KEGG   PATHWAY: mcal04930
Entry
mcal04930                   Pathway                                

Name
Type II diabetes mellitus - Mus caroli (Ryukyu mouse)
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
mcal04930  Type II diabetes mellitus
mcal04930

Organism
Mus caroli (Ryukyu mouse) [GN:mcal]
Gene
110299132  insulin-2 [KO:K04526]
110286053  insulin-1 [KO:K04526]
110300622  Insr; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
110292727  Irs1; insulin receptor substrate 1 [KO:K16172]
110300614  Irs2; insulin receptor substrate 2 [KO:K07187]
110293997  insulin receptor substrate 1-like [KO:K17445]
110287491  Irs4; insulin receptor substrate 4 [KO:K17446]
110308009  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110299855  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
110292624  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
110290798  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
110292183  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110301355  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
110304808  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
110311881  Adipoq; adiponectin [KO:K07296]
110297836  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
110311382  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
110292680  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
110292460  Prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
110311816  Socs1; suppressor of cytokine signaling 1 [KO:K04694]
110303375  Socs2; suppressor of cytokine signaling 2 [KO:K04695]
110304930  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
110309072  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
110300158  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
110294148  Mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
110308920  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
110304169  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
110284110  Tnf; tumor necrosis factor isoform X1 [KO:K03156]
110309154  Prkcd; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
110312510  Prkce; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
110295322  Pdx1; pancreas/duodenum homeobox protein 1 [KO:K07594]
110311017  Mafa; transcription factor MafA [KO:K07595]
110291094  Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
110296267  Hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
110302692  Hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
110303354  Hkdc1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
110307543  Hk3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
110305090  Gck; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
110301002  Pkm; pyruvate kinase PKM isoform X1 [KO:K00873] [EC:2.7.1.40]
110290727  Pklr; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
110298992  Kcnj11; ATP-sensitive inward rectifier potassium channel 11 isoform X1 [KO:K05004]
110297901  Abcc8; ATP-binding cassette sub-family C member 8 isoform X1 [KO:K05032]
110295755  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
110309492  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
110299941  Cacna1a; voltage-dependent P/Q-type calcium channel subunit alpha-1A isoform X1 [KO:K04344]
110289304  Cacna1b; voltage-dependent N-type calcium channel subunit alpha-1B isoform X1 [KO:K04849]
110292269  Cacna1e; voltage-dependent R-type calcium channel subunit alpha-1E isoform X1 [KO:K04852]
110304549  Cacna1g; voltage-dependent T-type calcium channel subunit alpha-1G [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
mcal04210  Apoptosis
mcal04910  Insulin signaling pathway
mcal04920  Adipocytokine signaling pathway
mcal04950  Maturity onset diabetes of the young
KO pathway
ko04930   
LinkDB

DBGET integrated database retrieval system