PMID-sentid Pub_year Sent_text comp_official_name comp_offsetprotein_name organism prot_offset 32655497-6 2020 The insulin-resistant state, commonly reported in AD brain, results in neuronal glucose deprivation, due to a dampening down of the PI3K/Akt pathway, including overactivity of the mammalian target of rapamycin 1 (mTORC1) complex, hyperphosphorylation of p53 and neuronal death. Sirolimus 200-209 insulin Homo sapiens 4-11 31794259-7 2020 However, acute inhibition of mTORC1 with rapamycin blocked Grb10 Ser476 phosphorylation and repressed a negative-feedback loop on PI3K/Akt signaling that increased myotube responsiveness to insulin. Sirolimus 41-50 insulin Homo sapiens 190-197 31406105-2 2019 Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. Sirolimus 12-21 insulin Homo sapiens 33-40 31941840-3 2020 Both TAC and SIR impaired insulin secretion in fasted and/or stimulated conditions. Sirolimus 13-16 insulin Homo sapiens 26-33 31941840-4 2020 Treatment with TAC or SIR increased amyloid deposition and islet macrophages, disrupted insulin granule formation, and induced broad transcriptional dysregulation related to peptide processing, ion/calcium flux, and the extracellular matrix; however, it did not affect regulation of beta cell mass. Sirolimus 22-25 insulin Homo sapiens 88-95 31167878-7 2019 Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Sirolimus 90-99 insulin Homo sapiens 34-41 31406105-2 2019 Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. Sirolimus 12-21 insulin Homo sapiens 74-81 31406105-2 2019 Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. Sirolimus 12-21 insulin Homo sapiens 74-81 30647914-3 2019 MTORC1 is activated in an interdependent manner by insulin/growth factors and nutrients, especially amino acids, and is inhibited by stressors such as hypoxia and by the drug rapamycin. Sirolimus 175-184 insulin Homo sapiens 51-58 31044492-1 2019 Insulin, insulin-like growth factor-1 (IGF-1) and essential amino acids activate the mechanistic target of rapamycin complex 1 (mTORC1), the main nutrient-sensitive kinase. Sirolimus 107-116 insulin Homo sapiens 0-7 31115485-7 2019 Rapamycin also increased Abeta clearance by promoting autophagy and reduced Tau hyperphosphorylation by upregulating the levels of insulin-degrading enzyme. Sirolimus 0-9 insulin Homo sapiens 131-138 30863363-12 2019 Compared to untreated T2D cells, rapamycin-exposed diabetic islets showed improved insulin secretion, reduced proportion of beta cells showing signs of apoptosis and better preserved insulin granules, mitochondria and ER ultrastructure; this was associated with significant reduction of PERK, CHOP and BiP gene expression. Sirolimus 33-42 insulin Homo sapiens 83-90 29282029-10 2017 However, addition of rapamycin, an inhibitor of the mTOR signaling pathways, 1 h before addition of estradiol or insulin increased the pAkt/Akt ratio and FASN expression, and this effect was inhibited by addition of DHA 48 h before rapamycin. Sirolimus 21-30 insulin Homo sapiens 113-120 29158477-3 2017 Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal beta cells in a dose- and time-dependent manner. Sirolimus 18-27 insulin Homo sapiens 55-62 29158477-6 2017 Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Sirolimus 43-52 insulin Homo sapiens 165-172 27922820-5 2016 In fact, rapamycin increased insulin sensitivity and reduced weight gain in 3 models, and decreased hyperinsulinemia in 2 models. Sirolimus 9-18 insulin Homo sapiens 29-36 27686967-0 2016 Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes. Sirolimus 0-9 insulin Homo sapiens 29-36 27686967-4 2016 We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT. Sirolimus 31-40 insulin Homo sapiens 44-51 27686967-5 2016 Treatment of brown adipocytes with rapamycin for 16h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Sirolimus 35-44 insulin Homo sapiens 77-84 27686967-8 2016 These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. Sirolimus 17-26 insulin Homo sapiens 30-37 27686967-9 2016 In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Akt phosphorylation in BAT. Sirolimus 31-40 insulin Homo sapiens 67-74 28954814-7 2017 Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. Sirolimus 41-50 insulin Homo sapiens 98-105 26733005-6 2016 RESULTS: Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Sirolimus 17-26 insulin Homo sapiens 45-52 27826244-6 2016 This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. Sirolimus 84-93 insulin Homo sapiens 107-114 27506738-7 2016 More interestingly, the glucose uptake and the phosphorylation of the insulin receptor were decreased by 3-MA stimulation and increased by rapamycin, illustrating that the responsiveness of insulin was regulated by autophagy. Sirolimus 139-148 insulin Homo sapiens 70-77 25875045-5 2015 The inhibitory effect of CRFR2 signaling required cAMP production and is involved the mammalian target of rapamycine pathway, as rapamycin reversed the inhibitory effect of CRFR2 stimulation on insulin-induced glucose uptake. Sirolimus 106-115 insulin Homo sapiens 194-201 26449763-0 2015 Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo. Sirolimus 22-31 insulin Homo sapiens 63-70 26449763-5 2015 In vitro, rapamycin treatment reversed inflammatory cytokine-stimulated IRS-1 serine phosphorylation, increased insulin signaling to AKT and enhanced glucose utilization. Sirolimus 10-19 insulin Homo sapiens 112-119 26449763-7 2015 Our results indicate a paradoxical effect of rapamycin on insulin resistance between the in vitro and in vivo environments under inflammatory stress and provide additional insight into the clinical application of rapamycin. Sirolimus 45-54 insulin Homo sapiens 58-65 26719046-7 2016 Furthermore, insulin induced activation of these kinases was abrogated by pretreatment with PP242 as compared with rapamycin. Sirolimus 115-124 insulin Homo sapiens 13-20 24835482-3 2015 Here we isolated mesenchymal stem cells from human hair follicles (HF-MSCs) and engineered them to overexpress the human insulin gene and release human insulin in a time- and dose-dependent manner in response to rapamycin. Sirolimus 212-221 insulin Homo sapiens 121-128 24755936-5 2015 To begin clarifying the mechanism(s) involved in insulin resistance induced by rapamycin, we compared several aspects of liver metabolism in mice treated with DR or rapamycin for 6 months. Sirolimus 79-88 insulin Homo sapiens 49-56 25643582-5 2015 Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Sirolimus 164-173 insulin Homo sapiens 18-25 24835482-3 2015 Here we isolated mesenchymal stem cells from human hair follicles (HF-MSCs) and engineered them to overexpress the human insulin gene and release human insulin in a time- and dose-dependent manner in response to rapamycin. Sirolimus 212-221 insulin Homo sapiens 152-159 25242764-10 2014 Chronic rapamycin treatment reduces adipose tissue size and beta-cell mass/function, causes hyperlipidemia, severe insulin resistance, and glucose intolerance, and promotes hepatic gluconeogenesis. Sirolimus 8-17 insulin Homo sapiens 115-122 25801056-6 2015 Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. Sirolimus 14-23 insulin Homo sapiens 131-138 25330241-5 2014 However, the effects of mTOR inhibitor, rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin-stimulated AKT activation. Sirolimus 89-98 insulin Homo sapiens 117-124 24650522-4 2014 Utilizing both rapamycin to inhibit mTORC1 activity and shRNA to knock down Rheb, we demonstrated that the decrease in Akt Ser473 phosphorylation stimulated by insulin after C2-ceramide incubation can be prevented. Sirolimus 15-24 insulin Homo sapiens 160-167 26120590-5 2013 Interestingly, pharmacological activation of AMPK can prevent activation of mTOR/p70S6K and insulin resistance, while inhibition of mTOR with rapamycin prevents insulin resistance, but not AMPK downregulation. Sirolimus 142-151 insulin Homo sapiens 161-168 23863152-3 2013 On the other hand, the rapamycin-insensitive mTORC2 responds to the presence of growth factors such as insulin by phosphorylating Akt to promote its maturation and allosteric activation. Sirolimus 23-32 insulin Homo sapiens 103-110 24810050-8 2014 Insulin-induced Akt phosphorylation was decreased and restored by rapamycin and an inhibitor of S6K. Sirolimus 66-75 insulin Homo sapiens 0-7 24085506-2 2013 However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents. Sirolimus 70-79 insulin Homo sapiens 106-113 23648089-4 2013 We find that rapamycin treatment leads to glucose intolerance in both young and old HET3 mice, but in contrast to the previously reported effect of injected rapamycin in C57BL/6 mice, HET3 mice treated with dietary rapamycin responded normally in an insulin tolerance test. Sirolimus 13-22 insulin Homo sapiens 250-257 22028412-6 2012 An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. Sirolimus 22-31 insulin Homo sapiens 180-187 23261705-4 2013 Pharmacological inhibition of MTORC1 with rapamycin abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. Sirolimus 42-51 insulin Homo sapiens 66-73 23261705-6 2013 Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by rapamycin. Sirolimus 150-159 insulin Homo sapiens 13-20 23160140-1 2013 Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown. Sirolimus 36-45 insulin Homo sapiens 97-104 23160140-7 2013 These findings suggest that CsA, tacrolimus and rapamycin enhance lipolysis, inhibit lipid storage and expression of lipogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy. Sirolimus 48-57 insulin Homo sapiens 212-219 22973301-0 2012 Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Sirolimus 0-9 insulin Homo sapiens 35-42 22973301-1 2012 Rapamycin, an inhibitor of mTOR complex 1 (mTORC1), improves insulin sensitivity in acute studies in vitro and in vivo by disrupting a negative feedback loop mediated by S6 kinase. Sirolimus 0-9 insulin Homo sapiens 61-68 22973301-2 2012 We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 h. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Sirolimus 13-22 insulin Homo sapiens 54-61 22973301-2 2012 We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 h. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Sirolimus 13-22 insulin Homo sapiens 177-184 22973301-8 2012 Thus, mTORC2 disruption, rather than inhibition of mitochondria, causes insulin resistance in rapamycin-treated myotubes, and this system may serve as a useful model to understand the effects of rapamycin on mTOR signaling in vivo. Sirolimus 94-103 insulin Homo sapiens 72-79 22842983-8 2012 We observed sensitivity to rapamycin-mediated growth inhibition and inactivation of insulin-mediated SGK1-Ser422 phosphorylation in ERalpha+ MCF-7 and T47D cells, but not in ERalpha- MDA-MB-231 or MCF10A-Myc cells. Sirolimus 27-36 insulin Homo sapiens 84-91 22281494-0 2012 Improved insulin sensitivity by rapamycin is associated with reduction of mTOR and S6K1 activities in L6 myotubes. Sirolimus 32-41 insulin Homo sapiens 9-16 23762265-4 2013 Forced expression of miR-99a or rapamycin treatment blocked insulin-induced PKM2 and HIF-1alpha expression, and glucose consumption and lactate production. Sirolimus 32-41 insulin Homo sapiens 60-67 22333157-7 2012 This is the first study to show that rapamycin reduces glucose uptake in human adipocytes through impaired insulin signalling and this may contribute to the development of insulin resistance associated with rapamycin therapy. Sirolimus 37-46 insulin Homo sapiens 107-114 22281494-8 2012 Taken together, these results suggest that rapamycin improved ER stress-induced insulin resistance via inhibition of mTOR/S6K1 hyperphosphorylation in L6 myotubes. Sirolimus 43-52 insulin Homo sapiens 80-87 23272222-6 2012 Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. Sirolimus 0-9 insulin Homo sapiens 44-51 21672148-1 2011 Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Sirolimus 0-9 insulin Homo sapiens 135-142 21854819-5 2011 The insulin-induced increase of tau protein level was abolished by LY294002 [an inhibitor of phosphoinositide 3-kinase (PI3K)] and rapamycin [an inhibitor of mammalian target of rapamycin (mTOR)], but not by PD98059 and U0126 [two inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)]. Sirolimus 131-140 insulin Homo sapiens 4-11 21602475-11 2011 Mimicking AMPK activators in the presence of insulin, rapamycin inhibited p70S6K and reduced IRS-1 phosphorylation on serine, resulting in the overphosphorylation of PKB/Akt and AS160. Sirolimus 54-63 insulin Homo sapiens 45-52 21672148-5 2011 In addition, rapamycin increased insulin resistance as shown by HOMA index. Sirolimus 13-22 insulin Homo sapiens 33-40 21296326-1 2011 The purpose of the present study was to evaluate the 3-year clinical outcomes after percutaneous coronary intervention with sirolimus-eluting stents in patients with insulin-treated diabetes mellitus (DM-insulin) and