Search for directed genic interactions:  

INS PRKAG2 (1 - 17 of 17)
PMID: 10866040
5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase.
... insulin does not activate AMPK in ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 10866040

5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase.
Source

Diabetes (June 2000)

Abstract

5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or beta-actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes.

PMID: 12196462
Isoform-specific regulation of 5' AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction.
Isoform-specific AMPK activity ... in response to insulin, ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 12196462

Isoform-specific regulation of 5' AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction.
Source

Diabetes (September 2002)

Abstract

Isoform-specific regulation of 5' AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction. Glucose transport can be activated in skeletal muscle in response to insulin via activation of phosphoinositide (PI) 3-kinase and in response to contractions or hypoxia, presumably via activation of 5' AMP-activated protein kinase (AMPK). We determined the effects of insulin and muscle contraction/hypoxia on PI 3-kinase, AMPK, and glucose transport activity in epitrochlearis skeletal muscle from insulin-resistant Zucker (fa/ fa) rats. Insulin-stimulated glucose transport in isolated skeletal muscle was reduced 47% in obese versus lean rats, with a parallel 42% reduction in tyrosine-associated PI 3-kinase activity. Contraction and hypoxia elicited normal responses for glucose transport in skeletal muscle from insulin-resistant obese rats. Isoform-specific AMPK activity was measured in skeletal muscle in response to insulin, contraction, or hypoxia. Contraction increased AMPKalpha1 activity 2.3-fold in lean rats, whereas no effect was noted in obese rats. Hypoxia increased AMPKalpha1 activity to a similar extent (more than sixfold) in lean and obese rats. Regardless of genotype, contraction, and hypoxia, each increased AMPKalpha2 activity more than fivefold, whereas insulin did not alter either AMPKalpha1 or -alpha2 activity in skeletal muscle. In conclusion, obesity-related insulin resistance is associated with an isoform-specific impairment in AMPKalpha1 in response to contraction. However, this impairment does not appear to affect contraction-stimulated glucose transport. Activation of AMPKalpha2 in response to muscle contraction/ exercise is associated with a parallel and normal increase in glucose transport in insulin-resistant skeletal muscle.

PMID: 14597982
AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets.
... insulin induced the ... the AMP-activated protein kinase (AMPK), ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 14597982

AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets.
Source

Thrombosis and haemostasis (November 2003)

Abstract

AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets. Little is known about the signaling cascades that eventually regulate the activity of the endothelial nitric oxide synthase (eNOS) in platelets. Here, we investigated the effects of insulin on the phosphorylation and activation of eNOS in washed human platelets and in endothelial cells. Insulin activated the protein kinase Akt in cultured endothelial cells and increased the phosphorylation of eNOS on Ser (1177) but failed to increase endothelial cyclic GMP levels or to elicit the relaxation of endothelium-intact porcine coronary arteries. In platelets, insulin also elicited the activation of Akt as well as the phosphorylation of eNOS and initiated NO production which was associated with increased cyclic GMP levels and the inhibition of thrombin-induced aggregation. The insulin-induced inhibition of aggregation was accompanied by a decreased Ca (2+) response to thrombin and was also prevented by N (omega) nitro-L-arginine. In platelets, but not in endothelial cells, insulin induced the activation of the AMP-activated protein kinase (AMPK), a metabolic stress-sensing kinase which was sensitive to the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin and the AMPK inhibitor iodotubercidin. Moreover, the insulin-mediated inhibition of thrombin-induced aggregation was prevented by iodotubercidin. Insulin-independent activation of the AMPK using 5-aminoimidazole-4-carboxamide ribonucleoside, increased platelet eNOS phosphorylation, increased cyclic GMP levels and attenuated platelet aggregation. These results highlight the differences in the signal transduction cascade activated by insulin in endothelial cells and platelets, and demonstrate that insulin stimulates the formation of NO in human platelets, in the absence of an increase in Ca (2+), by acti-vating PI3-K and AMPK which phosphorylates eNOS on Ser (1177).

