Type II diabetes mellitus (Homo sapiens)

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1-4Pancreatic beta cellMaturity onsetdiabetes of the youngglycation, hexosamine pathway,respiratory chainDNAtransient hyperglycemia hyperinsulinism+ps (serine phosphorylation)Adipoctokine signaling pathwayType II diabetes mellitusObesityCa 2+ dependentROSobesityAdipotocyte, heptocyte, skeletal muscle cell Glucose ( hyperglycemia)K++py (tyrosine phosphorylation)FFAInsulin signaling pathwayInsulin ResistancePrevention of membrane depolarizationImpaired Insulin SecretionAdipocytokine Signaling PathwayINSPDX-1GLUT2ApoptosisIRSVDCCmTORPYKKir6.2ERKJNKPyruvateP13KADIPOMafAIKKINSCa2+JNKTNF alphaGLUT4IRS PRKCDSOCSATPINSRSURF1GlucoseGKPRKCZ


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.
Source: KEGG

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  1. Henquin JC; ''Triggering and amplifying pathways of regulation of insulin secretion by glucose.''; Diabetes, 2000 PubMed
  2. 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
  3. Gual P, Le Marchand-Brustel Y, Tanti JF; ''Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.''; Biochimie, 2005 PubMed
  4. 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


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94959view10:10, 20 October 2017DeSlAdded lit. references
94958view09:44, 20 October 2017DeSlConnected all lines that I could
81779view19:00, 26 August 2015KhanspersModified description
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 !
63481view18:29, 10 May 2013AlexanderPicoFixed Xref for PYK
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45036view18:50, 6 October 2011KhanspersOntology Term : 'pancreatic beta cell' added !
45034view18:49, 6 October 2011KhanspersOntology Term : 'hyperglycemia' added !
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)
ADIPOGeneProductENSG00000181092 (Ensembl)
ATPMetaboliteHMDB00538 (HMDB)
ApoptosisPathwayWP254 (WikiPathways)
Ca2+MetaboliteHMDB00464 (HMDB)
ERKGeneProductENSG00000100030 (Ensembl)
GKGeneProductENSG00000198814 (Ensembl)
GLUT2GeneProductENSG00000163581 (Ensembl)
GLUT4GeneProductENSG00000181856 (Ensembl)
GlucoseMetaboliteHMDB00122 (HMDB)
IKKGeneProductENSG00000104365 (Ensembl)
INSGeneProductENSG00000129965 (Ensembl)
INSRGeneProductENSG00000171105 (Ensembl)
IRSGeneProductENSG00000169047 (Ensembl)
JNKGeneProductENSG00000107643 (Ensembl)
Kir6.2GeneProductENSG00000187486 (Ensembl)
MafAGeneProductENSG00000182759 (Ensembl)
P13KGeneProductENSG00000141506 (Ensembl)
PDX-1GeneProductENSG00000139515 (Ensembl)
PRKCZGeneProductENSG00000067606 (Ensembl)
PYKGeneProductENSG00000044446 (Ensembl)
PyruvateMetaboliteHMDB00243 (HMDB)
SOCSGeneProductENSG00000180008 (Ensembl)
SURF1GeneProductENSG00000148290 (Ensembl)
TNF alphaGeneProductENSG00000232810 (Ensembl)
VDCCGeneProductENSG00000141837 (Ensembl)
mTORGeneProductENSG00000198793 (Ensembl)

Annotated Interactions

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