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]. f81 e75 f9e f43 diabetes mellitus DOID:9351 Disease 11078440 PubMed Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000 Henquin JC 15733744 PubMed Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005 Gual P Le Marchand-Brustel Y Tanti JF hyperglycemia DOID:4195 Disease pancreatic beta cell CL:0000169 Cell Type disease pathway PW:0000013 Pathway Ontology hepatocyte CL:0000182 Cell Type type 2 diabetes mellitus pathway PW:0000208 Pathway Ontology adipocyte CL:0000136 Cell Type 11272200 PubMed Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes 2001 Chandra J Zhivotovsky B Zaitsev S Juntti-Berggren L Berggren PO Orrenius S 15759102 PubMed Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. J Mol Med (Berl) 2005 Kaneto H Matsuoka TA Nakatani Y Kawamori D Miyatsuka T Matsuhisa M Yamasaki Y cell of skeletal muscle CL:0000188 Cell Type