PMID: 16741157
Fatty acids attenuate insulin regulation of 5'-AMP-activated protein kinase and insulin cardioprotection after ischemia.
... insulin stimulated glycolysis ... inhibited AMPK activity ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 16741157

Fatty acids attenuate insulin regulation of 5'-AMP-activated protein kinase and insulin cardioprotection after ischemia.
Source

Circulation research (7/7/2006)

Abstract

Fatty acids attenuate insulin regulation of 5'-AMP-activated protein kinase and insulin cardioprotection after ischemia. The cardioprotective effect of insulin during ischemia-reperfusion has been associated with stimulation of glucose uptake and glycolysis. Although fatty acids and 5'-AMP activated protein kinase (AMPK) are regulators of glucose metabolism, it is unknown what effect insulin has on postischemic function and AMPK activity in the presence of high levels of fatty acid. Isolated ejecting mouse hearts were perfused with Krebs-Henseleit solution containing 5 mmol x L (-1) glucose and 0, 0.2, or 1.2 mmol x L (-1) palmitate, with or without 100 microU/mL insulin. During aerobic perfusion in the absence of palmitate, insulin stimulated glycolysis by 73% and glucose oxidation by 54%, while inhibiting AMPK activity by 43%. In the presence of 0.2 or 1.2 mmol x L (-1) palmitate, insulin stimulated glycolysis by 111% and 105% and glucose oxidation by 72% and 274% but no longer inhibited AMPK activity. During reperfusion of hearts in the absence of palmitate, insulin increased recovery of cardiac power by 47%. This was associated with a 97% increase in glycolysis and a 160% increase in glucose oxidation. However, in the presence of 1.2 mmol x L (-1) palmitate, insulin now decreased recovery of cardiac power by 42%. During reperfusion, glucose oxidation was inhibited by high fat, but insulin-stimulated glycolysis remained high, resulting in increased proton production. In the absence of fatty acids, insulin blunted the ischemia-induced activation of AMPK, but this effect was lost in the presence of fatty acids. We demonstrate that the cardioprotective effect of insulin and its ability to inhibit AMPK activity are lost in the presence of high concentrations of fatty acids.

PMID: 18577554
Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance.
... disrupted insulin signaling led to decreased AMPK activity ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 18577554

Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance.
Source

Reproduction (Cambridge, England; September 2008)

Abstract

Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance. Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

Decreased insulin signaling also resulted in decreased AMPK activation ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 18577554

Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance.
Source

Reproduction (Cambridge, England; September 2008)

Abstract

Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance. Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

PMID: 20501641
Disruption of AMPKalpha1 signaling prevents AICAR-induced inhibition of AS160/TBC1D4 phosphorylation and glucose uptake in primary rat adipocytes.
... and insulin-stimulated glucose ... of AMPK, ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 20501641

Disruption of AMPKalpha1 signaling prevents AICAR-induced inhibition of AS160/TBC1D4 phosphorylation and glucose uptake in primary rat adipocytes.
Source

Molecular endocrinology (Baltimore, Md.; July 2010)

Abstract

Disruption of AMPKalpha1 signaling prevents AICAR-induced inhibition of AS160/TBC1D4 phosphorylation and glucose uptake in primary rat adipocytes. The aim of this study was to investigate the molecular mechanisms by which AMP-kinase (AMPK) activation inhibits basal and insulin-stimulated glucose uptake in primary adipocytes. Rat epididymal adipocytes were exposed to 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) for 1 h. Subsequently, basal and insulin-stimulated glucose uptake and the phosphorylation of AMPK, acetyl-CoA carboxylase, Akt, and the Akt substrate of 160 kDa (AS160/TBC1D4) were determined. In order to investigate whether these effects of AICAR were mediated by AMPK activation, these parameters were also assessed in adipocytes either expressing LacZ (control) or a kinase-dead AMPKalpha1 mutant. AICAR increased AMPK activation without affecting basal and insulin-stimulated Akt1/2 phosphorylation on Thr (308) and Ser (473) residues. However, AMPK activation suppressed the phosphorylation of AS160/TBC1D4 and its interaction with the 14-3-3 signal transduction-regulatory protein, which was accompanied by significant reductions in plasma membrane glucose transporter 4 content and glucose uptake under basal and insulin-stimulated conditions. Phosphorylation of Akt substrates glycogen synthase kinase 3alpha and -beta were unaltered by AICAR, indicating that the AMPK-regulatory effects were specific to the AS160/TBC1D4 signaling pathway. Expression of the kinase-dead AMPKalpha1 mutant fully prevented the suppression of AS160/TBC1D4 phosphorylation, plasma membrane glucose transporter 4 content, and the inhibitory effect of AICAR-induced AMPK activation on basal and insulin-stimulated glucose uptake. This study is the first to provide evidence that disruption of AMPKalpha1 signaling prevents the suppressive effects of AMPK activation on AS160/TBC1D4 phosphorylation and glucose uptake, indicating that insulin-signaling steps that are common to white adipose tissue and skeletal muscle regulation of glucose uptake are distinctly affected by AMPK activation.

