Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways

Rui, Liangyou; Aguirre, Vincent; Kim, Jason K.; Shulman, Gerald I.; Lee, Anna; Corbould, A.; Dunaif, Andrea; White, Morris F.

doi:10.1172/jci10934

Cited by 535 publications

(470 citation statements)

References 34 publications

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“…The finding that IL-1β stimulated the phosphorylation of ERK but not Akt would also be consistent with this, since IL-1 is known to be a potent inhibitor of proteoglycan synthesis [28,29]. The mechanism by which ERK activity might inhibit IGF-I-stimulated proteoglycan synthesis is not clear but could involve a negative feedback loop through ERK-mediated serine phosphorylation of IRS-1, which has been shown to inhibit insulin signalling [30,31]. Further studies will be necessary to determine whether this mechanism contributes to inhibition of IGF-I signalling in chondrocytes.…”

Section: Discussionsupporting

confidence: 59%

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

Starkman

Cravero

DelCarlo

et al. 2005

Biochemical Journal

155

161

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The IGF-I (insulin-like growth factor-I) signalling pathway responsible for regulation of proteoglycan synthesis in chondrocytes has not been defined and is the focus of the present study. Chondrocytes isolated from normal human articular cartilage were stimulated with IGF-I in monolayer culture or in suspension in alginate. IGF-I activated members of both the PI3K (phosphoinositide 3-kinase) pathway and the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway. The PI3K inhibitors LY294002 and wortmannin blocked IGF-I-stimulated Akt phosphorylation without blocking ERK phosphorylation and this was associated with complete inhibition of proteoglycan synthesis. A decrease in IGF-I-stimulated proteoglycan synthesis was also observed upon inhibition of mTOR (mammalian target of rapamycin) and p70S6 kinase, both of which are downstream of Akt. The MEK (MAPK/ERK kinase) inhibitors PD98059 and U0126 blocked IGF-I-stimulated ERK phosphorylation but did not block the phosphorylation of Akt and did not decrease proteoglycan synthesis. Instead, in alginate- cultured chondrocytes, the MEK inhibitors increased IGF-I-stimulated proteoglycan synthesis when compared with cells treated with IGF-I alone. This is the first study to demonstrate that IGF-I stimulation of the PI3K signalling pathway is responsible for the ability of IGF-I to increase proteoglycan synthesis. Although IGF-I also activates the ERK/MAPK pathway, ERK activity is not required for proteoglycan synthesis and may serve as a negative regulator

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Section: Discussionsupporting

confidence: 59%

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

Starkman

Cravero

DelCarlo

et al. 2005

Biochemical Journal

155

161

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“…6 Furthermore, PTH is a widely recognized anabolic hormone for bone and is reported to function, in part, through enhanced IGF-I activity, 7 and IRS proteins. 8 The second of these three molecules to be examined is endothelial nitric oxide synthase (eNOS/NOS III), which is thought to be the most highly expressed NO synthase in osteoblasts. 9 This choice is based on observations that mice deficient in eNOS expression exhibit juvenile osteopenia and skeletal dysplasias.…”

Section: Introductionmentioning

confidence: 99%

Pulsed electromagnetic fields rapidly modulate intracellular signaling events in osteoblastic cells: Comparison to parathyroid hormone and insulin

Schnoke

Midura

2007

Journal Orthopaedic Research

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Pulsed electromagnetic field (PEMF) devices are approved for the healing of bone nonunions, but there is a lack of understanding as to their mechanism of action at the cell and molecular level. Intermittent parathyroid hormone (PTH) therapy is currently utilized for treatment of osteoporosis, and is also being investigated for the purpose of augmenting fracture healing. Insulin and IGF-1 are also thought to play important anabolic roles in osteogenesis. In this report, signaling pathways activated by acute PTH or insulin treatments were compared to those activated by PEMF treatment in osteoblast-like cells. Some signaling molecules like the extracellular response kinases 1/2 (Erk1/2) and the cAMP response element binding protein (CREB) were activated by insulin and PTH, respectively, but not by PEMF treatment. Other signaling molecules like the insulin receptor substrate-1 (IRS-1), the S6 ribosomal subunit kinase, and the endothelial nitric oxide synthase (eNOS) were phosphorylated by PTH, insulin, and PEMF to the same relative extent and within the same time frame. IRS-1, eNOS, and S6 have been implicated in bone anabolism, and our results suggest that the anabolic effects of PEMF may be mediated, in part, through the activation of these proteins. ß

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“…Circulating TNF-␣ may exert a direct effect on insulin-stimulated glucose uptake in skeletal muscle by promoting serine phosphorylation of the insulin receptor substrate-1 (IRS-1) (18,30), and in pregnancy, serine phosphorylation is increased in skeletal muscle late in gestation (34). Additionally, TNF-␣ is a chronic regulator of lipolytic tone in adipose tissue (23).…”

Section: Discussionmentioning

confidence: 99%

“…A variable infusion of 25% dextrose was adjusted periodically to clamp the plasma glucose concentration in all groups at basal level (ϳ5.7 mmol/l) for nonpregnant females. Blood was sampled through the venous catheter at times 0, 30,60,70,80,90,95,100,105,110,115, and 120 during the 120 min of the study.…”

Section: Methodsmentioning

confidence: 99%

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

Einstein

Fishman

Muzumdar

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Insulin resistance (IR) is a hallmark of pregnancy. Because increased visceral fat (VF) is associated with IR in nonpregnant states, we reasoned that fat accretion might be important in the development of IR during pregnancy. To determine whether VF depots increase in pregnancy and whether VF contributes to IR, we studied three groups of 6-mo-old female Sprague-Dawley rats: 1) nonpregnant sham-operated rats (Nonpreg; n = 6), 2) pregnant sham-operated rats (Preg; n = 6), and 3) pregnant rats in which VF was surgically removed 1 mo before mating (PVF−; n = 6). VF doubled by day 19 of pregnancy (Nonpreg 5.1 ± 0.3, Preg 10.0 ± 1.0 g, P < 0.01), and PVF− had similar amounts of VF compared with Nonpreg (PVF− 4.6 ± 0.8 g). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp in late gestation in chronically catheterized unstressed rats. Glucose IR (mg·kg−1·min−1) was highest in Nonpreg (19.4 ± 2.0), lowest in Preg (11.1 ± 1.4), and intermediate in PVF− (14.7 ± 0.6; P < 0.001 between all groups). During the clamp, Nonpreg had greater hepatic insulin sensitivity than Preg [hepatic glucose production (HGP): Nonpreg 4.5 ± 1.3, Preg 9.3 ± 0.5 mg·kg−1·min−1; P < 0.001]. With decreased VF, hepatic insulin sensitivity was similar to nonpregnant levels in PVF− (HGP 4.9 ± 0.8 mg·kg−1·min−1). Both pregnant groups had lower peripheral glucose uptake compared with Nonpreg. In parallel with hepatic insulin sensitivity, hepatic triglyceride content was increased in pregnancy (Nonpreg 1.9 ± 0.4 vs. Preg 3.2 ± 0.3 mg/g) and decreased with removal of VF (PVF− 1.3 ± 0.4 mg/g; P < 0.05). Accretion of visceral fat is an important component in the development of hepatic IR in pregnancy, and accumulation of hepatic triglycerides is a mechanism by which visceral fat may modulate insulin action in pregnancy.

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Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways

Cited by 535 publications

References 34 publications

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK

Pulsed electromagnetic fields rapidly modulate intracellular signaling events in osteoblastic cells: Comparison to parathyroid hormone and insulin

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

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