Naringin improves zidovudine- and stavudine-induced skeletal muscle complications in rats

Chronic use of nucleoside reverse transcriptase inhibitors (NRTIs) in managing human immunodeficiency virus (HIV) infection has been associated with several complications. Available management options for these complications have yielded controversial results, thus the need to urgently find newer alternatives. Naringin, a plant-derived flavonoid, has been shown to possess antioxidant and antiapoptotic properties which can be exploited in managing NRTI-induced complications. This study therefore investigated the effects of naringin on some NRTI-induced complications. Forty-nine rats (200–250 g) were divided into seven groups and were orally treated with stavudine (d4T)-only, d4T + naringin, d4T + vitamin E, zidovudine (AZT)-only, AZT + naringin, AZT + vitamin E, and distilled water, respectively. Drugs were administered once daily for 56 days, and oral glucose tolerance tests conducted on day 54 of the experiments and rats were thereafter sacrificed on day 56 by halothane overdose. Plasma samples and the left gastrocnemius muscles were stored at −80°C for further analysis. There was significant glucose intolerance, insulin resistance, oxidative stress, and apoptosis in the skeletal muscles of AZT- or d4T-only–treated rats. Naringin, however, significantly reduced fasting blood glucose and fasting plasma insulin concentrations, mitigated glucose intolerance, and insulin resistance in addition to reducing malondialdehyde and carbonyl protein concentrations when coadministered with either NRTIs. Furthermore, naringin improved antioxidant enzyme activities, reduced skeletal muscle BCL-2-associated X protein expression, and improved B-cell lymphoma-2 protein expression compared to AZT- or d4T-only–treated rats. Naringin ameliorated AZT- and d4T-induced complications and therefore should be further investigated as a possible nutritional supplement in managing HIV infection.

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Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e1014 ◽

1997 ◽

Vol 273 (5) ◽

pp. E1014-E1023 ◽

Cited By ~ 17

Author(s):

Jacob E. Friedman ◽

Tatsuya Ishizuka ◽

Sha Liu ◽

Craig J. Farrell ◽

David Bedol ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Glucose Intolerance ◽

Leptin Receptor ◽

Spontaneously Hypertensive Rat ◽

Regulatory Subunit ◽

Oral Glucose ◽

Spontaneously Hypertensive

Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3- O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85α regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.

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PI3K-GLUT4 Signal Pathway Associated with Effects of EX-B3 Electroacupuncture on Hyperglycemia and Insulin Resistance of T2DM Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7914387 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Bing-Yan Cao ◽

Rui Li ◽

Huan-Huan Tian ◽

Yan-Jia Ma ◽

Xiao-Gang Hu ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Expression ◽

Glucose Transporter ◽

Continuous Wave ◽

Cell Function ◽

Fasting Blood Glucose ◽

Resistance Index ◽

Tolerance Test ◽

Oral Glucose

Objectives.To explore electroacupuncture’s (EA’s) effects on fasting blood glucose (FBG) and insulin resistance of type 2 diabetic mellitus (T2DM) model rats and give a possible explanation for the effects.Method.It takes high fat diet and intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) for model preparation. Model rats were randomly divided into T2DM Model group, EA weiwanxiashu (EX-B3) group, and sham EA group (n=12/group). EA (2 Hz continuous wave, 2 mA, 20 min/day, 6 days/week, 4 weeks) was applied as intervention. FBG, area under curve (AUC) of oral glucose tolerance test (OGTT), insulin resistance index (HOMA-IR), pancreatic B cell function index (HOMA-B), skeletal muscle phosphorylated phosphatidylinositol-3-kinase (PI3K), glucose transporter 4 (GLUT4), and membrane GLUT4 protein expression were measured.Results.EA weiwanxiashu (EX-B3) can greatly upregulate model rat’s significantly reduced skeletal muscle PI3K (Y607) and membrane GLUT4 protein expression (P<0.01), effectively reducing model rats’ FBG and AUC of OGTT (P<0.01). The effects are far superior to sham EA group.Conclusion.EA weiwanxiashu (EX-B3) can upregulate skeletal muscle phosphorylated PI3K protein expression, to stimulate membrane translocation of GLUT4 and thereby increase skeletal muscle glucose intake to treat T2DM.

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Metabolic effects of prazosin on skeletal muscle insulin resistance in glucocorticoid-treated male rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00146.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. R62-R73 ◽

Cited By ~ 3

Author(s):