PMID: 20667975
Activation of AMP-activated protein kinase signaling pathway by adiponectin and insulin in mouse adipocytes: requirement of acyl-CoA synthetases FATP1 and Acsl1 and association with an elevation in AMP/ATP ratio.
... with AMPK activation by ... and insulin, ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 20667975

Activation of AMP-activated protein kinase signaling pathway by adiponectin and insulin in mouse adipocytes: requirement of acyl-CoA synthetases FATP1 and Acsl1 and association with an elevation in AMP/ATP ratio.
Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (November 2010)

Abstract

Activation of AMP-activated protein kinase signaling pathway by adiponectin and insulin in mouse adipocytes: requirement of acyl-CoA synthetases FATP1 and Acsl1 and association with an elevation in AMP/ATP ratio. Adiponectin activates AMP-activated protein kinase (AMPK) in adipocytes, but the underlying mechanism remains unclear. Here we tested the hypothesis that AMP, generated in activating fatty acids to their CoA derivatives, catalyzed by acyl-CoA synthetases, is involved in AMPK activation by adiponectin. Moreover, in adipocytes, insulin affects the subcellular localization of acyl-CoA synthetase FATP1. Thus, we also tested whether insulin activates AMPK in these cells and, if so, whether it activates through a similar mechanism. We examined these hypotheses by measuring the AMP/ATP ratio and AMPK activation on adiponectin and insulin stimulation and after knocking down acyl-CoA synthetases in adipocytes. We show that adiponectin activation of AMPK is accompanied by an ~2-fold increase in the cellular AMP/ATP ratio. Moreover, FATP1 and Acsl1, the 2 major acyl-CoA synthetase isoforms in adipocytes, are essential for AMPK activation by adiponectin. We also show that after 40 min. insulin activated AMPK in adipocytes, which was coupled with a 5-fold increase in the cellular AMP/ATP ratio. Knockdown studies show that FATP1 and Acsl1 are required for these processes, as well as for stimulation of long-chain fatty acid uptake by adiponection and insulin. These studies demonstrate that a change in cellular energy state is associated with AMPK activation by both adiponectin and insulin, which requires the activity of FATP1 and Acsl1.

PMID: 20724582
Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet.
... reduced insulin-stimulated Akt1 ... of 5'AMP-activated protein kinase (AMPK) in ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 20724582

Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet.
Source

Diabetes (November 2010)

Abstract

Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet. [OBJECTIVE] Chemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo. [RESEARCH DESIGN AND METHODS] We used recombinant adeno-associated virus to express human chemerin in LDL receptor knockout mice on high-fat diet. [RESULTS] Expression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5'AMP-activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue. [CONCLUSIONS] Chemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle.

PMID: 21486807
In vivo stimulation of oestrogen receptor a increases insulin-stimulated skeletal muscle glucose uptake.
... increased insulin-stimulated glucose ... of AMP-activated protein kinase (AMPK).   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 21486807

In vivo stimulation of oestrogen receptor a increases insulin-stimulated skeletal muscle glucose uptake.
Source

The Journal of physiology (4/15/2011)

Abstract

In vivo stimulation of oestrogen receptor a increases insulin-stimulated skeletal muscle glucose uptake. Previous studies suggest oestrogen receptor a (ERa) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ERa modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ERa activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg?¹), oestradiol benzoate (EB; 20 µg kg?¹), the ERß agonist diarylpropionitrile (DPN, 10 mg kg?¹) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting.Activation of ERa with PPT resulted in increased insulin-stimulated glucose uptake into the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles, activation of insulin signalling intermediates (as measured by phospho-Akt (pAkt) and pAkt substrate (PAS)) and phosphorylation of AMP-activated protein kinase (AMPK). GLUT4 protein was increased only in the EDL muscle. Rats treated with EB or DPN for 3 days did not show an increase in insulin-stimulated skeletal muscle glucose uptake compared to vehicle-treated animals. These new findings reveal that direct activation of ERa positively mediates glucose uptake and insulin action in skeletal muscle. Evidence that oestrogens and ERa stimulate glucose uptake has important implications for understanding mechanisms of glucose homeostasis, particularly in postmenopausal women.

