General Information:

Id: 964
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Obesity - [OMIM]
Mammalia
review
Reference: Frojdo S et al.(2009) Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans Biochim. Biophys. Acta 2: 83-92 [PMID: 19041393]

Interaction Information:

Comment The action of insulin is initiated by binding to its cognate receptor and activation of the receptor's intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face.
Formal Description
Interaction-ID: 5929

complex/PPI

Insulin

interacts (colocalizes) with

complex/PPI

Insulin receptor

Comment The action of insulin is initiated by binding to its cognate receptor and activation of the receptor's intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face.
Formal Description
Interaction-ID: 5931

complex/PPI

Insulin

increases_activity of

complex/PPI

Insulin receptor

by binding to insulin receptor
Comment The action of insulin is initiated by binding to its cognate receptor and activation of the receptor's intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face.
Formal Description
Interaction-ID: 5932

complex/PPI

Insulin

increases_phosphorylation of

complex/PPI

Insulin receptor

via autophosphorylation
Comment The activated insulin receptor phosphorylates IRS1 and IRS2.
Formal Description
Interaction-ID: 5936

complex/PPI

Insulin receptor

increases_phosphorylation of

gene/protein

IRS1

Drugbank entries Show/Hide entries for IRS1
Comment The activated insulin receptor phosphorylates IRS1 and IRS2.
Formal Description
Interaction-ID: 5940

complex/PPI

Insulin receptor

increases_phosphorylation of

gene/protein

IRS2

Comment Tyrosine phosphorylated IRS1/2 recruit the heterodimeric p85/p110 PI3K at the plasma membrane, where it produces the lipid second messenger PIP3, which in turn activates a serine/threonine phosphorylation cascade of PH-domain containing proteins.
Formal Description
Interaction-ID: 5941

protein modification

IRS1-phosTyr

increases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

Comment Tyrosine phosphorylated IRS1/2 recruit the heterodimeric p85/p110 PI3K at the plasma membrane, where it produces the lipid second messenger PIP3, which in turn activates a serine/threonine phosphorylation cascade of PH-domain containing proteins.
Formal Description
Interaction-ID: 5943

protein modification

IRS2-phosTyr

increases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

Comment Tyrosine phosphorylated IRS1/2 recruit the heterodimeric p85/p110 PI3K at the plasma membrane, where it produces the lipid second messenger PIP3, which in turn activates a serine/threonine phosphorylation cascade of PH-domain containing proteins.
Formal Description
Interaction-ID: 5944

complex/PPI

Phosphatidylinositol 3-kinase

increases_quantity of

Comment PIP3 targets include PDK1, the serine/threonine protein kinase B (PKB)/Akt, and the atypical protein kinases C zeta and lambda isoforms.
Formal Description
Interaction-ID: 5945

increases_activity of

gene/protein

PDPK1

Drugbank entries Show/Hide entries for PDPK1
Comment PIP3 targets include PDK1, the serine/threonine protein kinase B (PKB)/Akt, and the atypical protein kinases C zeta and lambda isoforms.
Formal Description
Interaction-ID: 5946

increases_activity of

gene/protein

AKT1

Drugbank entries Show/Hide entries for AKT1
Comment PIP3 targets include PDK1, the serine/threonine protein kinase B (PKB)/Akt, and the atypical protein kinases C zeta and lambda isoforms.
Formal Description
Interaction-ID: 5947

increases_activity of

gene/protein

PRKCZ

Comment PIP3 targets include PDK1, the serine/threonine protein kinase B (PKB)/Akt, and the atypical protein kinases C zeta and lambda isoforms.
Formal Description
Interaction-ID: 5948

increases_activity of

gene/protein

PRKCI

Drugbank entries Show/Hide entries for PRKCI
Comment Mechanistically, PDK1, PKB and atypical PKCs zeta and lambda, which all contain a PH-domain, are recruited at the plasma membrane by binding to PIP3; thereon, PDK1 phosphorylates PKB and atypical PKCs zeta and lambda on a threonine residue located in the activation loop of the catalytic domain, causing their activation.
Formal Description
Interaction-ID: 5949

