The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

Cammalleri, Catarina; Germinario, Ralph J.

doi:10.1194/jlr.m200245-jlr200

Cited by 16 publications

(16 citation statements)

References 29 publications

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“…Mechanisms for the PI-induced effects may differ between short-and long-term exposure. Thus short-term exposure appears to predominantly affect the glucose-transport system (Murata et al 2000, 2002, Ben-Romano et al 2003 whereas effects on insulin signaling at the level of IRS-1 (Schütt et al 2000, Cammalleri & Germinario 2003, PI3-kinase (Schütt et al 2000) and/or Akt (Schütt et al 2000, Rudich et al 2001, Ben-Romano et al 2003 are observed only after a longer exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Studies with various cell lines, including 3T3-L1 adipocytes and L6-myotubes, and in rats suggest, however, that PIs acutely inhibit the cellular glucose-transport system (Murata et al 2000, 2002, Ben-Romano et al 2003. In addition, there is evidence that, after longer incubation periods, PIs also affect insulin signaling at the level of insulin-receptor substrate (IRS)-1 phosphorylation (Schütt et al 2000, Cammalleri & Germinario 2003, association of the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase; Schütt et al 2000) and/or Thr 308 / Ser 473 -Akt phosphorylation (Schütt et al 2000, Rudich et al 2001, Ben-Romano et al 2003 in HepG2 hepatoma cells (Schütt et al 2000) or 3T3-L1 cells (Rudich et al 2001, Ben-Romano et al 2003 respectively. A potential role of impaired insulin signaling in the insulinresistance syndrome caused by PIs is also supported by a recent study on a novel activator of the insulin receptor tyrosine kinase, that was able to reverse PI-induced insulin resistance in 3T3-L1 cells and to prevent PI-induced insulin resistance in rats (Cheng et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells

Schütt¹,

Zhou²,

Meier³

et al. 2004

Journal of Endocrinology

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The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM -glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2·5, 5 and 5 µM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 µM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulinstimulated IRS-1 and Thr 308 -Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells

Schütt¹,

Zhou²,

Meier³

et al. 2004

Journal of Endocrinology

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“…Isolated adipocytes were incubated in KRH buffer for 1 h. After washing, adipocytes (2×10 5 cells/vial) in KRH buffer were incubated with DHH105 and/or insulin in the presence of 125 I-insulin (0.1 ng/ml; Perkin-Elmer Life and Analytical Sciences, Downers Grove, IL, USA) [20] for 2 h at 16°C in a shaking bath. Non-specific binding was measured in the presence of unlabelled insulin (50 μg, Sigma) and 125 I-insulin.…”

Section: Insulin Binding Competition Assaymentioning

confidence: 99%

Naphthalenemethyl ester derivative of dihydroxyhydrocinnamic acid, a component of cinnamon, increases glucose disposal by enhancing translocation of glucose transporter 4

et al. 2006

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Aims/hypothesis Cinnamon extracts have anti-diabetic effects. Phenolic acids, including hydrocinnamic acids, were identified as major components of cinnamon extracts. Against this background we sought to develop a new antidiabetic compound using derivatives of hydroxycinnamic acids purified from cinnamon. Methods We purified hydroxycinnamic acids from cinnamon, synthesised a series of derivatives, and screened them for glucose transport activity in vitro. We then selected the compound with the highest glucose transport activity in epididymal adipocytes isolated from male Sprague-Dawley rats in vitro, tested it for glucose-lowering activity in vivo, and studied the mechanisms involved. Results A naphthalenemethyl ester of 3,4-dihydroxyhydrocinnamic acid (DHH105) showed the highest glucose transport activity in vitro. Treatment of streptozotocininduced diabetic C57BL/6 mice and spontaneously diabetic ob/ob mice with DHH105 decreased blood glucose levels to near normoglycaemia. Further studies revealed that DHH105 increased the maximum speed of glucose transport and the translocation of glucose transporter 4 (GLUT4, now known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) in adipocytes, resulting in increased glucose uptake. In addition, DHH105 enhanced phosphorylation of the insulin receptor-β subunit and insulin receptor substrate-1 in adipocytes, both in vitro and in vivo. This resulted in the activation of phosphatidylinositol 3-kinase and Akt/protein kinase B, contributing to the translocation of GLUT4 to the plasma membrane. Conclusions/interpretation We conclude that DHH105 lowers blood glucose levels through the enhancement of glucose transport, mediated by an increase in insulinreceptor signalling. DHH105 may be a valuable candidate for a new anti-diabetic drug.

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“…ASP stimulation of TGS is unaltered by PTX treatment (181.9 6 14.6% for ASP alone vs. 216.3 6 10.7% for ASP 1 PTX, where basal is set at 100%; P 5 NS). Insulin also stimulates TGS in 3T3-L1 preadipocytes (27) through the insulin receptor, which belongs to the family of tyrosine kinase receptors. As expected, PTX had no inhibitory effect on the TGS stimulatory action of insulin (302.1 6 2.1% for insulin alone vs. 346.1 6 10.6% for insulin 1 PTX; P 5 NS).…”

Section: Immediate Postreceptor Events: Involvement Of G-proteinsmentioning

confidence: 99%

Targeting the signaling pathway of acylation stimulating protein

Maslowska

Legakis

Assadi

et al. 2006

Journal of Lipid Research

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Acylation stimulating protein (ASP; C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes/adipocytes through C5L2, a G-proteincoupled receptor. Here, ASP signaling is compared with insulin in 3T3-L1 cells. ASP stimulation is not Ga s or Ga i mediated (pertussis and cholera toxin insensitive), suggesting G aq as a candidate. Phospholipase C (PLC) is required, because the Ca 21 chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N9,N9-tetraacetic acid tetra(acetoxymethyl) ester and the PLC inhibitor U73122 decreased ASP stimulation of TGS by 93.1% (P , 0.0.001) and 86.1% (P , 0.004), respectively. Wortmannin and LY294002 blocked ASP effect by 69% (P , 0.001) and 116.1% (P , 0.003), respectively, supporting phosphatidylinositol 3-kinase (PI3K) involvement. ASP induced rapid, transient Akt phosphorylation (maximal, 5 min; basal, 45 min), which was blocked by Akt inhibition, resembling treatment by insulin. Downstream of PI3K, mamalian target of rapaycin (mTOR) is required for insulin but not ASP action. By contrast, both ASP and insulin activate the mitogen-activated protein kinase/extracellular signalregulated kinase (MAPK/ERK 1/2 ) pathway, with rapid, pronounced increases in ERK 1/2 phosphorylation, effects partially blocked by PD98059 (64.7% and 65.9% inhibition, respectively; P , 0.001). Time-dependent (maximal, 30 min) transient calcium-dependent phospholipase A 2 (cPLA 2 ) -Ser505

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The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

Cited by 16 publications

References 29 publications

Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells

Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells

Naphthalenemethyl ester derivative of dihydroxyhydrocinnamic acid, a component of cinnamon, increases glucose disposal by enhancing translocation of glucose transporter 4

Targeting the signaling pathway of acylation stimulating protein

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