PMID: 21602475
Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake.
Mimicking AMPK activators ... the presence of insulin, ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 21602475

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake.
Source

American journal of physiology. Heart and circulatory physiology (August 2011)

Abstract

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake. The AMP-activated protein kinase (AMPK) is known to increase cardiac insulin sensitivity on glucose uptake. AMPK also inhibits the mammalian target of rapamycin (mTOR) /p70 ribosomal S6 kinase (p70S6K) pathway. Once activated by insulin, mTOR/p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling. AMPK was postulated to act on insulin by inhibiting this mTOR/p70S6K-mediated negative feedback loop. We tested this hypothesis in cardiomyocytes. The stimulation of glucose uptake by AMPK activators and insulin correlated with AMPK and protein kinase B (PKB/Akt) activation, respectively. Both treatments induced the phosphorylation of Akt substrate 160 (AS160) known to control glucose uptake. Together, insulin and AMPK activators acted synergistically to induce PKB/Akt overactivation, AS160 overphosphorylation, and glucose uptake overstimulation. This correlated with p70S6K inhibition and with a decrease in serine phosphorylation of IRS-1, indicating the inhibition of the negative feedback loop. We used the mTOR inhibitor rapamycin to confirm these results. 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. However, rapamycin did not enhance the insulin-induced stimulation of glucose uptake. In conclusion, although the insulin-sensitizing effect of AMPK on PKB/Akt is explained by the inhibition of the insulin-induced negative feedback loop, its effect on glucose uptake is independent of this mechanism. This disconnection revealed that the PKB/Akt/AS160 pathway does not seem to be the rate-limiting step in the control of glucose uptake under insulin treatment.

PMID: 22452783
A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin.
... that AMPK not ... be activated by insulin, ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 22452783

A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin.
Source

The FEBS journal (September 2012)

Abstract

A modelling-experimental approach reveals insulin receptor substrate (IRS) -dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. Mammalian target of rapamycin (mTOR) kinase responds to growth factors, nutrients and cellular energy status and is a central controller of cellular growth. mTOR exists in two multiprotein complexes that are embedded into a complex signalling network. Adenosine monophosphate-dependent kinase (AMPK) is activated by energy deprivation and shuts off adenosine 5'-triphosphate (ATP) -consuming anabolic processes, in part via the inactivation of mTORC1. Surprisingly, we observed that AMPK not only responds to energy deprivation but can also be activated by insulin, and is further induced in mTORC1-deficient cells. We have recently modelled the mTOR network, covering both mTOR complexes and their insulin and nutrient inputs. In the present study we extended the network by an AMPK module to generate the to date most comprehensive data-driven dynamic AMPK-mTOR network model. In order to define the intersection via which AMPK is activated by the insulin network, we compared simulations for six different hypothetical model structures to our observed AMPK dynamics. Hypotheses ranking suggested that the most probable intersection between insulin and AMPK was the insulin receptor substrate (IRS) and that the effects of canonical IRS downstream cues on AMPK would be mediated via an mTORC1-driven negative-feedback loop. We tested these predictions experimentally in multiple set-ups, where we inhibited or induced players along the insulin-mTORC1 signalling axis and observed AMPK induction or inhibition. We confirmed the identified model and therefore report a novel connection within the insulin-mTOR-AMPK network: we conclude that AMPK is positively regulated by IRS and can be inhibited via the negative-feedback loop.

PMID: 22889511
L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway.
... and insulin-stimulated p-Akt ... and p-AMPK-a and ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 22889511

L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway.
Source

Metabolism: clinical and experimental (January 2013)