gene/protein

PDPK1

increases_phosphorylation of

gene/protein

AKT1

Drugbank entries Show/Hide entries for PDPK1 or AKT1
Comment Mechanistically, PDK1, PKB and atypical PKCs zeta and lambda, which all contain a PH-domain, are recruited at the plasma membrane by binding to PIP3; thereon, PDK1 phosphorylates PKB and atypical PKCs zeta and lambda on a threonine residue located in the activation loop of the catalytic domain, causing their activation.
Formal Description
Interaction-ID: 5950

gene/protein

PDPK1

increases_activity of

gene/protein

AKT1

Drugbank entries Show/Hide entries for PDPK1 or AKT1
Comment Mechanistically, PDK1, PKB and atypical PKCs zeta and lambda, which all contain a PH-domain, are recruited at the plasma membrane by binding to PIP3; thereon, PDK1 phosphorylates PKB and atypical PKCs zeta and lambda on a threonine residue located in the activation loop of the catalytic domain, causing their activation.
Formal Description
Interaction-ID: 5951

gene/protein

PDPK1

increases_phosphorylation of

gene/protein

PRKCZ

Drugbank entries Show/Hide entries for PDPK1
Comment Mechanistically, PDK1, PKB and atypical PKCs zeta and lambda, which all contain a PH-domain, are recruited at the plasma membrane by binding to PIP3; thereon, PDK1 phosphorylates PKB and atypical PKCs zeta and lambda on a threonine residue located in the activation loop of the catalytic domain, causing their activation.
Formal Description
Interaction-ID: 5952

gene/protein

PDPK1

increases_activity of

gene/protein

PRKCZ

Drugbank entries Show/Hide entries for PDPK1
Comment Mechanistically, PDK1, PKB and atypical PKCs zeta and lambda, which all contain a PH-domain, are recruited at the plasma membrane by binding to PIP3; thereon, PDK1 phosphorylates PKB and atypical PKCs zeta and lambda on a threonine residue located in the activation loop of the catalytic domain, causing their activation.
Formal Description
Interaction-ID: 5953

gene/protein

PDPK1

increases_phosphorylation of

gene/protein

PRKCI

Drugbank entries Show/Hide entries for PDPK1 or PRKCI
Comment Mechanistically, PDK1, PKB and atypical PKCs zeta and lambda, which all contain a PH-domain, are recruited at the plasma membrane by binding to PIP3; thereon, PDK1 phosphorylates PKB and atypical PKCs zeta and lambda on a threonine residue located in the activation loop of the catalytic domain, causing their activation.
Formal Description
Interaction-ID: 5955

gene/protein

PDPK1

increases_activity of

gene/protein

PRKCI

Drugbank entries Show/Hide entries for PDPK1 or PRKCI
Comment Upon PKB-mediated phosphorylation on Ser9, GSK-3 is inactivated.
Formal Description
Interaction-ID: 5956

gene/protein

AKT1

increases_phosphorylation of

gene/protein

GSK3B

at Ser9 of GSK3
Drugbank entries Show/Hide entries for AKT1 or GSK3B
Comment Upon PKB-mediated phosphorylation on Ser9, GSK-3 is inactivated.
Formal Description
Interaction-ID: 5962

gene/protein

AKT1

decreases_activity of

gene/protein

GSK3B

Drugbank entries Show/Hide entries for AKT1 or GSK3B
Comment The inactivation of GSK-3 relieves the inhibitory phosphorylation of GS, which becomes activated and promotes glycogen synthesis.
Formal Description
Interaction-ID: 5965

gene/protein

GSK3B

increases_phosphorylation of

gene/protein

GYS

Drugbank entries Show/Hide entries for GSK3B
Comment The inactivation of GSK-3 relieves the inhibitory phosphorylation of GS, which becomes activated and promotes glycogen synthesis.
Formal Description
Interaction-ID: 5967