those with non-insulin-treated DM (DM-non-insulin) compared to patients without DM. Sirolimus 124-133 insulin Homo sapiens 166-173 20936651-5 2011 IRS-1 (Ser302) phosphorylation was abolished by wortmannin and rapamycin, suggesting a feedback from the PI3K pathway on insulin signalling. Sirolimus 63-72 insulin Homo sapiens 121-128 25961241-8 2011 Long-term oestrogen/insulin-deprived MCF-7 cells had higher levels of phosphorylated p70S6K and developed increased sensitivity to growth inhibition by rapamycin. Sirolimus 152-161 insulin Homo sapiens 20-27 21046356-9 2011 Rapamycin monotherapy was also associated with a decrease in insulin antibody titre (median decrease 110 to 35.9 U/ml; p < 0.001) and fasting serum proinsulin (median decrease 0.51 to 0.28 pmol/l; p = 0.001). Sirolimus 0-9 insulin Homo sapiens 151-161 20484410-10 2010 However, rapamycin inhibited the activity of these complexes by decreasing the TSH and insulin-mediated stimulation of activating T172 phosphorylation of CDK4. Sirolimus 9-18 insulin Homo sapiens 87-94 21041974-9 2010 These results might suggest that special attention to patients with hemodialysis and insulin-treated DM is warranted in the setting of sirolimus-eluting stent deployment for DM patients. Sirolimus 135-144 insulin Homo sapiens 85-92 20299475-7 2010 These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop. Sirolimus 121-130 insulin Homo sapiens 61-68 20138985-9 2010 Inhibition of mTORC1 by rapamycin or amino acid deprivation partially abrogated insulin-mediated PRAS40-Ser183 phosphorylation in cultured cell lines. Sirolimus 24-33 insulin Homo sapiens 80-87 20299475-2 2010 Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive. Sirolimus 91-100 insulin Homo sapiens 27-34 20299475-2 2010 Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive. Sirolimus 91-100 insulin Homo sapiens 127-134 20299475-2 2010 Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive. Sirolimus 91-100 insulin Homo sapiens 127-134 19864431-5 2010 We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. Sirolimus 130-139 insulin Homo sapiens 15-22 20203102-3 2010 Acute inhibition of mTORC1/S6K1 by rapamycin increases insulin signaling and glucose uptake in myocytes and adipocytes, but whether these effects can be maintained under chronic inhibition of mTORC1 or S6K1 remains unclear. Sirolimus 35-44 insulin Homo sapiens 55-62 19940100-8 2010 Furthermore, the effects of leucine on insulin-stimulated 3-MG transport and IRS phosphorylation were abolished by rapamycin. Sirolimus 115-124 insulin Homo sapiens 39-46 19567519-12 2009 CONCLUSIONS: Rapamycin may provide a useful means of abrogating tumor growth and controlling hypoglycemia in malignant insulinomas by reducing the malignant beta-cell growth and proliferation as well as inhibiting insulin production. Sirolimus 13-22 insulin Homo sapiens 119-126 20847591-3 2009 We have now shown that the insulin-induced increase in the abundance of SREBP1c mRNA in cultured AML12 mouse hepatocytes was largely abolished by LY294002, an inhibitor of phosphoinositide 3-kinase, but was reduced only slightly by rapamycin, an inhibitor of mTOR. Sirolimus 232-241 insulin Homo sapiens 27-34 19168580-6 2009 Furthermore, Pin1 enhanced the insulin-induced extracellular signal-regulated protein kinase (ERK)1/2 phosphorylation through its interaction with p70S6K, whereas the inhibition of p70S6K activity by rapamycin suppressed insulin-induced ERK1/2 phosphorylation in SK-HEP-1 cells. Sirolimus 200-209 insulin Homo sapiens 31-38 19651294-6 2009 In this review, we summarize the role of mTOR and its inhibitor sirolimus (SRL) on chronic hyperglycemia and insulin resistance in beta cells, adipose tissue, liver, and muscle. Sirolimus 64-73 insulin Homo sapiens 109-116 19190264-4 2009 This effect of insulin on lipolysis was only observed when the mammalian target of rapamycin (mTOR) pathway was inhibited by rapamycin in the adipocytes. Sirolimus 83-92 insulin Homo sapiens 15-22 19168580-6 2009 Furthermore, Pin1 enhanced the insulin-induced extracellular signal-regulated protein kinase (ERK)1/2 phosphorylation through its interaction with p70S6K, whereas the inhibition of p70S6K activity by rapamycin suppressed insulin-induced ERK1/2 phosphorylation in SK-HEP-1 cells. Sirolimus 200-209 insulin Homo sapiens 221-228 19356713-5 2009 Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Sirolimus 219-228 insulin Homo sapiens 0-7 18431361-6 2008 When the cells were implanted into athymic mice that had been rendered diabetic with streptozotocin (STZ), insulin was detected in the plasma within 1 hour after addition of rapamycin. Sirolimus 174-183 insulin Homo sapiens 107-114 18586400-2 2008 By using calcium imaging and patch-clamping techniques to study the role of this signaling pathway in the activity of cultured hippocampal neurons, we found that rapamycin significantly reduces the spontaneous activities of network neurons as well as the efficacy of synaptic transmission through insulin-mTOR signaling pathway. Sirolimus 162-171 insulin Homo sapiens 297-304 17993646-7 2008 Furthermore, IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6. Sirolimus 124-133 insulin Homo sapiens 145-152 18431361-3 2008 Lentiviral vectors have been engineered to produce a fusion protein between the furin-cleavable proinsulin and the self-dimerization mutant of FK506-binding protein to yield bioactive insulin in keratinocytes; this insulin is released as a response to exogenous administration of a small organic molecule, rapamycin. Sirolimus 306-315 insulin Homo sapiens 184-191 18303120-6 2008 Treatment with rapamycin [a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1)] inhibited the increased PTEN expression and partially restored insulin-stimulated glucose transport and Akt activation to insulin-resistant cells. Sirolimus 15-24 insulin Homo sapiens 163-170 18303120-6 2008 Treatment with rapamycin [a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1)] inhibited the increased PTEN expression and partially restored insulin-stimulated glucose transport and Akt activation to insulin-resistant cells. Sirolimus 15-24 insulin Homo sapiens 222-229 18174523-11 2008 Rapamycin increased the stress-responsive c-Jun NH(2)-terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and beta-cell apoptosis. Sirolimus 0-9 insulin Homo sapiens 138-145 18174523-12 2008 Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin. Sirolimus 