effect of systemic in vivo insulin resistance on insulin sensitivity in the cumulus cell, cumulus cells from high fat-fed, insulin-resistant mice and women with polycystic ovary syndrome were examined. Both sets of cells displayed blunted insulin-stimulated glucose uptake. Our studies identify another tissue that, through a classical insulin-signaling pathway, demonstrates insulin-stimulated glucose uptake. Moreover, these findings suggest insulin resistance occurs in these cells under conditions of systemic insulin resistance.

Acute exercise increases insulin sensitivity in adult sheep: a new preclinical model

2015 ◽  
Vol 308 (6) ◽  
pp. R500-R506 ◽  
Author(s):  
Glenn K. McConell ◽  
Gunveen Kaur ◽  
Filippe Falcão-Tebas ◽  
Yet H. Hong ◽  
Kathryn L. Gatford
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Infusion Rate ◽  
Acute Exercise ◽  
Citrate Synthase ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Large Animal ◽  
Adult Sheep

In healthy humans and rodents, chronic and acute exercise improves subsequent insulin sensitivity of skeletal muscle. A large animal species with similar metabolic responses to exercise would permit longitudinal studies, including repeated biopsies of muscle and other tissues not possible in rodents, and enable study of interactions with insulin-resistant physiological states not feasible in humans. Therefore, we examined whether acute exercise increases insulin sensitivity in adult sheep. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp (HEC) in mature female sheep ( n = 7). Sheep were familiarized to treadmill walking and then performed an acute exercise bout (30 min, 8% slope, up to 4.4 km/h). A second HEC was conducted ∼18 h after the acute exercise. Musculus semimembranosus biopsies were obtained before and after each HEC. Glucose infusion rate during the HEC increased 40% ( P = 0.003) and insulin sensitivity (glucose infusion rate/plasma insulin concentration) increased 32% ( P = 0.028) after acute exercise. Activation of proximal insulin signaling in skeletal muscle after the HEC, measured as Ser473 phosphorylation of Akt, increased approximately five-fold in response to insulin ( P < 0.001) and was unaltered by acute exercise performed 18 h earlier. PGC1α and GLUT4 protein, glycogen content and citrate synthase activity in skeletal muscle did not change in response to insulin or exercise. In conclusion, improved insulin sensitivity and unchanged proximal insulin signaling on the day after acute exercise in sheep are consistent with responses in humans and rodents, suggesting that the sheep is an appropriate large-animal model in which to study responses to exercise.

Quantity of sucrose alters the tissue pattern and time course of insulin resistance in young rats

1995 ◽  
Vol 269 (3) ◽  
pp. R641-R646 ◽  
Author(s):  
M. J. Pagliassotti ◽  
P. A. Prach
Keyword(s):  
Insulin Resistance ◽  
Total Energy ◽  
Infusion Rate ◽  
Time Course ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Young Rats ◽  
Sucrose Diet

To determine the effects of the amount of sucrose in the diet on insulin-stimulated glucose metabolism, euglycemic hyperinsulinemic clamps were performed on male Wistar rats after one of the following dietary treatments (n = 6-8/treatment): 1) high-starch diet (68% of total energy) for 8 wk (ST8), 16 wk (ST16), or 30 wk (ST30); 2) high-sucrose diet (68% of total energy) for 8 wk (SU8), 16 wk (SU16), or 30 wk (SU30); or 3) low-sucrose diet (18% of total energy) for 8 wk (SUL8), 16 wk (SUL16), or 30 wk (SUL30). Body weights were similar in starch- and sucrose-fed rats at 8 wk (502 +/- 9 g), 16 wk (563 +/- 10 g), and 30 wk (607 +/- 26 g). The glucose infusion rate (mumol.g-1.min-1) required to maintain similar glycemia during clamps was 73.1 +/- 8.8 in ST8, 29.7 +/- 4.9 in SU8 (P < 0.05 vs. ST8 and SUL8), and 76.4 +/- 8.2 in SUL8; 69.9 +/- 8.1 in ST16, 35.1 +/- 5.1 in SU16 (P < 0.05 vs. ST16 and SUL16), and 63.2 +/- 6.5 in SUL16; and 65.4 +/- 7.7 in ST30, 26.0 +/- 5.3 (P < 0.05 vs. ST30), and 36.3 +/- 6.0 in SUL30 (P < 0.05 vs. ST30). Impaired suppression of hepatic glucose production accounted for 43, 39, and 34% of the decrease in the glucose infusion rate in SU8 compared with ST8, SU16 compared with ST16, and SU30 compared with ST30, respectively, but 78% in SUL30 compared with ST30. These results suggest that both high- and low-sucrose diets can produce insulin resistance in young rats.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

scholarly journals Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Hong-Jie Chen ◽  
Chih-Yuan Ko ◽  
Jian-Hua Xu ◽  
Yu-Chu Huang ◽  
James Swi-Bea Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Ethyl Acetate ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Lipid Accumulation ◽  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Glucose Transporter 2 ◽  
Tnf Α ◽  
Mouse Hepatocytes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

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