gene/protein

GSK3B

decreases_activity of

gene/protein

GYS

Drugbank entries Show/Hide entries for GSK3B
Comment The inactivation of GSK-3 relieves the inhibitory phosphorylation of GS, which becomes activated and promotes glycogen synthesis.
Formal Description
Interaction-ID: 5968

gene/protein

GYS

increases_activity of

Comment PKB also regulates the insulin-stimulated translocation of the glucose transporter GLUT-4 at the plasma membrane, resulting in increased glucose uptake.
Formal Description
Interaction-ID: 6023

gene/protein

AKT1

increases_transport of

gene/protein

SLC2A4

to the plasma membrane
Drugbank entries Show/Hide entries for AKT1
Comment PKB also regulates the insulin-stimulated translocation of the glucose transporter GLUT-4 at the plasma membrane, resulting in increased glucose uptake.
Formal Description
Interaction-ID: 6031

gene/protein

AKT1

increases_activity of

gene/protein

SLC2A4

Drugbank entries Show/Hide entries for AKT1
Comment PKB also regulates the insulin-stimulated translocation of the glucose transporter GLUT-4 at the plasma membrane, resulting in increased glucose uptake.
Formal Description
Interaction-ID: 6032

gene/protein

SLC2A4

increases_activity of

process

glucose import

Comment PKB phosphorylates and inhibits the RabGTPase activating protein AS160.
Formal Description
Interaction-ID: 6033

gene/protein

AKT1

increases_phosphorylation of

gene/protein

TBC1D4

Drugbank entries Show/Hide entries for AKT1
Comment PKB phosphorylates and inhibits the RabGTPase activating protein AS160.
Formal Description
Interaction-ID: 6037

gene/protein

AKT1

decreases_activity of

gene/protein

TBC1D4

Drugbank entries Show/Hide entries for AKT1
Comment Activated IRS1/2 recruit Grb2, which associates to SOS and activates the Erk1/2 MAPK pathway.
Formal Description
Interaction-ID: 6038

gene/protein

IRS1

increases_quantity of

complex/PPI

GRB2-SOS complex

Drugbank entries Show/Hide entries for IRS1
Comment Activated IRS1/2 recruit Grb2, which associates to SOS and activates the Erk1/2 MAPK pathway.
Formal Description
Interaction-ID: 6046

gene/protein

IRS2

increases_quantity of

complex/PPI

GRB2-SOS complex

Comment Activated IRS1/2 recruit Grb2, which associates to SOS and activates the Erk1/2 MAPK pathway.
Formal Description
Interaction-ID: 6048

complex/PPI

GRB2-SOS complex

increases_activity of

process

MAPK cascade

Comment Alterations of the activation status of the proximal insulin signaling enzymes (IR, IRS1/2, PI3K), and downstream targets (PDK, PKB and its targets GSK-3 and AS160, aPKCs, and MAPK-family protein kinases) have been studied in muscle and adipose tissue from insulin resistant, obese and type 2 diabetic subjects, and the underlying insulin resistance has been attributed to defects in one or more steps of the insulin signaling cascade.
Formal Description
Interaction-ID: 6051

affects_activity of

disease

Insulin resistance

Comment IRS1 tyrosine phosphorylation is diminished in skeletal muscle of obese and type 2 diabetic patients undergoing an hyperinsulinaemic clamp - leading to an almost blunted interaction with p85.
Formal Description
Interaction-ID: 6058

decreases_phosphorylation of

gene/protein

IRS1

in skeletal muscle
Drugbank entries Show/Hide entries for IRS1
Comment IRS1 tyrosine phosphorylation is diminished in skeletal muscle of obese and type 2 diabetic patients undergoing an hyperinsulinaemic clamp - leading to an almost blunted interaction with p85.
Formal Description
Interaction-ID: 6081

disease

Obesity

decreases_phosphorylation of

gene/protein

IRS1

in skeletal muscle
Drugbank entries Show/Hide entries for IRS1
Comment IRS1 tyrosine phosphorylation is diminished in skeletal muscle of obese and type 2 diabetic patients undergoing an hyperinsulinaemic clamp - leading to an almost blunted interaction with p85.
Formal Description
Interaction-ID: 6083

