Regulation of glycogen synthase activation in isolated hepatocytes

Pugazhenthi, Subbiah; Khandelwal, Ramji L.

doi:10.1007/bf01076568

Cited by 33 publications

(11 citation statements)

References 64 publications

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“…of GSK-3 and subsequent activation of glycogen synthase a in isolated hepatocytes (Pugazhenthi & Khandelwal 1995). In the present study, by using Ro 31-8220, a staurosporine derivative and potent bisindolylmaleimide inhibitor of several PKC isoforms -mainly , 1 , 11 , and´ (Wilkinson et al 1993), a moderate, although significant, inhibition of the GLP-1-induced increase in glycogen-synthase a activity was detected, as previously observed in rat hepatocytes (Redondo et al 2003).…”

Section: Figuresupporting

confidence: 84%

Cell signalling of glucagon-like peptide-1 action in rat skeletal muscle

Acitores

González²,

Sancho³

et al. 2004

Journal of Endocrinology

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Glucagon-like peptide-1 (GLP-1), an incretin with glucose-dependent insulinotropic and insulinindependent antidiabetic properties, has insulin-like effects on glucose metabolism in extrapancreatic tissues participating in overall glucose homeostasis. These effects are exerted through specific receptors not associated with cAMP, an inositol phosphoglycan being a possible second messenger. In rat hepatocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB), protein kinase C (PKC) and protein phosphatase 1 (PP-1) has been shown to be involved in the GLP-1-induced stimulation of glycogen synthase. We have investigated the role of enzymes known or suggested to mediate the actions of insulin in the GLP-1-induced increase in glycogen synthase a activity in rat skeletal muscle strips.We first explored the effect of GLP-1, compared with that of insulin, on the activation of PI3K, PKB, p70s6 kinase (p70s6k) and p44/42 mitogen-activated protein kinases (MAPKs) and the action of specific inhibitors of these kinases on the insulin-and GLP-1-induced increment in glycogen synthase a activity.The study showed that GLP-1, like insulin, activated PI3K/PKB, p70s6k and p44/42. Wortmannin (a PI3K inhibitor) reduced the stimulatory action of insulin on glycogen synthase a activity and blocked that of GLP-1, rapamycin (a 70s6k inhibitor) did not affect the action of GLP-1 but abolished that of insulin, PD98059 (MAPK inhibitor) was ineffective on insulin but blocked the action of GLP-1, okadaic acid (a PP-2A inhibitor) and tumour necrosis factor-(a PP-1 inhibitor) were both ineffective on GLP-1 but abolished the action of insulin, and Ro 31-8220 (an inhibitor of some PKC isoforms) reduced the effect of GLP-1 while completely preventing that of insulin.It was concluded that activation of PI3K/PKB and MAPKs is required for the GLP-1-induced increment in glycogen synthase a activity, while PKC, although apparently participating, does not seem to play an essential role; unlike in insulin signaling, p70s6k, PP-1 and PP-2A do not seem to be needed in the action of GLP-1 upon glycogen synthase a activity in rat muscle.

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Section: Figuresupporting

confidence: 84%

Cell signalling of glucagon-like peptide-1 action in rat skeletal muscle

Acitores

González²,

Sancho³

et al. 2004

Journal of Endocrinology

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“…The serine/threonine protein kinase GSK-3 inhibits GS by phosphorylation (3) and is considered to be a major regulator of GS in several cell types including liver cells (1). We investigated the effect of insulin and bpV(phen) on GSK-3 activity and found that both agents were comparably inhibitory (Fig.…”

Section: Insulin and Bpv(phen) Modulation Of Pkb/akt And Gsk-3 Activimentioning

confidence: 99%

“…Whereas there have been numerous studies of GS activation in skeletal muscle, the modulators of GS in liver have been less completely evaluated. Studies to date indicate that glucose and insulin are the major physiologic effectors of hepatic GS activation (1,2). It appears that glucose and/or its metabolite glucose 6-phosphate activate hepatic GS by physically associating with critical regulatory enzymes upstream of GS or with GS itself (2,4,5), although other mechanisms have been suggested (6).…”

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confidence: 99%

Regulation of Glycogen Synthase in Rat Hepatocytes

Lavoie

Band

Kong

et al. 1999

Journal of Biological Chemistry

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We examined the signaling pathways regulating glycogen synthase (GS) in primary cultures of rat hepatocytes. The activation of GS by insulin and glucose was completely reversed by the phosphatidylinositol 3-kinase inhibitor wortmannin. Wortmannin also inhibited insulin-induced phosphorylation and activation of protein kinase B/Akt (PKB/Akt) as well as insulin-induced inactivation of GS kinase-3 (GSK-3), consistent with a role for the phosphatidylinositol 3-kinase/PKB-Akt/ GSK-3 axis in insulin-induced GS activation. Although wortmannin completely inhibited the significantly greater level of GS activation produced by the insulinmimetic bisperoxovanadium 1,10-phenanthroline (bpV-(phen)), there was only minimal accompanying inhibition of bpV(phen)-induced phosphorylation and activation of PKB/Akt, and inactivation of GSK-3. Thus, PKB/Akt activation and GSK-3 inactivation may be necessary but are not sufficient to induce GS activation in rat hepatocytes. Rapamycin partially inhibited the GS activation induced by bpV(phen) but not that effected by insulin. Both insulin-and bpV(phen)-induced activation of the atypical protein kinase C (/) (PKC (/)) was reversed by wortmannin. Inhibition of PKC (/) with a pseudosubstrate peptide had no effect on GS activation by insulin, but substantially reversed GS activation by bpV(phen). The combination of this inhibitor with rapamycin produced an additive inhibitory effect on bpV-(phen)-mediated GS activation. Taken together, our results indicate that the signaling components mammalian target of rapamycin and PKC (/) as well as other yet to be defined effector(s) contribute to the modulation of GS in rat hepatocytes.Much current work has focused on defining the nature of the downstream effectors mediating key effects of insulin. The regulation of glycogen synthase (GS), 1 the rate-limiting enzyme in glycogen synthesis, by insulin has received increasing attention. GS is regulated by a complex interplay of diurnal, nutritional, and hormonal factors (reviewed in Refs. 1-3) that ultimately modulate the phosphorylation state and hence the activity of the enzyme. Whereas there have been numerous studies of GS activation in skeletal muscle, the modulators of GS in liver have been less completely evaluated. Studies to date indicate that glucose and insulin are the major physiologic effectors of hepatic GS activation (1, 2). It appears that glucose and/or its metabolite glucose 6-phosphate activate hepatic GS by physically associating with critical regulatory enzymes upstream of GS or with GS itself (2, 4, 5), although other mechanisms have been suggested (6). The mechanisms by which insulin effects activation of GS and stimulation of glycogen synthesis in liver are poorly defined, although data have been obtained indicating that modulation of PP1-G (1, 7) as well as PKB/Akt (8) and GSK-3 (9) may be involved. Insulin activation of the insulin receptor kinase (IRK) is followed by tyrosine phosphorylation of insulin receptor substrates (IRSs), the two major ones in liver being IRS-1 and -2 ...

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“…This regulation of GSK-3β is influenced by cell stressors such as hypoxia, oxidative stress, heat shock, but also by factors such as changes in glucose concentration and high GDP content. Although these physicochemical properties are important non-physiological characteristics of various PDF (Pugazhenthi and Khandelwal 1995;Cuzzocrea et al 2007), a direct association between GSK-3β and PD has not yet been described.…”

Section: Introductionmentioning

confidence: 99%