KEGG   PATHWAY: rno04930
rno04930                    Pathway                                

Type II diabetes mellitus - Rattus norvegicus (rat)
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
rno04930  Type II diabetes mellitus

Rattus norvegicus (rat) [GN:rno]
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24954  Insr; insulin receptor preproprotein [KO:K04527] [EC:]
25467  Irs1; insulin receptor substrate 1 [KO:K16172]
29376  Irs2; insulin receptor substrate 2 [KO:K07187]
84021  Irs3; insulin receptor substrate 3 [KO:K17445]
315350  Irs4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
25139  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
246253  Adipoq; adiponectin precursor [KO:K07296]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
25522  Prkcz; protein kinase C zeta type [KO:K18952] [EC:]
252971  Socs1; suppressor of cytokine signaling 1 [KO:K04694]
84607  Socs2; suppressor of cytokine signaling 2 [KO:K04695]
89829  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
305828  Socs4; suppressor of cytokine signaling 4 [KO:K04697]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
24835  Tnf; tumor necrosis factor [KO:K03156]
170538  Prkcd; protein kinase C delta type [KO:K06068] [EC:]
29340  Prkce; protein kinase C epsilon type [KO:K18050] [EC:]
29535  Pdx1; pancreas/duodenum homeobox protein 1 [KO:K07594]
366949  Mafa; transcription factor MafA [KO:K07595]
25351  Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
25058  Hk1; hexokinase-1 [KO:K00844] [EC:]
25059  Hk2; hexokinase-2 [KO:K00844] [EC:]
25060  Hk3; hexokinase-3 [KO:K00844] [EC:]
100364027  Hkdc1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:]
24385  Gck; hexokinase-4 isoform 2 [KO:K12407] [EC:]
25630  Pkm; pyruvate kinase PKM [KO:K00873] [EC:]
100364062  pyruvate kinase PKM [KO:K00873] [EC:]
24651  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:]
83535  Kcnj11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
25559  Abcc8; ATP-binding cassette sub-family C member 8 [KO:K05032]
24239  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
29716  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
25398  Cacna1a; voltage-dependent P/Q-type calcium channel subunit alpha-1A [KO:K04344]
257648  Cacna1b; voltage-dependent N-type calcium channel subunit alpha-1B isoform 1 [KO:K04849]
54234  Cacna1e; voltage-dependent R-type calcium channel subunit alpha-1E [KO:K04852]
29717  Cacna1g; voltage-dependent T-type calcium channel subunit alpha-1G isoform 1 [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)
rno04210  Apoptosis
rno04910  Insulin signaling pathway
rno04920  Adipocytokine signaling pathway
rno04950  Maturity onset diabetes of the young
KO pathway

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