NOT increases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

in skeletal muscle
Comment IRS1 tyrosine phosphorylation is diminished in skeletal muscle of obese and type 2 diabetic patients undergoing an hyperinsulinaemic clamp - leading to an almost blunted interaction with p85.
Formal Description
Interaction-ID: 6085

disease

Obesity

NOT increases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

in skeletal muscle
Comment In adipocytes derived from type 2 diabetic patients, reduced IRS1 tyrosine phosphorylation appeared to be the first upstream signaling step to be reduced.
Formal Description
Interaction-ID: 6107

decreases_phosphorylation of

gene/protein

IRS1

in adipose tissue; at Tyr residues of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment Initial studies in rodents demonstrated that JNK-mediated phosphorylation of IRS1 Ser307 (i.e. Ser312 in human IRS1), a residue located close to the PTB domain, promoted insulin resistance by impairing IRS1 binding to the activated insulin receptor. Other kinases have subsequently been shown to target Ser312, including IKK-beta and mTOR.
Formal Description
Interaction-ID: 6113

gene/protein

MAPK8

increases_phosphorylation of

gene/protein

IRS1

at Ser312 of IRS1
Drugbank entries Show/Hide entries for MAPK8 or IRS1
Comment Initial studies in rodents demonstrated that JNK-mediated phosphorylation of IRS1 Ser307 (i.e. Ser312 in human IRS1), a residue located close to the PTB domain, promoted insulin resistance by impairing IRS1 binding to the activated insulin receptor. Other kinases have subsequently been shown to target Ser312, including IKK-beta and mTOR.
Formal Description
Interaction-ID: 6116

gene/protein

IKBKB

increases_phosphorylation of

gene/protein

IRS1

at Ser312 of IRS1
Drugbank entries Show/Hide entries for IKBKB or IRS1
Comment Initial studies in rodents demonstrated that JNK-mediated phosphorylation of IRS1 Ser307 (i.e. Ser312 in human IRS1), a residue located close to the PTB domain, promoted insulin resistance by impairing IRS1 binding to the activated insulin receptor. Other kinases have subsequently been shown to target Ser312, including IKK-beta and mTOR.
Formal Description
Interaction-ID: 6117

gene/protein

MTOR

increases_phosphorylation of

gene/protein

IRS1

at Ser312 of IRS1
Drugbank entries Show/Hide entries for MTOR or IRS1
Comment Initial studies in rodents demonstrated that JNK-mediated phosphorylation of IRS1 Ser307 (i.e. Ser312 in human IRS1), a residue located close to the PTB domain, promoted insulin resistance by impairing IRS1 binding to the activated insulin receptor. Other kinases have subsequently been shown to target Ser312, including IKK-beta and mTOR.
Formal Description
Interaction-ID: 6119

protein modification

IRS1-phosSer312

increases_activity of

disease

Insulin resistance

Comment Initial studies in rodents demonstrated that JNK-mediated phosphorylation of IRS1 Ser307 (i.e. Ser312 in human IRS1), a residue located close to the PTB domain, promoted insulin resistance by impairing IRS1 binding to the activated insulin receptor. Other kinases have subsequently been shown to target Ser312, including IKK-beta and mTOR.
Formal Description
Interaction-ID: 6120

protein modification

IRS1-phosSer312

NOT interacts (colocalizes) with

complex/PPI

Insulin receptor

Comment Besides Ser312, other serine/threonine phosphorylation sites endowed with potential regulatory roles are those located in proximity to the SH2 domain binding motifs YxxM. Among those residues is Ser636, that, once phosphorylated by MAPK or mTOR, negatively modulates p85 PI3K binding to IRS1.
Formal Description
Interaction-ID: 6149