101-110 insulin Homo sapiens 29-36 18174523-13 2008 CONCLUSIONS: Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing beta-cell function and mass. Sirolimus 13-22 insulin Homo sapiens 64-71 17993646-4 2008 Here we show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes. Sirolimus 18-27 insulin Homo sapiens 70-77 17698027-6 2007 Experiments using chimeric apoB UTR-luciferase constructs transfected into HepG2 cells followed by treatment with wortmannin, a PI-3K inhibitor, and rapamycin, an mTOR inhibitor, showed that signaling via PI-3K and mTOR pathways is necessary for insulin-mediated inhibition of chimeric 5" UTR-luciferase expression. Sirolimus 149-158 insulin Homo sapiens 246-253 18093179-8 2008 In parallel, it was observed that LY294002 and rapamycin almost completely blocked the effects of insulin and IGF-1 on MCT2 protein expression, whereas PD98059 and SB202190 (a p38K inhibitor) had no effect on insulin-induced MCT2 expression and only a slight effect on IGF-1-induced MCT2 expression. Sirolimus 47-56 insulin Homo sapiens 98-105 18093179-8 2008 In parallel, it was observed that LY294002 and rapamycin almost completely blocked the effects of insulin and IGF-1 on MCT2 protein expression, whereas PD98059 and SB202190 (a p38K inhibitor) had no effect on insulin-induced MCT2 expression and only a slight effect on IGF-1-induced MCT2 expression. Sirolimus 47-56 insulin Homo sapiens 209-216 17920355-1 2007 The effect of insulin therapy on adverse cardiovascular outcomes in diabetic patients has been debated and a reduced benefit in clinical restenosis outcomes after sirolimus stenting has been reported among diabetic patients requiring insulin therapy. Sirolimus 163-172 insulin Homo sapiens 234-241 17353769-0 2007 In vivo and in vitro effect of sirolimus on insulin secretion. Sirolimus 31-40 insulin Homo sapiens 44-51 17371596-6 2007 Incubation of rapamycin (inhibitor of mTOR) inhibited amino acid or insulin-dependent p70 S6 kinase phosphorylation, blocked (P < 0.05) the inhibitory effects of 1.0 x PC AA on protein degradation, but did not alter the inhibitory effects of insulin or leucine CONCLUSION: In a C2C12 myotube model of myofibrillar protein turnover, amino acid limitation increases proteolysis in a ubiquitin-proteasome-dependent manner. Sirolimus 14-23 insulin Homo sapiens 68-75 17371596-6 2007 Incubation of rapamycin (inhibitor of mTOR) inhibited amino acid or insulin-dependent p70 S6 kinase phosphorylation, blocked (P < 0.05) the inhibitory effects of 1.0 x PC AA on protein degradation, but did not alter the inhibitory effects of insulin or leucine CONCLUSION: In a C2C12 myotube model of myofibrillar protein turnover, amino acid limitation increases proteolysis in a ubiquitin-proteasome-dependent manner. Sirolimus 14-23 insulin Homo sapiens 245-252 17379645-6 2007 Short-term treatment with rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, completely abrogated the ability of insulin to increase the rate and magnitude of Ca2+ signaling and production of inositol 1,4,5-trisphosphate in response to bradykinin stimulation, indicating that insulin potentiates Gq protein-coupled receptor signaling through an mTOR-dependent pathway. Sirolimus 26-35 insulin Homo sapiens 124-131 17379645-6 2007 Short-term treatment with rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, completely abrogated the ability of insulin to increase the rate and magnitude of Ca2+ signaling and production of inositol 1,4,5-trisphosphate in response to bradykinin stimulation, indicating that insulin potentiates Gq protein-coupled receptor signaling through an mTOR-dependent pathway. Sirolimus 26-35 insulin Homo sapiens 287-294 17329620-12 2007 In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway. Sirolimus 15-24 insulin Homo sapiens 36-43 17244624-4 2007 Rapamycin, but not adiponectin, enhanced insulin-stimulated Akt phosphorylation in HeLa cells, which lack LKB1, and exogenous expression of LKB1 in HeLa cells rescued the insulin-sensitizing effect of adiponectin. Sirolimus 0-9 insulin Homo sapiens 41-48 17244624-4 2007 Rapamycin, but not adiponectin, enhanced insulin-stimulated Akt phosphorylation in HeLa cells, which lack LKB1, and exogenous expression of LKB1 in HeLa cells rescued the insulin-sensitizing effect of adiponectin. Sirolimus 0-9 insulin Homo sapiens 171-178 17353769-8 2007 CONCLUSIONS: This study suggests that sirolimus, at plasma-drug concentrations usually targeted in clinical practice, (1) increases basal and stimulated insulin levels in vivo and insulin content in vitro regardless of culture duration; (2) is able to reduce apoptosis. Sirolimus 38-47 insulin Homo sapiens 153-160 17353769-8 2007 CONCLUSIONS: This study suggests that sirolimus, at plasma-drug concentrations usually targeted in clinical practice, (1) increases basal and stimulated insulin levels in vivo and insulin content in vitro regardless of culture duration; (2) is able to reduce apoptosis. Sirolimus 38-47 insulin Homo sapiens 180-187 17353769-1 2007 BACKGROUND: The effects of sirolimus on insulin secretion are still debated. Sirolimus 27-36 insulin Homo sapiens 40-47 17353769-6 2007 RESULTS: (1) Basal and stimulated insulin levels and GDR increased during sirolimus administration and returned to baseline after a wash-out period; (2) regardless of culture duration, sirolimus dose-dependently decreased apoptosis and increased insulin content. Sirolimus 185-194 insulin Homo sapiens 34-41 17353769-6 2007 RESULTS: (1) Basal and stimulated insulin levels and GDR increased during sirolimus administration and returned to baseline after a wash-out period; (2) regardless of culture duration, sirolimus dose-dependently decreased apoptosis and increased insulin content. Sirolimus 185-194 insulin Homo sapiens 246-253 16952420-5 2007 Rapamycin treatment partially decreased the phosphorylation of mTOR but completely abolished the phosphorylation of p70(S6K) in the absence as well as presence of insulin in both cell lines. Sirolimus 0-9 insulin Homo sapiens 163-170 16952420-9 2007 Parental HepG2 cells showed decline in the cell proliferation after 48 h and the presence of insulin prolonged cell survival until 120 h and this effect were also inhibited by rapamycin under serum deprived conditions. Sirolimus 176-185 insulin Homo sapiens 93-100 17077083-0 2006 Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. Sirolimus 103-112 insulin Homo sapiens 38-45 17125709-13 