Type II diabetes mellitus (WP1584)

Homo sapiens

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: [http://www.kegg.jp/dbget-bin/www_bget?pathway+map04930 KEGG] Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1584 CPTAC Assay Portal].


Abhishek , Kristina Hanspers , Chris Evelo , Alex Pico , Daniela Digles , Martina Summer-Kutmon , Denise Slenter , Sharestha Drall , Egon Willighagen , and Eric Weitz


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Homo sapiens




Disease Ontology

diabetes mellitus hyperglycemia

Cell Type Ontology

type B pancreatic cell hepatocyte fat cell cell of skeletal muscle

Pathway Ontology

disease pathway type 2 diabetes mellitus pathway


Label Type Compact URI Comment
Glucose Metabolite chebi:17234
Ca2+ Metabolite hmdb:HMDB0000464
Pyruvate Metabolite hmdb:HMDB0000243
ATP Metabolite hmdb:HMDB0000538
Glucose Metabolite hmdb:HMDB0000122
FFA Metabolite chebi:17234
Kir6.2 GeneProduct ensembl:ENSG00000187486
TNF alpha GeneProduct ensembl:ENSG00000232810
INSR GeneProduct ensembl:ENSG00000171105
ERK GeneProduct ensembl:ENSG00000100030
MAFA GeneProduct ensembl:ENSG00000182759
GLUT4 GeneProduct ensembl:ENSG00000181856
GLUT2 GeneProduct ensembl:ENSG00000163581
PRKCZ GeneProduct ensembl:ENSG00000067606
INS GeneProduct ensembl:ENSG00000129965
P13K GeneProduct ensembl:ENSG00000141506
ADIPOQ GeneProduct ensembl:ENSG00000181092
PYK GeneProduct ensembl:ENSG00000044446
JNK GeneProduct ensembl:ENSG00000107643
GK GeneProduct ensembl:ENSG00000198814
IKK GeneProduct ensembl:ENSG00000104365
VDCC GeneProduct ensembl:ENSG00000141837
INS GeneProduct ensembl:ENSG00000129965
SOCS GeneProduct ensembl:ENSG00000180008
JNK GeneProduct ensembl:ENSG00000107643
IRS GeneProduct ensembl:ENSG00000169047
MTOR GeneProduct ensembl:ENSG00000198793
PDX-1 GeneProduct ensembl:ENSG00000139515
PRKCD GeneProduct ensembl:ENSG00000163932
SURF1 GeneProduct ensembl:ENSG00000148290
IRS GeneProduct ensembl:ENSG00000169047


  1. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Henquin JC. Diabetes. 2000 Nov;49(11):1751–60. PubMed Europe PMC Scholia
  2. Role of apoptosis in pancreatic beta-cell death in diabetes. Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S. Diabetes. 2001 Feb;50 Suppl 1:S44-7. PubMed Europe PMC Scholia
  3. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Gual P, Le Marchand-Brustel Y, Tanti JF. Biochimie. 2005 Jan;87(1):99–109. PubMed Europe PMC Scholia
  4. Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, et al. J Mol Med (Berl). 2005 Jun;83(6):429–39. PubMed Europe PMC Scholia