gene/protein

MTOR

increases_phosphorylation of

gene/protein

IRS1

at Ser636 of IRS1
Drugbank entries Show/Hide entries for MTOR or IRS1
Comment Besides Ser312, other serine/threonine phosphorylation sites endowed with potential regulatory roles are those located in proximity to the SH2 domain binding motifs YxxM. Among those residues is Ser636, that, once phosphorylated by MAPK or mTOR, negatively modulates p85 PI3K binding to IRS1.
Formal Description
Interaction-ID: 6157

gene/protein

MAPK

increases_phosphorylation of

gene/protein

IRS1

at Ser636 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment Besides Ser312, other serine/threonine phosphorylation sites endowed with potential regulatory roles are those located in proximity to the SH2 domain binding motifs YxxM. Among those residues is Ser636, that, once phosphorylated by MAPK or mTOR, negatively modulates p85 PI3K binding to IRS1.
Formal Description
Interaction-ID: 6158

protein modification

IRS1-phosSer636

decreases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

Comment In primary culture of myotubes from type 2 diabetic patients, basal and insulin-stimulated levels of IRS1 phospho-Ser636 were increased.
Formal Description
Interaction-ID: 6177

increases_quantity of

protein modification

IRS1-phosSer636

in myotubes
Comment IRS1 Ser312 phosphorylation was increased in muscle biopsies from obese and type 2 diabetic patients.
Formal Description
Interaction-ID: 6178

increases_quantity of

protein modification

IRS1-phosSer312

in muscle
Comment PKC-alpha/IRAK phosphorylates IRS1 at Ser24, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6179

gene/protein

PRKCA

increases_phosphorylation of

gene/protein

IRS1

at Ser24 of IRS1
Drugbank entries Show/Hide entries for PRKCA or IRS1
Comment PKC-alpha/IRAK phosphorylates IRS1 at Ser24, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6185

gene/protein

PRKCA

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser24 of IRS1
Drugbank entries Show/Hide entries for PRKCA or IRS1
Comment PKC-alpha/IRAK phosphorylates IRS1 at Ser24, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6186

gene/protein

IRAK

increases_phosphorylation of

gene/protein

IRS1

at Ser24 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKC-alpha/IRAK phosphorylates IRS1 at Ser24, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6187

gene/protein

IRAK

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser24 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKC phosphorylates IRS1 at Ser318, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6188

gene/protein

Protein kinase C

increases_phosphorylation of

gene/protein

IRS1

at Ser318 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKC phosphorylates IRS1 at Ser318, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6189

gene/protein

Protein kinase C

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser318 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment GSK-3 phosphorylates IRS1 at Ser332, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6190

gene/protein

GSK3

increases_phosphorylation of

gene/protein

IRS1

at Ser332 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment GSK-3 phosphorylates IRS1 at Ser332, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6191

gene/protein

GSK3

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser332 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKB phosphorylates IRS1 at Ser522, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6192

gene/protein

AKT1

increases_phosphorylation of

gene/protein

IRS1

at Ser522 of IRS1
Drugbank entries Show/Hide entries for AKT1 or IRS1
Comment PKB phosphorylates IRS1 at Ser522, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6193

gene/protein

AKT1

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser522 of IRS1
Drugbank entries Show/Hide entries for AKT1 or IRS1
Comment PKC-zeta phosphorylates IRS1 at Ser570, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6194

gene/protein

PRKCZ

increases_phosphorylation of

gene/protein

IRS1

at Ser570 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKC-zeta phosphorylates IRS1 at Ser570, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6196

gene/protein

PRKCZ

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser570 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKB phosphorylates IRS1 at Ser629, resulting in increased IRS1 activity.
Formal Description
Interaction-ID: 6197

gene/protein

AKT1

increases_phosphorylation of

gene/protein

IRS1

at Ser629 of IRS1
Drugbank entries Show/Hide entries for AKT1 or IRS1
Comment PKB phosphorylates IRS1 at Ser629, resulting in increased IRS1 activity.
Formal Description
Interaction-ID: 6198

