Type II diabetes mellitus (Homo sapiens)

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+py (tyrosine phosphorylation)Maturity onsetdiabetes of the youngObesityFFAType II diabetes mellitusDNAAdipoctokine signaling pathwayGlucose ( hyperglycemia)K+Impaired Insulin SecretionobesityPrevention of membrane depolarization+ps (serine phosphorylation)transient hyperglycemia hyperinsulinismAdipocytokine Signaling PathwayCa 2+ dependentPancreatic beta cellInsulin ResistanceROSInsulin signaling pathwayAdipotocyte, heptocyte, skeletal muscle cell glycation, hexosamine pathway,respiratory chainIRSPYKINSKir6.2PRKCZSOCSATPCa2+TNF alphaPyruvateIRSGKADIPOGLUT2 PRKCDJNKApoptosisPDX-1VDCCINSRmTORJNKSURF1MafAIKKERKGLUT4INSGlucoseP13K


Insulin resistance is strongly associated with type II diabetes. "Diabetogenic" factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process.

The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction.

Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively.

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Ontology Terms



  1. Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S; ''Role of apoptosis in pancreatic beta-cell death in diabetes.''; Diabetes, 2001 PubMed Europe PMC Scholia
  2. Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y; ''Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes.''; J Mol Med (Berl), 2005 PubMed Europe PMC Scholia
  3. Henquin JC; ''Triggering and amplifying pathways of regulation of insulin secretion by glucose.''; Diabetes, 2000 PubMed Europe PMC Scholia
  4. Gual P, Le Marchand-Brustel Y, Tanti JF; ''Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.''; Biochimie, 2005 PubMed Europe PMC Scholia


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111210view21:19, 24 July 2020Ssd1805Ontology Term : 'diabetes mellitus' added !
111209view21:15, 24 July 2020Ssd1805Ontology Term : 'DOID:9352' removed !
108356view19:37, 11 December 2019KhanspersOntology Term : 'disease pathway' added !
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105849view23:15, 15 August 2019KhanspersModified description
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81778view18:58, 26 August 2015KhanspersModified description
72094view21:35, 24 October 2013Mkutmonupdated datasource for "Apoptosis"
67730view11:55, 26 June 2013DdiglesOntology Term : 'type 2 diabetes mellitus pathway' added !
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45032view18:47, 6 October 2011KhanspersOntology Term : 'DOID:9351' removed !
45031view18:47, 6 October 2011KhanspersOntology Term : 'type 2 diabetes mellitus' added !
45030view18:47, 6 October 2011KhanspersOntology Term : 'Diabetes' added !
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External references


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NameTypeDatabase referenceComment
PRKCDGeneProductENSG00000163932 (Ensembl Human)
ADIPOGeneProductENSG00000181092 (Ensembl Human)
ATPMetaboliteHMDB00538 (HMDB)
Ca2+MetaboliteHMDB00464 (HMDB)
ERKGeneProductENSG00000100030 (Ensembl Human)
GKGeneProductENSG00000198814 (Ensembl Human)
GLUT2GeneProductENSG00000163581 (Ensembl Human)
GLUT4GeneProductENSG00000181856 (Ensembl Human)
GlucoseMetaboliteHMDB00122 (HMDB)
IKKGeneProductENSG00000104365 (Ensembl Human)
INSGeneProductENSG00000129965 (Ensembl Human)
INSRGeneProductENSG00000171105 (Ensembl Human)
IRSGeneProductENSG00000169047 (Ensembl Human)
JNKGeneProductENSG00000107643 (Ensembl Human)
Kir6.2GeneProductENSG00000187486 (Ensembl Human)
MafAGeneProductENSG00000182759 (Ensembl Human)
P13KGeneProductENSG00000141506 (Ensembl Human)
PDX-1GeneProductENSG00000139515 (Ensembl Human)
PRKCZGeneProductENSG00000067606 (Ensembl Human)
PYKGeneProductENSG00000107643 (Ensembl Human)
PyruvateMetaboliteHMDB00243 (HMDB)
SOCSGeneProductENSG00000180008 (Ensembl Human)
SURF1GeneProductENSG00000148290 (Ensembl Human)
TNF alphaGeneProductENSG00000232810 (Ensembl Human)
VDCCGeneProductENSG00000141837 (Ensembl Human)
mTORGeneProductENSG00000198793 (Ensembl Human)

Annotated Interactions

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