2006 CONCLUSIONS: Sirolimus-eluting stent implantation in diabetics with very small vessels is safe and effective, even in insulin-dependent patients. Sirolimus 13-22 insulin Homo sapiens 118-125 16896936-13 2006 CONCLUSIONS/INTERPRETATION: Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. Sirolimus 54-63 insulin Homo sapiens 135-142 16896936-14 2006 The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance. Sirolimus 22-31 insulin Homo sapiens 159-166 16506055-6 2006 The insulin-induced increase of HIF-1alpha is blunted by the translation inhibitor cycloheximide, LY294002, PD98059, SP600125 and rapamycin, but not by SB203580. Sirolimus 130-139 insulin Homo sapiens 4-11 16763566-2 2006 In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin-sensitive manner. Sirolimus 70-79 insulin Homo sapiens 15-22 16651733-6 2006 Wortmannin and rapamycin were demonstrated to deactivate suppression of AQP3 expression by insulin and troglitazone, suggesting that the signal transducers, phosphoinositide 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR), are involved in the signal pathway for regulating transcription of AQP3. Sirolimus 15-24 insulin Homo sapiens 91-98 16129690-4 2005 Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. Sirolimus 44-53 insulin Homo sapiens 155-162 16455781-5 2006 In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. Sirolimus 57-66 insulin Homo sapiens 39-46 16455781-5 2006 In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. Sirolimus 57-66 insulin Homo sapiens 95-102 16680182-1 2006 The development by the Edmonton group of a sirolimus-based, steroid-free, low-tacrolimus regimen is a significant breakthrough that allows the rate of insulin independence after islet transplantation to increase from 13% to 80% at 1 year; however, the rate is reduced to 50% at 3 years, attributed to prolonged tacrolimus exposure. Sirolimus 43-52 insulin Homo sapiens 151-158 16545079-9 2006 Inhibition of mTOR by rapamycin markedly impairs insulin-activated protein synthesis. Sirolimus 22-31 insulin Homo sapiens 49-56 16396989-10 2006 Rapamycin completely blocked insulin-activated mTOR/p70S(6)K signaling and mitogenesis. Sirolimus 0-9 insulin Homo sapiens 29-36 16129690-4 2005 Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. Sirolimus 44-53 insulin Homo sapiens 286-293 16107580-2 2005 This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic beta cell response. Sirolimus 113-122 insulin Homo sapiens 137-144 16298655-12 2005 However, recipients on sirolimus treatment had significantly lower insulinemia during the test and consequently more favorable indices of insulin action as assessed by HOMA-IR. Sirolimus 23-32 insulin Homo sapiens 67-74 16107580-6 2005 The increase of insulin resistance and the decrease of disposition index significantly correlated with the change of serum triglyceride concentration after the conversion to sirolimus-based therapy (R(2) = 0.30, P = 0.0002; and R(2) = 0.19, P = 0.004, respectively). Sirolimus 174-183 insulin Homo sapiens 16-23 15604215-9 2005 Inhibition of mTOR/S6K1 by rapamycin blunted insulin-induced Ser636/Ser639 phosphorylation of IRS-1, leading to a rapid (approximately 5 min) and persistent increase in IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. Sirolimus 27-36 insulin Homo sapiens 45-52 15988698-7 2005 Rapamycin, an inhibitor or mTOR, could partially improve insulin-stimulated glucose uptake through maintaining IRS-1 protein levels. Sirolimus 0-9 insulin Homo sapiens 57-64 16099428-1 2005 In 3T3-L1 adipocytes, insulin or anisomycin stimulated phosphorylation of IRS-1 at Ser(307) and Ser(636/639), both of which were partially reduced by the mTOR inhibitor, rapamycin, or the JNK inhibitor, SP600125, and were further inhibited by a combination of them. Sirolimus 170-179 insulin Homo sapiens 22-29 15576463-4 2005 Inhibition of mTOR/S6K1 by rapamycin increased insulin-stimulated glucose transport by as much as 45% in 3T3-L1 adipocytes. Sirolimus 27-36 insulin Homo sapiens 47-54 15576463-6 2005 However, insulin-induced activation of Akt was increased by rapamycin. Sirolimus 60-69 insulin Homo sapiens 9-16 15576463-8 2005 As in murine cells, rapamycin treatment of human adipocytes inhibited S6K1, blunted Ser636/639 phosphorylation of IRS-1, leading to increased Akt activation and glucose uptake by insulin. Sirolimus 20-29 insulin Homo sapiens 179-186 15677500-3 2005 In this study, we report that tacrolimus, sirolimus, and mycophenolic acid, when added to cultures of freshly isolated human islets, induce a downregulation of the synthesis and secretion of insulin. Sirolimus 42-51 insulin Homo sapiens 191-198 15576463-9 2005 Further studies in 3T3-L1 adipocytes revealed that rapamycin prevented the relocalization of IRS-1 from the low-density membranes to the cytosol in response to insulin. Sirolimus 51-60 insulin Homo sapiens 160-167 15041369-2 2004 The development by the Edmonton group of a sirolimus-based, steroid-free, low-tacrolimus regimen was a significant breakthrough that allowed the rate of insulin independence after islet transplantation to increase from 13% to 80% at 1 year. Sirolimus 43-52 insulin Homo sapiens 153-160 15123681-10 2004 Pretreatment of matured U937 cells with rapamycin blocked chronic insulin + high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Sirolimus 40-49 insulin Homo sapiens 66-73 15123524-9 2004 However, among patients receiving sirolimus-eluting stents, there remains a trend toward a higher frequency of repeat intervention in diabetic patients compared with nondiabetic patients, particularly in the insulin-requiring patients. Sirolimus 34-43 insulin Homo sapiens 208-215 15020250-3 2004 We further investigated the role of mTOR in regulating serine 307 phosphorylation, demonstrating that serine 307 phosphorylation in response to insulin, anisomycin, or tumor necrosis factor was quantitatively and temporally associated with activation of mTOR and could be inhibited by rapamycin. Sirolimus 285-294 insulin Homo sapiens 144-151 15586002-1 2005 PURPOSE OF REVIEW: The aim of this article is to summarize recent advances in the understanding of the regulation of the target of rapamycin (TOR), a protein kinase that is regulated independently by insulin, amino acids and energy sufficiency and which participates in the control of the component of protein synthesis responsible for cell growth. Sirolimus 131-140 insulin Homo sapiens 