gene/protein

AKT1

increases_activity of

gene/protein

IRS1

via phosphorylation at Ser629 of IRS1
Drugbank entries Show/Hide entries for AKT1 or IRS1
Comment PKC phosphorylates IRS1 at Ser1101, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6199

gene/protein

Protein kinase C

increases_phosphorylation of

gene/protein

IRS1

at Ser1101 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment PKC phosphorylates IRS1 at Ser1101, resulting in reduced IRS1 activity.
Formal Description
Interaction-ID: 6200

gene/protein

Protein kinase C

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser1101 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment Phosphorylation at Ser302 and at Ser1223 increases IRS1 activity.
Formal Description
Interaction-ID: 6202

gene/protein

Kinase

increases_activity of

gene/protein

IRS1

via phosphorylation at Ser302 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment Phosphorylation at Ser302 and at Ser1223 increases IRS1 activity.
Formal Description
Interaction-ID: 6203

gene/protein

Kinase

increases_activity of

gene/protein

IRS1

via phosphorylation at Ser1223 of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment While IRS1 Ser/Thr phosphorylation was initially viewed solely as a negative regulatory mechanism, it is now clear that both positive and negative modulation of IRS1 function arise from different phosphorylation patterns.
Formal Description
Interaction-ID: 6214

process

phosphorylation

affects_activity of

gene/protein

IRS1

Drugbank entries Show/Hide entries for IRS1
Comment In the few studies in which PI3K activity associated to IRS1 or IRS2 have been performed side by side, a decrease has been observed in both IRS1- and IRS2-associated insulin-stimulated PI3K activity in muscle biopsies from obese type 2 diabetic patients, whereas a selective alteration of insulin-induced IRS1-associated PI3K activity is observed in myotubes derived from obese type 2 diabetic patients.
Formal Description
Interaction-ID: 6215

decreases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

in muscle; in obese type 2 diabetic patients
Comment In the few studies in which PI3K activity associated to IRS1 or IRS2 have been performed side by side, a decrease has been observed in both IRS1- and IRS2-associated insulin-stimulated PI3K activity in muscle biopsies from obese type 2 diabetic patients, whereas a selective alteration of insulin-induced IRS1-associated PI3K activity is observed in myotubes derived from obese type 2 diabetic patients.
Formal Description
Interaction-ID: 6218

decreases_activity of

gene/protein

IRS1

in muscle; in obese type 2 diabetic patients
Drugbank entries Show/Hide entries for IRS1
Comment In the few studies in which PI3K activity associated to IRS1 or IRS2 have been performed side by side, a decrease has been observed in both IRS1- and IRS2-associated insulin-stimulated PI3K activity in muscle biopsies from obese type 2 diabetic patients, whereas a selective alteration of insulin-induced IRS1-associated PI3K activity is observed in myotubes derived from obese type 2 diabetic patients.
Formal Description
Interaction-ID: 6219

decreases_activity of

gene/protein

IRS2

in muscle; in obese type 2 diabetic patients
Comment In the few studies in which PI3K activity associated to IRS1 or IRS2 have been performed side by side, a decrease has been observed in both IRS1- and IRS2-associated insulin-stimulated PI3K activity in muscle biopsies from obese type 2 diabetic patients, whereas a selective alteration of insulin-induced IRS1-associated PI3K activity is observed in myotubes derived from obese type 2 diabetic patients.
Formal Description
Interaction-ID: 6220