Emily C. Dunford ◽

Erin R. Mandel ◽

Sepideh Mohajeri ◽

Tara L. Haas ◽

Michael C. Riddell

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Protein Expression ◽

Muscle Atrophy ◽

Rodent Model ◽

Skeletal Muscle Atrophy ◽

Oral Glucose ◽

Capillary Rarefaction

High-dose glucocorticoids (GC) induce skeletal muscle atrophy, insulin resistance, and reduced muscle capillarization. Identification of treatments to prevent or reverse capillary rarefaction and metabolic deterioration caused by prolonged elevations in GCs would be therapeutically beneficial. Chronic administration of prazosin, an α1-adrenergic antagonist, increases skeletal muscle capillarization in healthy rodents and, recently, in a rodent model of elevated GCs and hyperglycemia. The purpose of this study was to determine whether prazosin administration would improve glucose tolerance and insulin sensitivity, through prazosin-mediated sparing of capillary rarefaction, in this rodent model of increased GC exposure. Prazosin was provided in drinking water (50 mg/l) to GC-treated or control rats (400 mg implants of either corticosterone or a wax pellet) for 7 or 14 days ( n = 5–14/group). Whole body measures of glucose metabolism were correlated with skeletal muscle capillarization (C:F) at 7 and 14 days in the four groups of rats. Individual C:F was found to be predictive of insulin sensitivity ( r2 = 0.4781), but not of glucose tolerance ( r2 = 0.1601) and compared with water only, prazosin treatment decreased insulin values during oral glucose challenge by approximately one-third in corticosterone (Cort)-treated animals. Cort treatment, regardless of duration, induced significant glycolytic skeletal muscle atrophy ( P < 0.05), decreased IRS-1 protein content ( P < 0.05), and caused elevations in FOXO1 protein expression ( P < 0.05), which were unaffected with prazosin administration. In summary, it appears that α1-adrenergic antagonism improves Cort-induced skeletal muscle vascular impairments and reduces insulin secretion during an oral glucose tolerance test, but is unable to improve the negative alterations directly affecting the myocyte, including muscle size and muscle signaling protein expression.

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Abstract 20140: Minibrain Relate Kinase / Dyrk1B Links Skeletal Muscle Glycolytic Metabolism with Insulin Resistance and Causes Metabolic Syndrome

Circulation ◽

10.1161/circ.130.suppl_2.20140 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Mohsen Fathzadeh ◽

Ali Reza Keramati ◽

Gwang Go ◽

Rajvir Singh ◽

Kazem Sarajzadeh ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Protein Expression ◽

Ppar Gamma ◽

Glycolytic Metabolism ◽

Expression Levels ◽

Fiber Composition ◽

Mutation Carriers ◽

Fast Twitch

We have identified a novel nonconservative mutation in Minibrain related serine/threonine kinase (Mirk/ Dyrk1B) in outlier kindreds with metabolic syndrome. The mutation substitutes cysteine for arginine (R102C) and segregates with most traits of metabolic syndrome, including central obesity, diabetes and hypertension. Oral glucose tolerance test (OGTT) in young nondiabetic mutation carriers revealed insulin resistance compared to noncarrier family members. Since skeletal muscle (SM) is the largest organ for glucose uptake and metabolism, we obtained Vastus Lateralis biopsies of mutation carriers and their unaffected relatives and examined them for gene/protein expression by deep RNA sequencing (RNA-Seq) and Western blot analysis and for fiber composition by immunostaining. The fiber composition data demonstrated fewer slow-twitch fibers (35% vs. 75%) and more fast -twitch fibers (65% vs. 25%) in SM of mutation carriers vs. controls. Interestingly, there were increased protein expression levels of fast-twitch fiber type proteins (MYH11, MYLPF), pyruvate dehydrogenase kinase, pyruvate kinase, and neuronal nitric oxide synthase in SM of mutation carriers vs. noncarriers. Consistent with these findings, the protein expression levels of the master regulator of cellular energy metabolism mitochondrial biogenesis, PPAR-gamma coactivator (PGC-1a), were reduced and the nuclear expression levels of FOXO1 and NFAT were increased. Similar findings were observed when wildtype and mutant (R102C) Dyrk1B were overexpressed in C2C12 cells. The overexpression of the kinase deficient Dyrk1B (Y271/273F) similarly resulted in reduced expression of PGC-1a and increased expression of nuclear FOXO1, suggesting kinase independent effects. Taken together, these findings suggest that enhanced kinase-independent activities of Dyrk1B, either through increased expression or by its gain of function mutation R102C induce insulin resistance by promoting glycolytic metabolism and reducing oxidative phosphorylation. In conclusion, Dyrk1B is a potential target for development of novel drugs that aim to enhance skeletal muscle insulin sensitivity.

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Immobilization rapidly induces thioredoxin-interacting protein gene expression together with insulin resistance in rat skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00951.2017 ◽

2018 ◽

Vol 125 (2) ◽

pp. 596-604 ◽

Cited By ~ 1

Author(s):

Emi Kawamoto ◽

Keigo Tamakoshi ◽

Song-Gyu Ra ◽

Hiroyuki Masuda ◽

Kentaro Kawanaka

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Expression ◽

Glucose Uptake ◽

Rapid Development ◽

Plaster Cast ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Transcription Inhibitor ◽