200-207 15020250-2 2004 Rapamycin, an inhibitor of the kinase mTOR, can prevent serine 307 phosphorylation and the development of insulin resistance. Sirolimus 0-9 insulin Homo sapiens 106-113 14970836-9 2004 Insulin-stimulated 4E-BP1 phosphorylation in 3T3-L1 preadipocytes was only partially affected by rapamycin, consistent with the differentiation data. Sirolimus 97-106 insulin Homo sapiens 0-7 14617207-6 2003 The introduction of a steroid-free, sirolimus-based, anti-rejection protocol and islets prepared from two (or rarely three) donors led to high rates of insulin independence. Sirolimus 36-45 insulin Homo sapiens 152-159 14970836-6 2004 In contrast, rapamycin completely inhibited insulin-stimulated p70 S6K activation, assessed by phosphorylation of p70 S6K and its substrate, S6. Sirolimus 13-22 insulin Homo sapiens 44-51 12032842-8 2002 A crosstalk between P70S6K and p38-MAPK was observed under rapamycin treatment in both insulin or active AKT induced myogenesis. Sirolimus 59-68 insulin Homo sapiens 87-94 14557767-0 2003 Insulin independence after conversion to tacrolimus and sirolimus-based immunosuppression in islet-kidney recipients. Sirolimus 56-65 insulin Homo sapiens 0-7 12800089-0 2003 Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. Sirolimus 13-22 insulin Homo sapiens 47-54 12800089-4 2003 Pretreatment of L6 cells with sodium orthovanadate (Na(3)VO(4)) plus the mTOR inhibitor rapamycin caused a 5-fold increase in insulin-responsive glucose uptake at 2 hours when compared to insulin alone. Sirolimus 88-97 insulin Homo sapiens 126-133 12800089-4 2003 Pretreatment of L6 cells with sodium orthovanadate (Na(3)VO(4)) plus the mTOR inhibitor rapamycin caused a 5-fold increase in insulin-responsive glucose uptake at 2 hours when compared to insulin alone. Sirolimus 88-97 insulin Homo sapiens 188-195 12914928-4 2003 However, we recently found that the regulation of the IGFBP1 but not the PEPCK or G6Pase genes by insulin was sensitive to rapamycin, an inhibitor of mTOR. Sirolimus 123-132 insulin Homo sapiens 98-105 12800089-8 2003 Finally, treatment of L6 cells with subtherapeutic amounts of vanadyl sulfate and rapamycin induced a synergistic 3-fold increase in insulin-induced glucose uptake at 2 hours. Sirolimus 82-91 insulin Homo sapiens 133-140 12393186-3 2002 Rapamycin, which binds to FRAP/mTOR and completely suppressed the activation of p70S6 kinase by insulin, almost completely blocked the induction of the hexokinase II gene, and caused an approximately 50% inhibition of the induction of the Fra-1 gene. Sirolimus 0-9 insulin Homo sapiens 96-103 12032842-6 2002 C2Ras myoblasts failed to restore differentiation when rapamycin or PD169316 were added in the presence of insulin+PD98059, indicating that the activation of both P70S6K and p38-MAPK was necessary to reach a fully differentiated phenotype. Sirolimus 55-64 insulin Homo sapiens 107-114 11784721-5 2002 Importantly, we demonstrate that insulin regulation of the thymine-rich insulin response element of the IGFBP-1 promoter was also inhibited by rapamycin. Sirolimus 143-152 insulin Homo sapiens 33-40 12051762-0 2002 Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Sirolimus 0-9 insulin Homo sapiens 29-36 12051762-0 2002 Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Sirolimus 0-9 insulin Homo sapiens 67-74 12051762-2 2002 In this study, to investigate whether rapamycin (an mTOR inhibitor) could prevent insulin resistance induced by hyperinsulinemia, 3T3-L1 adipocytes were incubated chronically in the presence of insulin with or without the addition of rapamycin. Sirolimus 38-47 insulin Homo sapiens 82-89 12051762-2 2002 In this study, to investigate whether rapamycin (an mTOR inhibitor) could prevent insulin resistance induced by hyperinsulinemia, 3T3-L1 adipocytes were incubated chronically in the presence of insulin with or without the addition of rapamycin. Sirolimus 38-47 insulin Homo sapiens 117-124 12051762-5 2002 Rapamycin prevented the reduction of IRS-1 protein levels and insulin-induced PKB Ser-473 phosphorylation with a partial normalization of insulin-induced glucose transport. Sirolimus 0-9 insulin Homo sapiens 62-69 11784721-5 2002 Importantly, we demonstrate that insulin regulation of the thymine-rich insulin response element of the IGFBP-1 promoter was also inhibited by rapamycin. Sirolimus 143-152 insulin Homo sapiens 72-79 11695998-10 2001 In cultured human myotubes, up-regulation of p85alpha, p55alpha and p50alpha mRNAs by insulin was abolished by LY294002 (10 microM) and by rapamycin (50 nM), suggesting that the PI 3-kinase/protein kinase B/p70 S6 kinase pathway could be involved in the stimulation of grb-1 gene expression by insulin in human muscle cells. Sirolimus 139-148 insulin Homo sapiens 86-93 11948686-2 2002 Inhibition of mTOR with rapamycin resulted in approximately 50% inhibition of the insulin-induced degradation of IRS-1. Sirolimus 24-33 insulin Homo sapiens 82-89 11695998-10 2001 In cultured human myotubes, up-regulation of p85alpha, p55alpha and p50alpha mRNAs by insulin was abolished by LY294002 (10 microM) and by rapamycin (50 nM), suggesting that the PI 3-kinase/protein kinase B/p70 S6 kinase pathway could be involved in the stimulation of grb-1 gene expression by insulin in human muscle cells. Sirolimus 139-148 insulin Homo sapiens 294-301 10464317-4 1999 Insulin-augmented (125)I-alpha(2)M* binding to macrophages was severely reduced by wortmannin, LY294002, PD98059, SB203580, or rapamycin. Sirolimus 127-136 insulin Homo sapiens 0-7 11574405-11 2001 Glucose- and insulin-stimulated translocation of PDX-1 to the nucleoplasm was inhibited by wortmannin and SB 203580, indicating that a pathway involving PI 3-kinase and SAPK2/p38 was involved; translocation was unaffected by PD 098959 and rapamycin, suggesting that neither mitogen-activated protein kinase nor p70(s6k) were involved. Sirolimus 239-248 insulin Homo sapiens 13-20 11500364-2 2001 Insulin induces dephosphorylation of eEF2 and inactivation of eEF2 kinase, and these effects are blocked by rapamycin, which inhibits the mammalian target of rapamycin, mTOR. Sirolimus 108-117 insulin Homo sapiens 0-7 11438661-1 2001 A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). Sirolimus 23-32 insulin Homo sapiens 123-130 11438661-3 2001 After prolonged insulin stimulation, inhibition of the redistribution of IRS-1 by rapamycin resulted in increased levels of IRS-1 and the associated