NOT affects_activity of

gene/protein

IRS2

in myotubes; in obese type 2 diabetic patients
Comment In the few studies in which PI3K activity associated to IRS1 or IRS2 have been performed side by side, a decrease has been observed in both IRS1- and IRS2-associated insulin-stimulated PI3K activity in muscle biopsies from obese type 2 diabetic patients, whereas a selective alteration of insulin-induced IRS1-associated PI3K activity is observed in myotubes derived from obese type 2 diabetic patients.
Formal Description
Interaction-ID: 6221

decreases_activity of

gene/protein

IRS1

in myotubes; in obese type 2 diabetic patients
Drugbank entries Show/Hide entries for IRS1
Comment The PI3K downstream target PKB, a serine/threonine kinase of which alpha, beta and gamma isoforms have been reported, is a key enzyme mediating the metabolic actions of insulin. PKB activation occurs through phosphorylation of Thr308 and Ser473, mediated by PDK1 and the rictor-mTor complex respectively.
Formal Description
Interaction-ID: 6225

gene/protein

PDPK1

increases_activity of

gene/protein

AKT1

via phosphorylation at Thr308 of AKT
Drugbank entries Show/Hide entries for PDPK1 or AKT1
Comment The PI3K downstream target PKB, a serine/threonine kinase of which alpha, beta and gamma isoforms have been reported, is a key enzyme mediating the metabolic actions of insulin. PKB activation occurs through phosphorylation of Thr308 and Ser473, mediated by PDK1 and the rictor-mTor complex respectively.
Formal Description
Interaction-ID: 6230

gene/protein

PDPK1

increases_phosphorylation of

gene/protein

AKT1

at Thr308 of AKT
Drugbank entries Show/Hide entries for PDPK1 or AKT1
Comment The PI3K downstream target PKB, a serine/threonine kinase of which alpha, beta and gamma isoforms have been reported, is a key enzyme mediating the metabolic actions of insulin. PKB activation occurs through phosphorylation of Thr308 and Ser473, mediated by PDK1 and the rictor-mTor complex respectively.
Formal Description
Interaction-ID: 6231

complex/PPI

mTORC2 complex

increases_activity of

gene/protein

AKT1

via phosphorylation at Ser473 of AKT
Drugbank entries Show/Hide entries for AKT1
Comment The PI3K downstream target PKB, a serine/threonine kinase of which alpha, beta and gamma isoforms have been reported, is a key enzyme mediating the metabolic actions of insulin. PKB activation occurs through phosphorylation of Thr308 and Ser473, mediated by PDK1 and the rictor-mTor complex respectively.
Formal Description
Interaction-ID: 6235

complex/PPI

mTORC2 complex

increases_phosphorylation of

gene/protein

AKT1

at Ser473 of AKT
Drugbank entries Show/Hide entries for AKT1
Comment While PKB-alpha is involved in the regulation of lipid metabolism, the activation of glycogen synthesis in skeletal muscle, and in insulin action in adipose cells, it is PKB-beta (the major isoform expressed in skeletal muscle) that is considered to be the key isoform involved in insulin metabolic actions.
Formal Description
Interaction-ID: 6236

gene/protein

AKT1

affects_activity of

Drugbank entries Show/Hide entries for AKT1
Comment While PKB-alpha is involved in the regulation of lipid metabolism, the activation of glycogen synthesis in skeletal muscle, and in insulin action in adipose cells, it is PKB-beta (the major isoform expressed in skeletal muscle) that is considered to be the key isoform involved in insulin metabolic actions.
Formal Description
Interaction-ID: 6247

gene/protein

AKT1

affects_activity of

in skeletal muscle
Drugbank entries Show/Hide entries for AKT1
Comment While PKB-alpha is involved in the regulation of lipid metabolism, the activation of glycogen synthesis in skeletal muscle, and in insulin action in adipose cells, it is PKB-beta (the major isoform expressed in skeletal muscle) that is considered to be the key isoform involved in insulin metabolic actions.
Formal Description
Interaction-ID: 6249

gene/protein

AKT1

affects_activity of

in adipose tissue
Drugbank entries Show/Hide entries for AKT1
Comment While PKB-alpha is involved in the regulation of lipid metabolism, the activation of glycogen synthesis in skeletal muscle, and in insulin action in adipose cells, it is PKB-beta (the major isoform expressed in skeletal muscle) that is considered to be the key isoform involved in insulin metabolic actions.
Formal Description
Interaction-ID: 6251

