KEGG   PATHWAY: cge04930
Entry
cge04930                    Pathway                                
Name
Type II diabetes mellitus - Cricetulus griseus (Chinese hamster)
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
cge04930  Type II diabetes mellitus
cge04930

Organism
Cricetulus griseus (Chinese hamster) [GN:cge]
Gene
100760716  Ins; insulin [KO:K04526]
100766818  Insr; insulin receptor isoform X2 [KO:K04527] [EC:2.7.10.1]
100755710  Irs1; insulin receptor substrate 1 [KO:K16172]
100771848  Irs2; insulin receptor substrate 2 isoform X2 [KO:K07187]
100751390  insulin receptor substrate 1 [KO:K17445]
100773159  insulin receptor substrate 4 isoform X2 [KO:K17446]
100771181  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
100750761  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100774067  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100689251  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100769225  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100689252  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100766656  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
100763032  Adipoq; adiponectin [KO:K07296]
100759514  Mapk1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
100753149  Mapk3; mitogen-activated protein kinase 3 isoform X2 [KO:K04371] [EC:2.7.11.24]
100755421  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100756860  protein kinase C zeta type isoform X2 [KO:K18952] [EC:2.7.11.13]
100751218  Socs1; suppressor of cytokine signaling 1 isoform X2 [KO:K04694]
100769267  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
100750379  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
100750488  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
100771734  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100754361  mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
100764964  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100764780  Tnf; tumor necrosis factor isoform X1 [KO:K03156]
100774348  Prkcd; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
100763552  Prkce; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
100757561  Pdx1; pancreas/duodenum homeobox protein 1 [KO:K07594]
113834505  transcription factor MafA [KO:K07595]
100750908  Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 isoform X2 [KO:K07593]
100772205  Hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
100765413  Hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
100765703  Hkdc1; hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
100765901  Hk3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100763110  Gck; hexokinase-4 isoform X2 [KO:K12407] [EC:2.7.1.2]
100751347  Pkm; pyruvate kinase PKM isoform X2 [KO:K00873] [EC:2.7.1.40]
100774420  LOW QUALITY PROTEIN: pyruvate kinase PKM-like [KO:K00873] [EC:2.7.1.40]
100755461  Pklr; pyruvate kinase PKLR isoform X2 [KO:K12406] [EC:2.7.1.40]
100764690  Kcnj11; ATP-sensitive inward rectifier potassium channel 11 isoform X2 [KO:K05004]
100764394  Abcc8; ATP-binding cassette sub-family C member 8 isoform X3 [KO:K05032]
100754788  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C isoform X30 [KO:K04850]
100772497  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100758171  Cacna1a; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X2 [KO:K04344]
100770495  Cacna1b; voltage-dependent N-type calcium channel subunit alpha-1B isoform X3 [KO:K04849]
100773594  Cacna1e; voltage-dependent R-type calcium channel subunit alpha-1E isoform X2 [KO:K04852]
100761932  Cacna1g; voltage-dependent T-type calcium channel subunit alpha-1G isoform X9 [KO:K04854]
Compound
C00002  ATP
C00022  Pyruvate
C00031  D-Glucose
C00076  Calcium cation
C00162  Fatty acid
C00238  Potassium cation
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
Related
pathway
cge04210  Apoptosis
cge04910  Insulin signaling pathway
cge04920  Adipocytokine signaling pathway
cge04950  Maturity onset diabetes of the young
KO pathway
ko04930   

DBGET integrated database retrieval system