phosphatidylinositol (PI) 3-kinase in both the LDM and cytosol, whereas the proteasome inhibitor lactacystin increased the levels only in the cytosol. Sirolimus 82-91 insulin Homo sapiens 16-23 11438661-4 2001 Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associated PI 3-kinase localized at the LDM was suggested to be important in the regulation of glucose transport. Sirolimus 6-15 insulin Homo sapiens 45-52 11013237-3 2001 Insulin further stimulates glycogen synthesis in the presence of lithium ions, an effect abolished by wortmannin and rapamycin. Sirolimus 117-126 insulin Homo sapiens 0-7 11147790-4 2001 Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. Sirolimus 15-24 insulin Homo sapiens 78-85 11042022-3 2000 Insulin rescued serum-deprived immortalized brown adipocytes from apoptosis through phosphatidylinositol (PI) 3-kinase and Akt pathways, but independently of p70S6-kinase, as demonstrated by the use of inhibitors such as LY294002 or Rapamycin, and transfection experiments with dominant-negative constructs of Akt or p85 subunit of PI 3-kinase. Sirolimus 233-242 insulin Homo sapiens 0-7 10567366-8 1999 On the other hand, the insulin effect was totally abolished by LY294002 (10 microM) and rapamycin (50 nM). Sirolimus 88-97 insulin Homo sapiens 23-30 10551878-9 1999 Rapamycin abrogated the insulin-mediated increase in GLUT1 protein synthesis through partial inhibition of GLUT1 mRNA translation and partial inhibition of the rise in GLUT1 mRNA. Sirolimus 0-9 insulin Homo sapiens 24-31 11231341-7 2001 Rapamycin abrogated 4E-BP1 phosphorylation in response to insulin, suggesting involvement of mammalian target of rapamycin (mTOR), a kinase downstream of Akt. Sirolimus 0-9 insulin Homo sapiens 58-65 11272147-1 2001 Recent findings have demonstrated that the branched-chain amino acid leucine can activate the translational regulators, phosphorylated heat- and acid-stable protein regulated by insulin (PHAS-I) and p70 S6 kinase (p70S6k), in an insulin-independent and rapamycin-sensitive manner through mammalian target of rapamycin (mTOR), although the mechanism for this activation is undefined. Sirolimus 253-262 insulin Homo sapiens 178-185 11272147-1 2001 Recent findings have demonstrated that the branched-chain amino acid leucine can activate the translational regulators, phosphorylated heat- and acid-stable protein regulated by insulin (PHAS-I) and p70 S6 kinase (p70S6k), in an insulin-independent and rapamycin-sensitive manner through mammalian target of rapamycin (mTOR), although the mechanism for this activation is undefined. Sirolimus 253-262 insulin Homo sapiens 229-236 10516161-7 1999 Rapamycin inhibited 4E-BP phosphorylation in response to insulin but had no effect on eIF-4F complex formation. Sirolimus 0-9 insulin Homo sapiens 57-64 10446394-7 1999 This was further supported by the observation that troglitazone was able to reduce PEPCK mRNA levels in the presence of the insulin signaling pathway inhibitors wortmannin, rapamycin, and PD98059. Sirolimus 173-182 insulin Homo sapiens 124-131 10100627-1 1999 The signalling pathways by which insulin triggers protein synthesis were studied using an antisense strategy to deplete ERK1/ERK2 and rapamycin to inhibit the p70S6K pathway. Sirolimus 134-143 insulin Homo sapiens 33-40 9755080-10 1998 We have previously shown that GLUT-1 protein synthesis in these cells is stimulated by insulin via the mTOR-p70 S6 kinase pathway, based on its sensitivity to rapamycin. Sirolimus 159-168 insulin Homo sapiens 87-94 9852118-1 1998 Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. Sirolimus 122-131 insulin Homo sapiens 161-168 9636226-4 1998 Insulin also increased by severalfold the 32P content of mTOR that was determined after purifying the protein from 32P-labeled adipocytes with rapamycin.FKBP12 agarose beads. Sirolimus 143-152 insulin Homo sapiens 0-7 9879060-2 1998 To study postreceptor signaling events leading to insulin-stimulated glycogen synthesis in these cells, we have employed pathway-specific chemical inhibitors such as LY294002, rapamycin and PD98059 to inhibit phosphatidylinositol-3-kinase (PI3K), p70 ribosomal S6 kinase and mitogen-activated protein kinase (MAPK) kinase/MAPK, respectively. Sirolimus 176-185 insulin Homo sapiens 50-57 9632736-7 1998 Upon addition of rapamycin or wortmannin to insulin-treated cells, the decrease in activity of p70 was closely correlated with the disappearance of anti-Thr-412(P) immunoreactivity and the most slowly migrating p70 polypeptides, whereas considerable phosphorylation at Ser-434 and Thr-252 persisted after the disappearance of 40 S kinase activity. Sirolimus 17-26 insulin Homo sapiens 44-51 9497382-4 1998 Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Sirolimus 144-153 insulin Homo sapiens 0-7 9371685-8 1997 Translation of another class of mRNAs, those with 5"-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Sirolimus 189-198 insulin Homo sapiens 112-119 9480896-7 1998 Rapamycin, an inhibitor of p70 S6 kinase action, strongly inhibited the potentiating effects of ethanol on insulin- and PCho-induced mitogenesis. Sirolimus 0-9 insulin Homo sapiens 107-114 9458731-6 1998 Both rapamycin and wortmannin completely blocked the insulin-induced changes in 4E-BP1 phosphorylation and association of 4E-BP1 and eIF-4E; PD-98059 had no effect on either parameter. Sirolimus 5-14 insulin Homo sapiens 53-60 9498625-6 1998 The stimulation by insulin of ERK-2 was blocked by a mitogen-activated protein (MEK) inhibitor (PD 98059) and of p70rsk by rapamycin. Sirolimus 123-132 insulin Homo sapiens 19-26 9248697-7 1997 Incubating 3T3-L1 adipocytes with rapamycin and wortmannin inhibited insulin-stimulated phosphorylation of PHAS-I at concentrations similar to those that inhibited activation of p70S6K. Sirolimus 34-43 insulin Homo sapiens 69-76 9334222-1 1997 The proteins eIF-4E BP1 and p70 S6 kinase each undergo an insulin/mitogen-stimulated phosphorylation in situ that is partially inhibited by rapamycin. Sirolimus 140-149 insulin Homo sapiens 58-65 8663315-5 1996 Treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), or with rapamycin, an inhibitor of the pathway from the insulin receptor to p70/p85 ribosomal S6 protein kinase (p70(s6k)), prevented the induction of HKII mRNA by insulin. Sirolimus 96-105 insulin Homo sapiens 144-151 9109420-0 1997 Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. Sirolimus 107-116 insulin