ENTRY ko04930 Pathway NAME Type II diabetes mellitus DESCRIPTION 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. CLASS Human Diseases; Endocrine and metabolic disease PATHWAY_MAP ko04930 Type II diabetes mellitus DISEASE H00409 Type 2 diabetes mellitus ORTHOLOGY K00844 HK; hexokinase [EC:2.7.1.1] K00873 PK, pyk; pyruvate kinase [EC:2.7.1.40] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2 K04344 CACNA1A, CAV2.1; voltage-dependent calcium channel P/Q type alpha-1A K04371 ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24] K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04526 INS; insulin K04527 INSR, CD220; insulin receptor [EC:2.7.10.1] K04694 SOCS1, JAB; suppressor of cytokine signaling 1 K04695 SOCS2, CIS2; suppressor of cytokine signaling 2 K04696 SOCS3, CIS3; suppressor of cytokine signaling 3 K04697 SOCS4; suppressor of cytokine signaling 4 K04849 CACNA1B, CAV2.2; voltage-dependent calcium channel N type alpha-1B K04850 CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C K04851 CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D K04852 CACNA1E, CAV2.3; voltage-dependent calcium channel R type alpha-1E K04854 CACNA1G, CAV3.1; voltage-dependent calcium channel T type alpha-1G K05004 KCNJ11, KIR6.2; potassium inwardly-rectifying channel subfamily J member 11 K05032 ABCC8, SUR1; ATP-binding cassette subfamily C (CFTR/MRP) member 8 K06068 PRKCD; novel protein kinase C delta type [EC:2.7.11.13] K07187 IRS2; insulin receptor substrate 2 K07191 SLC2A4, GLUT4; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4 K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K07296 ADIPOQ, ACDC; adiponectin K07593 SLC2A2, GLUT2; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2 K07594 IPF1, PDX1; insulin promoter factor 1 K07595 MAFA; transcription factor MAFA K12406 PKLR; pyruvate kinase isozymes R/L [EC:2.7.1.40] K12407 GCK; glucokinase [EC:2.7.1.2] K16172 IRS1; insulin receptor substrate 1 K17445 IRS3; insulin receptor substrate 3 K17446 IRS4; insulin receptor substrate 4 K18050 PRKCE; novel protein kinase C epsilon type [EC:2.7.11.13] K18952 PRKCZ; atypical protein kinase C zeta type [EC:2.7.11.13] COMPOUND C00002 ATP C00022 Pyruvate C00031 D-Glucose C00076 Calcium cation C00162 Fatty acid C00238 Potassium cation REFERENCE PMID:15823385 AUTHORS Stumvoll M, Goldstein BJ, van Haeften TW. TITLE Type 2 diabetes: principles of pathogenesis and therapy. JOURNAL Lancet 365:1333-46 (2005) DOI:10.1016/S0140-6736(05)61032-X REFERENCE PMID:15733744 AUTHORS Gual P, Le Marchand-Brustel Y, Tanti JF. TITLE Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. JOURNAL Biochimie 87:99-109 (2005) DOI:10.1016/j.biochi.2004.10.019 REFERENCE PMID:11078440 AUTHORS Henquin JC. TITLE Triggering and amplifying pathways of regulation of insulin secretion by glucose. JOURNAL Diabetes 49:1751-60 (2000) DOI:10.2337/diabetes.49.11.1751 REFERENCE PMID:11272200 AUTHORS Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S. TITLE Role of apoptosis in pancreatic beta-cell death in diabetes. JOURNAL Diabetes 50 Suppl 1:S44-7 (2001) DOI:10.2337/diabetes.50.2007.S44 REFERENCE PMID:15759102 AUTHORS Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y. TITLE Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. JOURNAL J Mol Med 83:429-39 (2005) DOI:10.1007/s00109-005-0640-x REFERENCE PMID:12480546 AUTHORS Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y, Kawashima J, Shirotani T, Ichinose K, Brownlee M, Araki E. TITLE Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. JOURNAL Biochem Biophys Res Commun 300:216-22 (2003) DOI:10.1016/S0006-291X(02)02832-2 REFERENCE PMID:11390407 AUTHORS Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC. TITLE Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. JOURNAL J Biol Chem 276:31099-104 (2001) DOI:10.1074/jbc.M104115200 REFERENCE PMID:9011569 AUTHORS Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y. TITLE Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. JOURNAL J Clin Invest 99:144-50 (1997) DOI:10.1172/JCI119126 REFERENCE PMID:7491105 AUTHORS Sharma A, Olson LK, Robertson RP, Stein R. TITLE The reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. JOURNAL Mol Endocrinol 9:1127-34 (1995) DOI:10.1210/mend.9.9.7491105 REFERENCE PMID:15258147 AUTHORS Robertson RP. TITLE Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. JOURNAL J Biol Chem 279:42351-4 (2004) DOI:10.1074/jbc.R400019200 REFERENCE PMID:9974390 AUTHORS Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T. TITLE Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. JOURNAL Science 283:981-5 (1999) DOI:10.1126/science.283.5404.981 REFERENCE PMID:11325516 AUTHORS Novelli M, Fabregat ME, Fernandez-Alvarez J, Gomis R, Masiello P. TITLE Metabolic and functional studies on isolated islets in a new rat model of type 2 diabetes. JOURNAL Mol Cell Endocrinol 175:57-66 (2001) DOI:10.1016/S0303-7207(01)00400-2 REFERENCE PMID:15585596 AUTHORS Yang SN, Berggren PO. TITLE Beta-cell CaV channel regulation in physiology and pathophysiology. JOURNAL Am J Physiol Endocrinol Metab 288:E16-28 (2005) DOI:10.1152/ajpendo.00042.2004 REL_PATHWAY ko04210 Apoptosis ko04910 Insulin signaling pathway ko04920 Adipocytokine signaling pathway ko04950 Maturity onset diabetes of the young ///