Abstract

L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway. [OBJECTIVE] The amino acid Arginine (Arg) is the main biological precursor of nitric oxide (NO) and has been described to improve insulin sensitivity in diabetes and obesity. We investigated the molecular mechanisms involved in the long-term effects of Arg on glucose and lipid metabolism. [MATERIALS AND METHODS] L6 myotubes were treated with Arg (7mmol/L) for 6days. D-Mannitol (7mmol/L) was used as control; spermine NONOate (10µmol/L) and L-NAME (100µmol/L) were used to evaluate the NO/c-GMP pathway role. Basal and insulin-induced (120 nmol/L) glycogen synthesis, glucose uptake and lipid oxidation, c-GMP and nitrite levels, and the intracellular signaling pathways were evaluated. [RESULTS] Arg-treatment increased: 1) basal and insulin-stimulated glycogen synthesis; 2) glucose uptake; 3) palmitate oxidation; 4) p-Akt (Ser (473)), total and plasma membrane GLUT4 content, total and p-AMPK-a and p-ACC (Ser (79)), p-GSK-3a/ß (Ser (21/9)) and 5) nitrite and c-GMP levels. L-NAME treatment suppressed Arg effects on: 1) nitrite and c-GMP content; 2) glycogen synthesis and glucose uptake; 3) basal and insulin-stimulated p-Akt (Ser (473)), total and p-AMPK-a and ACC, and nNOS expression. [CONCLUSION] We provide evidence that Arg improves glucose and lipid metabolism in skeletal muscle, in parallel with increased phosphorylation of Akt and AMPK-a. These effects were mediated by the NO/c-GMP pathway. Thus, arginine treatment enhances signal transduction and has a beneficial effect of metabolism in skeletal muscle through direct activation of Akt and AMPK pathways.

PMID: 23095119
Acute regulation of 5'-AMP-activated protein kinase by long-chain fatty acid, glucose and insulin in rat primary adipocytes.
While insulin had no ... basal AMPK activity ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 23095119

Acute regulation of 5'-AMP-activated protein kinase by long-chain fatty acid, glucose and insulin in rat primary adipocytes.
Source

Bioscience reports (2012)

Abstract

Acute regulation of 5'-AMP-activated protein kinase by long-chain fatty acid, glucose and insulin in rat primary adipocytes. Palmitate increased AMPK (5'-AMP-activated protein kinase) activity, glucose utilization and 2-DOG (2-deoxyglucose) transport in rat adipocytes. All three effects were blocked by the AMPK inhibitor Compound C, leading to the conclusion that in response to an increase in long-chain NEFA (non-esterified fatty acid) concentration AMPK mediated an enhancement of adipocyte glucose transport, thereby providing increased glycerol 3-phosphate for FA (fatty acid) esterification to TAG (triacylglycerol). Activation of AMPK in response to palmitate was not due to an increase in the adipocyte AMP: ATP ratio. Glucose decreased AMPK activity and effects of palmitate and glucose on AMPK activity were antagonistic. While insulin had no effect on basal AMPK activity insulin did decrease AMPK activity in the presence of palmitate and also decreased the percentage effectiveness of palmitate to increase the transport of 2-DOG. It is suggested that activation of adipocyte AMPK by NEFA, as well as decreasing the activity of hormone-sensitive lipase, could modulate adipose tissue dynamics by increasing FA esterification and, under certain circumstances, FA synthesis.

PMID: 23277190
Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes.
... in response to insulin, ... of AMPK in ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 23277190

Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes.
Source

Journal of molecular and cellular cardiology (March 2013)

Abstract

Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes. Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that is increased in the metabolic syndrome due to overexpression in the adipocytes. The effects of CT-1 on cardiomyocyte substrate metabolism remain unknown. We therefore determined the effects of CT-1 on basal and stimulated glucose transport in cardiomyocytes exposed to a low dose (1nM) or a high dose (10nM). Dose-response curves for insulin showed that 1nM CT-1 reduced insulin responsiveness, while 10nM CT-1 increased insulin responsiveness. In either condition insulin sensitivity was unaffected. Similarly 1nM CT-1 reduced the stimulation of glucose transport in response to metabolic stress, induced by the mitochondrial poison oligomycin, while 10nM CT-1 increased this response. Reduction of stimulated glucose transport by 1nM CT-1 was associated with overexpression of SOCS-3, a protein known to hinder proximal insulin signaling, and increased phosphorylation of STAT5. In cardiomyocytes exposed to 1nM CT-1 there was also reduced phosphorylation of Akt and AS160 in response to insulin, and of AMPK in response to oligomycin. Insulin-stimulated glucose transport and signaling were restored by inhibition of STAT5 activity. On the other hand in cardiomyocytes exposed to 10nM CT-1 there was increased phosphorylation of the AS160 and Akt in response to insulin. Most importantly, basal and oligomycin-stimulated phosphorylation of AMPK was markedly increased in cardiomyocytes exposed to 10nM CT-1. The enhancement of basal and stimulated-glucose transport was abolished in cardiomyocytes treated with the calmodulin-dependent kinase II (CaMKII) inhibitor KN93, and so was AMPK phosphorylation. This suggests that activation of CaMKII mediates activation of AMPK by a high dose of CT-1 independently of metabolic stress. Our results point to a role for CT-1 in the regulation of myocardial glucose metabolism and implicate entirely separate mechanisms in the inhibitory or stimulatory effects of CT-1 on glucose transport at low or high concentrations respectively.