Male Wistar Rats

Acute short duration of disuse induces the development of insulin resistance for glucose uptake in rodent skeletal muscle. Because thioredoxin-interacting protein (TXNIP) has been implicated in the downregulation of insulin signaling and glucose uptake, we examined the possibility that muscle disuse rapidly induces insulin resistance via increased TXNIP mRNA and protein expression. Male Wistar rats were subjected to unilateral 6-h hindlimb immobilization by plaster cast. At the end of this period, the soleus muscles from both immobilized and contralateral nonimmobilized hindlimbs were excised and examined. The 6-h immobilization resulted in an increase in TXNIP mRNA and protein expressions together with a decrease in insulin-stimulated 2-deoxyglucose uptake in the rat soleus muscle. Additionally, in the rats euthanized 6 h after the plaster cast removal, TXNIP protein expression and insulin-stimulated glucose uptake in the immobilized muscle had both been restored to a normal level. Various interventions (pretreatment with transcription inhibitor actinomycin D or AMP-dependent protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide) also suppressed the increase in TXNIP protein expression in 6-h-immobilized muscle together with partial prevention of insulin resistance for glucose uptake. These results suggested the possibility that increased TXNIP protein expression in immobilized rat soleus muscles was associated with the rapid induction of insulin resistance for glucose uptake in that tissue. NEW & NOTEWORTHY The cellular mechanism by which disuse rapidly induces muscle insulin resistance for glucose uptake remains to be identified. Using a rat hindlimb immobilization model, our findings suggest the possibility that transcriptional upregulation of thioredoxin-interacting protein is associated with the immobilization-induced rapid development of insulin resistance in skeletal muscle.

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The Effect of Chrysin-Loaded Phytosomes on Insulin Resistance and Blood Sugar Control in Type 2 Diabetic db/db Mice

Molecules ◽

10.3390/molecules25235503 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5503

Author(s):

Seong-min Kim ◽

Jee-Young Imm

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Phosphoenolpyruvate Carboxykinase ◽

Glucose Transporter ◽

Fasting Blood Glucose ◽

Normal Diet ◽

Molar Ratio ◽

Oral Glucose ◽

Peroxisome Proliferator ◽

Model Assessment

Although a variety of beneficial health effects of natural flavonoids, including chrysin, has been suggested, poor solubility and bioavailability limit their practical use. As a promising delivery system, chrysin-loaded phytosomes (CPs) were prepared using egg phospholipid (EPL) at a 1:3 molar ratio and its antidiabetic effects were assessed in db/db diabetic mice. Male C57BLKS/J-db/db mice were fed a normal diet (control), chrysin diet (100 mg chrysin/kg), CP diet (100 mg chrysin equivalent/kg), metformin diet (200 mg/kg) or EPL diet (vehicle, the same amount of EPL used for CP preparation) for 9 weeks. Administration of CP significantly decreased fasting blood glucose and insulin levels in db/db mice compared with the control. An oral glucose tolerance test and homeostatic model assessment for insulin resistance were significantly improved in the CP group (p < 0.05). CP treatment suppressed gluconeogenesis via downregulation of phosphoenolpyruvate carboxykinase while it promoted glucose uptake in the skeletal muscle and liver of db/db mice (p < 0.05). The CP-mediated improved glucose utilization in the muscle was confirmed by upregulation of glucose transporter type 4, hexokinase2 and peroxisome proliferator-activated receptor γ during treatment (p < 0.05). The CP-induced promotion of GLUT4 plasma translocation was confirmed in the skeletal muscle of db/db mice (p < 0.05). Based on the results, CP showed greater antidiabetic performance compared to the control by ameliorating insulin resistance in db/db mice and phytosome can be used as an effective antidiabetic agent.

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Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00159.2017 ◽

2018 ◽

Vol 314 (2) ◽

pp. R181-R190 ◽

Cited By ~ 12

Author(s):

Jacob T. Mey ◽

Brian K. Blackburn ◽

Edwin R. Miranda ◽

Alec B. Chaves ◽

Joan Briller ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Expression ◽

Enzyme System ◽

Vastus Lateralis ◽

Negative Regulator ◽

Glucose Disposal ◽

Carbonyl Stress ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance

Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m2) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m2). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m−2·min−1)–euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (−78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (−31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

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Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00346.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. E892-E900 ◽

Cited By ~ 62

Author(s):

Erik J. Henriksen ◽

Tyson R. Kinnick ◽

Mary K. Teachey ◽

Matthew P. O'Keefe ◽

David Ring ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Transport ◽

Glycogen Synthase ◽

Oral Glucose ◽

Type I ◽

Insulin Resistant ◽

Zucker Diabetic Fatty Rats ◽

Zdf Rats ◽

Glycogen Synthase Activity

A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 × 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.

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Insulin signaling displayed a differential tissue-specific response to low-dose dihydrotestosterone in female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. E353-E365 ◽

Cited By ~ 4

Author(s):

Stanley Andrisse ◽

Katelyn Billings ◽

Ping Xue ◽

Sheng Wu

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Energy Storage ◽

Protein Expression ◽

Insulin Signaling ◽

Low Dose ◽

Specific Response ◽

Pituitary Cells ◽

Reproductive Tissues ◽

Mrna And Protein Expression

Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low-dose dihydrotestosterone (DHT), a model of PCOS, on insulin signaling in metabolic and reproductive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and white adipose tissue (WAT) from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared with controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin-signaling genes were not lowered in DHT mice compared with control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice compared with controls. DHT mice were hyperinsulinemic. However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepatocytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage vs. reproductive tissues independent of hyperinsulinemia.

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