KEGG   PATHWAY: rno04930Help
Entry
rno04930                    Pathway                                

Name
Type II diabetes mellitus - Rattus norvegicus (rat)
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 diseases
BRITE hierarchy
Pathway map
Type II diabetes mellitus
rno04930

All organismsOrtholog table
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24506  
Ins2; insulin 2 [KO:K04526]
24505  
Ins1; insulin 1 [KO:K04526]
24954  
Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
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; insulin receptor substrate 4 [KO:K17446]
25513  
Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
60664  
Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
29741  
Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
497931  
Pik3r5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
85243  
Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
170911  
Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
366508  
Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
298947  
Pik3cg; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
25139  
Slc2a4; solute carrier family 2 member 4 [KO:K07191]
246253  
Adipoq; adiponectin, C1Q and collagen domain containing [KO:K07296]
116590  
Mapk1; mitogen activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  
Mapk3; mitogen activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
56718  
Mtor; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
25522  
Prkcz; protein kinase C, zeta [KO:K18952] [EC:2.7.11.13]
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 kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
25272  
Mapk10; mitogen activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
50658  
Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
116554  
Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
24835  
Tnf; tumor necrosis factor [KO:K03156]
tumor necrosis factor; K03156 tumor necrosis factor superfamily, member 2 [KO:K03156]
170538  
Prkcd; protein kinase C, delta [KO:K06068] [EC:2.7.11.13]
29340  
Prkce; protein kinase C, epsilon [KO:K18050] [EC:2.7.11.13]
29535  
Pdx1; pancreatic and duodenal homeobox 1 [KO:K07594]
366949  
Mafa; v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A [KO:K07595]
25351  
Slc2a2; solute carrier family 2 member 2 [KO:K07593]
25058  
Hk1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
25059  
Hk2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
25060  
Hk3; hexokinase 3 [KO:K00844] [EC:2.7.1.1]
hexokinase 1-like; K00844 hexokinase [EC:2.7.1.1] [KO:K00844] [EC:2.7.1.1]
24385  
Gck; glucokinase [KO:K12407] [EC:2.7.1.2]
25630  
Pkm; pyruvate kinase, muscle [KO:K00873] [EC:2.7.1.40]
RGD1561179; M2 pyruvate kinase-like [KO:K00873] [EC:2.7.1.40]
24651  
Pklr; pyruvate kinase, liver and RBC [KO:K12406] [EC:2.7.1.40]
83535  
Kcnj11; potassium voltage-gated channel subfamily J member 11 [KO:K05004]
25559  
Abcc8; ATP binding cassette subfamily C member 8 [KO:K05032]
24239  
Cacna1c; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
29716  
Cacna1d; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
25398  
Cacna1a; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
257648  
Cacna1b; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
54234  
Cacna1e; calcium voltage-gated channel subunit alpha1 E [KO:K04852]
29717  
Cacna1g; calcium voltage-gated channel subunit alpha1 G [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)
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)
Reference
  Authors
Henquin JC.
  Title
Triggering and amplifying pathways of regulation of insulin secretion by glucose.
  Journal
Diabetes 49:1751-60 (2000)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
KO pathway
 

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