PMID: 23771523
Inhibition of lung tumorigenesis by metformin is associated with decreased plasma igf-I and diminished receptor tyrosine kinase signaling.
... not activation of AMPK in ... and insulin.   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 23771523

Inhibition of lung tumorigenesis by metformin is associated with decreased plasma igf-I and diminished receptor tyrosine kinase signaling.
Source

Cancer prevention research (Philadelphia, Pa.; August 2013)

Abstract

Inhibition of lung tumorigenesis by metformin is associated with decreased plasma igf-I and diminished receptor tyrosine kinase signaling. Metformin is the most commonly prescribed drug for type II diabetes and is associated with decreased cancer risk. Previously, we showed that metformin prevented tobacco carcinogen (NNK) -induced lung tumorigenesis in a non-diabetic mouse model, which was associated with decreased IGF-I/insulin receptor signaling but not activation of AMPK in lung tissues, as well as decreased circulating levels of IGF-I and insulin. Here, we used liver IGF-I-deficient (LID) mice to determine the importance of IGF-I in NNK-induced lung tumorigenesis and chemoprevention by metformin. LID mice had decreased lung tumor multiplicity and burden compared with wild-type (WT) mice. Metformin further decreased lung tumorigenesis in LID mice without affecting IGF-I levels, suggesting that metformin can act through IGF-I-independent mechanisms. In lung tissues, metformin decreased phosphorylation of multiple receptor tyrosine kinases (RTK) as well as levels of GTP-bound Ras independently of AMPK. Metformin also diminished plasma levels of several cognate ligands for these RTKs. Tissue distribution studies using [(14) C] -metformin showed that uptake of metformin was high in liver but four-fold lower in lungs, suggesting that the suppression of RTK activation by metformin occurs predominantly via systemic, indirect effects. Systemic inhibition of circulating growth factors and local RTK signaling are new AMPK-independent mechanisms of action of metformin that could underlie its ability to prevent tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res; 6 (8); 801-10. ©2013 AACR.

PMID: 9118478
Upregulation of 5'-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit.
... of insulin resulted in ... in AMPK activity ...   (details)

INS PRKAG2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  AMPK   (PRKAA1   PRKAA2   PRKAB1   PRKAB2   PRKAG1   PRKAG2 )

PMID: 9118478

Upregulation of 5'-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit.
Source

Circulation research (April 1997)

Abstract

Upregulation of 5'-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. In newborn rabbits, fatty acid oxidation rates in the heart significantly increase between 1 and 7 days after birth. This is due in part to a decrease in malonyl coenzyme A (CoA) production by acetyl CoA carboxylase (ACC). In other tissues, 5'-AMP-activated protein kinase (AMPK) can phosphorylate and inhibit ACC activity. In this study, we show that 1- and 7-day-old rabbit hearts have a high AMPK activity, with AMPK expression and activity being greatest in 7-day-old hearts. Hearts were also perfused in the Langendorff mode with Krebs-Henseleit buffer containing 0.4 mmol/L [14C] palmitate and 11 mmol/L glucose +/- 100 microU/mL insulin. In the absence of insulin, fatty acid oxidation rates were significantly higher in 7-day-old hearts compared with 1-day-old hearts. AMPK activity was also greater in 7-day-old hearts compared with 1-day-old hearts (909 +/- 60 and 585 +/- 75 pmol.min-1.mg protein-1, respectively; P < .05). In 1-day-old hearts, the presence of insulin resulted in a significant decrease in AMPK activity, an increase in ACC activity, and a decrease in fatty acid oxidation rates. In 7-day-old hearts, AMPK activity was also decreased by insulin, although ACC activity remained low and fatty acid oxidation rates remained high. Stimulation of AMPK in 7-day-old hearts with 200 mumol/L 5-amino 4-imidazolecarboxamide ribotide resulted in a further decrease in ACC activity and an increase in fatty acid oxidation rates. These data suggest that AMPK, ACC, and fatty acid oxidation are sensitive to insulin in 1-day-old rabbit hearts and that the decrease in circulating insulin levels seen after birth leads to an increased activity of AMPK. This can then lead to a phosphorylation and inhibition of ACC activity, with a resultant increase in fatty acid oxidation rates.