scholarly journals Oral hormonal therapy with ethinylestradiol–levonorgestrel improves insulin resistance, obesity, and glycogen synthase kinase-3 independent of circulating mineralocorticoid in estrogen-deficient rats

2018 ◽  
Vol 96 (6) ◽  
pp. 577-586 ◽  
Author(s):  
Oluwaseun A. Adeyanju ◽  
Olaniyi A. Soetan ◽  
Ayodele O. Soladoye ◽  
Lawrence A. Olatunji
Keyword(s):  
Insulin Resistance ◽  
Hormonal Therapy ◽  
Cell Function ◽  
Glycogen Synthase ◽  
Hdl Cholesterol ◽  
Glycogen Synthase Kinase ◽  
Ovariectomized Rats ◽  
Glycogen Synthase Kinase 3 ◽  
Model Assessment ◽  
Ovx Rats

Estrogen deficiency has been associated with increased incidence of cardiovascular diseases , and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen–progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen-deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol–levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-β, triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic β-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen-deficient rats.

Ameliorative effect of low-dose spironolactone on obesity and insulin resistance is through replenishment of estrogen in ovariectomized rats

2019 ◽  
Vol 97 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Lawrence A. Olatunji ◽  
Oluwaseun A. Adeyanju ◽  
Olugbenga S. Michael ◽  
Taofeek O. Usman ◽  
Rita C. Tostes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Low Dose ◽  
Glycogen Synthase ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Atherogenic Dyslipidemia ◽  
Beneficial Effects ◽  
Ovx Rats ◽  
Ameliorative Effect ◽  
Hormonal Therapies

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-β, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17β-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.

Low-intensity exercise in the prevention of cardiac insulin resistance-related inflammation and disturbances in NOS and MMP-9 regulation in fructose-fed ovariectomized rats

2019 ◽  
Vol 44 (11) ◽  
pp. 1219-1229 ◽  
Author(s):  
Jelena Stanisic ◽  
Goran Koricanac ◽  
Milan Kostic ◽  
Mojca Stojiljkovic ◽  
Tijana Culafic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Insulin Level ◽  
Ovariectomized Rats ◽  
Model Assessment ◽  
Homa Index ◽  
Low Intensity ◽  
Ovx Rats ◽  
Tnf Α ◽  
Low Intensity Exercise

Exercise is important nonpharmacological treatment for improvement of insulin sensitivity in menopause. However, its effect on menopausal cardiac insulin resistance is needing further research. We investigated protective effects of low-intensity exercise on cardiac insulin signaling, inflammation, regulation of nitric oxide synthase (NOS) and matrix metalloproteinase 9 (MMP-9) in ovariectomized (OVX) Wistar rats, submitted to 10% fructose solution for 9 weeks. OVX rats were divided into control, sedentary fructose, and exercise fructose groups. Measurements of physical and biochemical characteristics were carried out to evaluate metabolic syndrome development. Messenger RNA and protein levels and phosphorylation of cardiac insulin signaling molecules, endothelial and inducible NOS (eNOS and iNOS), p65 subunit of nuclear factor κB (NFκB), tumor necrosis factor α (TNF-α), suppressor of cytokine signaling 3 (SOCS3), and MMP-9 were analyzed. Fructose increased insulin level, homeostasis model assessment (HOMA) index, and visceral adipose tissue weight, while low-intensity exercise prevented insulin level and HOMA index increase. Fructose also decreased cardiac pAkt (Ser473), peNOS (Ser1177) and increased insulin receptor substrate 1 (IRS1) phosphorylation at Ser307, pNFκB (Ser276) and NFκB and MMP-9 content, without any effect on iNOS, protein-tyrosine phosphatase 1B, TNF-α, and SOCS3. Exercise prevented changes in pIRS1 (Ser307), pAkt (Ser473), peNOS (Ser1177), pNFκB (Ser276), and NFκB expression. In addition, exercise increased pIRS1 (Tyr632), pAkt (Thr308), and eNOS expression. Low-intensity exercise prevented cardiac insulin signaling disarrangement in fructose-fed OVX rats and therefore eNOS dysfunction, as well as pro-inflammatory signaling activation, without effect on tissue remodeling, suggesting physical training as a way to reduce cardiovascular risk.

scholarly journals Kinome Analysis Reveals Nongenomic Glucocorticoid Receptor-Dependent Inhibition of Insulin Signaling

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3555-3562 ◽  
Author(s):  
Mark Löwenberg ◽  
Jurriaan Tuynman ◽  
Meike Scheffer ◽  
Auke Verhaar ◽  
Louis Vermeulen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Molecular Mechanism ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Immunosuppressive Agents ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Short Term Treatment ◽  
Dependent Inhibition

Glucocorticoids (GCs) are powerful immunosuppressive agents that control genomic effects through GC receptor (GR)-dependent transcriptional changes. A common complication of GC therapy is insulin resistance, but the underlying molecular mechanism remains obscure. Evidence is increasing for rapid genomic-independent GC action on cellular physiology. Here, we generate a comprehensive description of nongenomic GC effects on insulin signaling using peptide arrays containing 1176 different kinase consensus substrates. Reduced kinase activities of the insulin receptor (INSR) and several downstream INSR signaling intermediates (i.e. p70S6k, AMP-activated protein kinase, glycogen synthase kinase-3, and Fyn) were detected in adipocytes and T lymphocytes due to short-term treatment with dexamethasone (DEX), a synthetic fluorinated GC. Western blot analysis confirmed suppressed phosphorylation of the INSR and a series of downstream INSR targets (i.e. INSR substrate-1, p70S6k, protein kinase B, phosphoinositide-dependent protein kinase, Fyn, and glycogen synthase kinase-3) after DEX treatment. DEX inhibited insulin signaling through a GR-dependent (RU486 sensitive) and transcription-independent (actinomycin D insensitive) mechanism. Overall, we postulate here a molecular mechanism for GC-induced insulin resistance based on nongenomic GR-dependent inhibition of insulin signaling.

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