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Entry
mmu04930                    Pathway                                

Name
Type II diabetes mellitus - Mus musculus (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 diseases
BRITE hierarchy
Pathway map
Type II diabetes mellitus
mmu04930

All organismsOrtholog table
Organism
Mus musculus (mouse) [GN:mmu]
Gene
16334  
Ins2; insulin II [KO:K04526]
16333  
Ins1; insulin I [KO:K04526]
16337  
Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
16367  
Irs1; insulin receptor substrate 1 [KO:K16172]
384783  
Irs2; insulin receptor substrate 2 [KO:K07187]
16369  
Irs3; insulin receptor substrate 3 [KO:K17445]
16370  
Irs4; insulin receptor substrate 4 [KO:K17446]
18709  
Pik3r2; phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 2 (p85 beta) [KO:K02649]
18708  
Pik3r1; phosphatidylinositol 3-kinase, regulatory subunit, polypeptide 1 (p85 alpha) [KO:K02649]
320207  
Pik3r5; phosphoinositide-3-kinase, regulatory subunit 5, p101 [KO:K02649]
18710  
Pik3r3; phosphatidylinositol 3 kinase, regulatory subunit, polypeptide 3 (p55) [KO:K02649]
30955  
Pik3cg; phosphoinositide-3-kinase, catalytic, gamma polypeptide [KO:K00922] [EC:2.7.1.153]
18706  
Pik3ca; phosphatidylinositol 3-kinase, catalytic, alpha polypeptide [KO:K00922] [EC:2.7.1.153]
18707  
Pik3cd; phosphatidylinositol 3-kinase catalytic delta polypeptide [KO:K00922] [EC:2.7.1.153]
74769  
Pik3cb; phosphatidylinositol 3-kinase, catalytic, beta polypeptide [KO:K00922] [EC:2.7.1.153]
20528  
Slc2a4; solute carrier family 2 (facilitated glucose transporter), member 4 [KO:K07191]
11450  
Adipoq; adiponectin, C1Q and collagen domain containing [KO:K07296]
26413  
Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  
Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
56717  
Mtor; mechanistic target of rapamycin (serine/threonine kinase) [KO:K07203] [EC:2.7.11.1]
18762  
Prkcz; protein kinase C, zeta [KO:K18952] [EC:2.7.11.13]
12703  
Socs1; suppressor of cytokine signaling 1 [KO:K04694]
216233  
Socs2; suppressor of cytokine signaling 2 [KO:K04695]
12702  
Socs3; suppressor of cytokine signaling 3 [KO:K04696]
67296  
Socs4; suppressor of cytokine signaling 4 [KO:K04697]
16150  
Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:2.7.11.10]
26419  
Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
26420  
Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
26414  
Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
21926  
Tnf; tumor necrosis factor [KO:K03156]
18753  
Prkcd; protein kinase C, delta [KO:K06068] [EC:2.7.11.13]
18754  
Prkce; protein kinase C, epsilon [KO:K18050] [EC:2.7.11.13]
18609  
Pdx1; pancreatic and duodenal homeobox 1 [KO:K07594]
378435  
Mafa; v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) [KO:K07595]
20526  
Slc2a2; solute carrier family 2 (facilitated glucose transporter), member 2 [KO:K07593]
15277  
Hk2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
212032  
Hk3; hexokinase 3 [KO:K00844] [EC:2.7.1.1]
15275  
Hk1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
216019  
Hkdc1; hexokinase domain containing 1 [KO:K00844] [EC:2.7.1.1]
103988  
Gck; glucokinase [KO:K12407] [EC:2.7.1.2]
18746  
Pkm; pyruvate kinase, muscle [KO:K00873] [EC:2.7.1.40]
18770  
Pklr; pyruvate kinase liver and red blood cell [KO:K12406] [EC:2.7.1.40]
16514  
Kcnj11; potassium inwardly rectifying channel, subfamily J, member 11 [KO:K05004]
20927  
Abcc8; ATP-binding cassette, sub-family C (CFTR/MRP), member 8 [KO:K05032]
12288  
Cacna1c; calcium channel, voltage-dependent, L type, alpha 1C subunit [KO:K04850]
12289  
Cacna1d; calcium channel, voltage-dependent, L type, alpha 1D subunit [KO:K04851]
12286  
Cacna1a; calcium channel, voltage-dependent, P/Q type, alpha 1A subunit [KO:K04344]
12287  
Cacna1b; calcium channel, voltage-dependent, N type, alpha 1B subunit [KO:K04849]
12290  
Cacna1e; calcium channel, voltage-dependent, R type, alpha 1E subunit [KO:K04852]
12291  
Cacna1g; calcium channel, voltage-dependent, T type, alpha 1G subunit [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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