KEGG   PATHWAY: mcal04930
mcal04930                   Pathway                                

Type II diabetes mellitus - Mus caroli (Ryukyu mouse)
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.
Human Diseases; Endocrine and metabolic disease
Pathway map
mcal04930  Type II diabetes mellitus

Mus caroli (Ryukyu mouse) [GN:mcal]
110299132  insulin-2 [KO:K04526]
110286053  insulin-1 [KO:K04526]
110300622  Insr; insulin receptor isoform X1 [KO:K04527] [EC:]
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:]
110292183  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
110301355  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
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:]
110311382  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
110292680  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
110292460  Prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:]
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:]
110294148  Mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:]
110308920  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:]
110304169  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:]
110284110  Tnf; tumor necrosis factor isoform X1 [KO:K03156]
110309154  Prkcd; protein kinase C delta type isoform X1 [KO:K06068] [EC:]
110312510  Prkce; protein kinase C epsilon type [KO:K18050] [EC:]
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:]
110302692  Hk1; hexokinase-1 [KO:K00844] [EC:]
110303354  Hkdc1; putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:]
110307543  Hk3; hexokinase-3 isoform X1 [KO:K00844] [EC:]
110305090  Gck; glucokinase isoform X1 [KO:K12407] [EC:]
110301002  Pkm; pyruvate kinase PKM isoform X1 [KO:K00873] [EC:]
110290727  Pklr; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:]
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]
C00002  ATP
C00022  Pyruvate
C00031  D-Glucose
C00076  Calcium cation
C00162  Fatty acid
C00238  Potassium cation
Stumvoll M, Goldstein BJ, van Haeften TW.
Type 2 diabetes: principles of pathogenesis and therapy.
Lancet 365:1333-46 (2005)
Gual P, Le Marchand-Brustel Y, Tanti JF.
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
Biochimie 87:99-109 (2005)
Henquin JC.
Triggering and amplifying pathways of regulation of insulin secretion by glucose.
Diabetes 49:1751-60 (2000)
Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S.
Role of apoptosis in pancreatic beta-cell death in diabetes.
Diabetes 50 Suppl 1:S44-7 (2001)
Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y.
Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes.
J Mol Med 83:429-39 (2005)
Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y, Kawashima J, Shirotani T, Ichinose K, Brownlee M, Araki E.
Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells.
Biochem Biophys Res Commun 300:216-22 (2003)
Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC.
Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress.
J Biol Chem 276:31099-104 (2001)
Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y.
Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.
J Clin Invest 99:144-50 (1997)
Sharma A, Olson LK, Robertson RP, Stein R.
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.
Mol Endocrinol 9:1127-34 (1995)
Robertson RP.
Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes.
J Biol Chem 279:42351-4 (2004)
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.
Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion.
Science 283:981-5 (1999)
Novelli M, Fabregat ME, Fernandez-Alvarez J, Gomis R, Masiello P.
Metabolic and functional studies on isolated islets in a new rat model of type 2 diabetes.
Mol Cell Endocrinol 175:57-66 (2001)
Yang SN, Berggren PO.
Beta-cell CaV channel regulation in physiology and pathophysiology.
Am J Physiol Endocrinol Metab 288:E16-28 (2005)
mcal04210  Apoptosis
mcal04910  Insulin signaling pathway
mcal04920  Adipocytokine signaling pathway
mcal04950  Maturity onset diabetes of the young
KO pathway

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