gene/protein

AKT2

affects_activity of

in muscle
Drugbank entries Show/Hide entries for AKT2
Comment Although PKB-gamma is preferentially expressed in non-insulin dependent tissues, reduced PKB-gamma activity in skeletal muscle of obese and insulin resistant subjects has been reported.
Formal Description
Interaction-ID: 6252

disease

Insulin resistance

decreases_activity of

gene/protein

AKT3

in skeletal muscle
Comment Whether insulin-induced activation of PKB in insulin resistance and type 2 diabetes is impaired is a debated matter: studies reported significant reductions of insulin-stimulated Ser473 or Thr308 phosphorylation in skeletal muscle of type 2 diabetic patients, while others showed no alterations of phosphorylation or enzymatic activity of PKB between control subjects and type 2 diabetic patients.
Formal Description
Interaction-ID: 6254

complex/PPI

Insulin

increases_activity of

gene/protein

AKT1

Drugbank entries Show/Hide entries for AKT1
Comment All studies in humans, independently from the tissue under study and the methodology employed, have shown impairment of aPKC activity in obesity, insulin resistance and type 2 diabetes.
Formal Description
Interaction-ID: 6255

disease

Obesity

affects_activity of

gene/protein

aPRKC

Comment All studies in humans, independently from the tissue under study and the methodology employed, have shown impairment of aPKC activity in obesity, insulin resistance and type 2 diabetes.
Formal Description
Interaction-ID: 6257

disease

Insulin resistance

affects_activity of

gene/protein

aPRKC

Comment All studies in humans, independently from the tissue under study and the methodology employed, have shown impairment of aPKC activity in obesity, insulin resistance and type 2 diabetes.
Formal Description
Interaction-ID: 6258

affects_activity of

gene/protein

aPRKC

Comment ERK1/2 phosphorylation in muscle biopsies was similar between control subjects and type 2 diabetic patients as was ERK1/2 phosphorylation and activity and MEK1 activity. These observations were followed by the study of muscle biopsy-derived myotubes from control subjects and type 2 diabetic patients, showing that the phosphorylation levels of ERK1/.2 were similar, both in the absence and presence of insulin. However, other studies have reported a high basal phosphorylation state of ERK1/2 in muscle and adipose tissue from type 2 diabetic patients compared to control subjects. Some of the studies reported that the high levels of ERK1/2 basal phosphorylation is accompanied by a lack of further insulin stimulated phosphorylation in the type 2 diabetic patients.
Formal Description
Interaction-ID: 6330

NOT affects_phosphorylation of

gene/protein

MAPK3/1

in muscle
Comment The level of JNK1 phosphorylation has been reported to be elevated in the basal state in type 2 diabetic patients compared to control subjects, both in muscle and adipose tissue, with the high basal state possibly causing the lack of an insulin-stimulated JNK activity.
Formal Description
Interaction-ID: 6331

increases_phosphorylation of

gene/protein

MAPK8

in muscle, in adipose tissue
Drugbank entries Show/Hide entries for MAPK8
Comment p38 MAPK phosphorylation was shown to be increased in basal state in muscle tissue from obese and type 2 diabetic patients compared to control subjects, with similar results observed in adipose tissue.
Formal Description
Interaction-ID: 6333

increases_phosphorylation of

gene/protein

p38 MAPK

in muscle, in adipose tissue
Comment Upon insulin stimulation, p38 phosphorylation increased in control subjects, while it decreased in muscle tissue of type 2 diabetic patients, and remained unchanged in adipose tissue from type 2 diabetic patients.
Formal Description
Interaction-ID: 6334

complex/PPI

Insulin

affects_phosphorylation of

gene/protein

p38 MAPK

Comment The action of insulin is initiated by binding to its cognate receptor and activation of the receptor's intrinsic protein tyrosine kinase activity, resulting in the phosphorylation of tyrosine residues located in the cytoplasmic face.
Formal Description
Interaction-ID: 73819

complex/PPI

Insulin receptor

increases_activity of