Homo sapiens 0-7 9109420-3 1997 Thus rapamycin-insensitive pathways mediate the acute effect of insulin on glycogen synthase in the major insulin-responsive tissues. Sirolimus 5-14 insulin Homo sapiens 64-71 9109420-3 1997 Thus rapamycin-insensitive pathways mediate the acute effect of insulin on glycogen synthase in the major insulin-responsive tissues. Sirolimus 5-14 insulin Homo sapiens 106-113 9006957-8 1997 Expression of a dominant negative mutant of the p85 subunit of PI 3"-kinase or treatments with the PI 3"-kinase inhibitor wortmannin only partially (approximately 40-50%) reduced the combined effects of ChoP, ATP, and insulin on DNA synthesis; in contrast, the pp70 S6 kinase inhibitor rapamycin almost completely inhibited these effects. Sirolimus 286-295 insulin Homo sapiens 218-225 8939971-3 1996 The effects of insulin were attenuated by rapamycin and wortmannin, two agents that block activation of p70(S6K). Sirolimus 42-51 insulin Homo sapiens 15-22 8663315-5 1996 Treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), or with rapamycin, an inhibitor of the pathway from the insulin receptor to p70/p85 ribosomal S6 protein kinase (p70(s6k)), prevented the induction of HKII mRNA by insulin. Sirolimus 96-105 insulin Homo sapiens 252-259 8663315-7 1996 In addition, rapamycin blocked the insulin-induced expression of an HKII promoter-chloramphenicol acetyltransferase fusion gene transiently transfected into L6 myotubes, whereas PD98059 had no such effect. Sirolimus 13-22 insulin Homo sapiens 35-42 7679106-2 1993 Rapamycin completely blocked activation of pp70-S6 kinase by insulin in 3T3-L1 adipocytes, but did not inhibit insulin-stimulated glucose transport, translocation of GLUT4 to the cell surface, or activation of pp90rsk or pp44mapk by insulin. Sirolimus 0-9 insulin Homo sapiens 61-68 7629182-7 1995 Moreover, rapamycin attenuated the stimulation of PHAS-I phosphorylation by insulin and markedly inhibited dissociation of PHAS-I.eIF-4E, without decreasing MAP kinase activity. Sirolimus 10-19 insulin Homo sapiens 76-83 7629182-8 1995 Rapamycin abolished the effects of insulin on increasing phosphorylation of ribosomal protein S6 and on activating p70S6K. Sirolimus 0-9 insulin Homo sapiens 35-42 7797543-9 1995 The immunosuppressant rapamycin, a potent inhibitor of insulin or phorbol ester stimulation of p70/p85 ribosomal S6 protein kinase, has no significant effect on the regulation of PEPCK gene expression by insulin or phorbol esters. Sirolimus 22-31 insulin Homo sapiens 55-62 8633019-6 1996 The insulin effect on 4E-BP1 phosphorylation and p70s6k activation in both cell types is blocked by SQ20006, wortmannin, and rapamycin. Sirolimus 125-134 insulin Homo sapiens 4-11 7826337-6 1995 Rapamycin inhibited insulin-stimulated glucose incorporation into glycogen to a similar extent and with similar dose-dependency, while having no effect on insulin-stimulated glucose transport. Sirolimus 0-9 insulin Homo sapiens 20-27 7679106-5 1993 These data demonstrate that rapamycin blocks insulin activation of pp70-S6 kinase in 3T3-L1 adipocytes and that pp70-S6 kinase is not required in the signaling pathway leading to insulin-stimulated glucose transport. Sirolimus 28-37 insulin Homo sapiens 45-52 33497611-3 2021 They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Sirolimus 191-200 insulin Homo sapiens 239-246 34122092-16 2021 However, rapamycin could cooperate with KD to enhance autophagic activation to increase insulin sensitivity in LO2 cells. Sirolimus 9-18 insulin Homo sapiens 88-95 33482580-0 2021 Methionine controls insulin/mammalian target of rapamycin complex 1 activity by modulating tuberous sclerosis complex 2 stability. Sirolimus 48-57 insulin Homo sapiens 20-27 35048556-5 2022 In the presence of rapamycin, the split sec-TEVp-based RAPID components dimerize, regain their proteolytic activity, and remove the KDEL retention signal from insulin. Sirolimus 19-28 insulin Homo sapiens 159-166 35014047-4 2022 The stimulatory effects of insulin upon cell proliferation and 3 H-DG uptake were hampered by rapamycin, LY294001 and BAY-876, in both cell lines. Sirolimus 94-103 insulin Homo sapiens 27-34 33977204-1 2021 The mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. Sirolimus 24-33 insulin Homo sapiens 192-199 33382998-5 2021 While insulin-activated IRS/PI3K/PKB pathway cascades are primarily known to reduce glucose production, it was recently discovered to increase the Hh signaling pathway"s stability, thereby activating the PI3K/PKB/mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. Sirolimus 233-242 insulin Homo sapiens 6-13 33124663-9 2021 Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile. Sirolimus 0-9 insulin Homo sapiens 54-61 33124663-10 2021 CONCLUSIONS: Rapamycin reduced insulin requirement, but did not restore beta-cell function in patients with long-standing type 1 diabetes. Sirolimus 13-22 insulin Homo sapiens 31-38 32755490-5 2021 However, it has been hypothesised that mammalian target of rapamycin complex 1 (mTORC1) hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake due to insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. Sirolimus 59-68 insulin Homo sapiens 166-173 32865663-4 2020 Mechanistic (formerly mammalian) target of rapamycin (mTOR), sirtuin (SIRT) and insulin/insulin growth factor 1 (IGF1) signalling pathways are among the most important pathways in ageing-associated conditions, such as neurodegeneration. Sirolimus 43-52 insulin Homo sapiens 80-87 32879008-1 2020 Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Sirolimus 123-132 insulin Homo sapiens 17-24 32759469-1 2020 While the growth factors like insulin initiate a signaling cascade to induce conformational changes in the mechanistic target of rapamycin complex 1 (mTORC1), amino acids cause the complex to localize to the site of activation, the lysosome. Sirolimus 129-138 insulin Homo sapiens 30-37 33522203-0 2021 Effect of Shenzhu Tiaopi granule on hepatic insulin resistance in diabetic Goto-Kakizakirats via liver kinase B1/adenosine 5"-monophosphate/mammalian target of rapamycin signaling pathway. Sirolimus 160-169 insulin Homo sapiens 44-51 32779245-2 2020 Several data support the involvement of the mammalian target of rapamycin complex 1 (mTORC1) signaling in the interplay between androgens, insulin, insulin-like growth factor (IGF1), and high glycemic index diet in acne. Sirolimus 64-73 insulin Homo sapiens 139-174