KEGG   PATHWAY: ko04930
Entry
ko04930                     Pathway                                
Name
Type II diabetes mellitus
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
ko04930  Type II diabetes mellitus
ko04930

Disease
H00409  Type 2 diabetes mellitus
Orthology
K04526  insulin
K04527  insulin receptor [EC:2.7.10.1]
K16172  insulin receptor substrate 1
K07187  insulin receptor substrate 2
K17445  insulin receptor substrate 3
K17446  insulin receptor substrate 4
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K07191  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
K07296  adiponectin
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K18952  atypical protein kinase C zeta type [EC:2.7.11.13]
K04694  suppressor of cytokine signaling 1
K04695  suppressor of cytokine signaling 2
K04696  suppressor of cytokine signaling 3
K04697  suppressor of cytokine signaling 4
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K03156  tumor necrosis factor superfamily, member 2
K06068  novel protein kinase C delta type [EC:2.7.11.13]
K18050  novel protein kinase C epsilon type [EC:2.7.11.13]
K07594  insulin promoter factor 1
K07595  transcription factor MAFA
K07593  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2
K00844  hexokinase [EC:2.7.1.1]
K12407  glucokinase [EC:2.7.1.2]
K00873  pyruvate kinase [EC:2.7.1.40]
K12406  pyruvate kinase isozymes R/L [EC:2.7.1.40]
K05004  potassium inwardly-rectifying channel subfamily J member 11
K05032  ATP-binding cassette subfamily C (CFTR/MRP) member 8
K04850  voltage-dependent calcium channel L type alpha-1C
K04851  voltage-dependent calcium channel L type alpha-1D
K04344  voltage-dependent calcium channel P/Q type alpha-1A
K04849  voltage-dependent calcium channel N type alpha-1B
K04852  voltage-dependent calcium channel R type alpha-1E
K04854  voltage-dependent calcium channel T type alpha-1G
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
ko04210  Apoptosis
ko04910  Insulin signaling pathway
ko04920  Adipocytokine signaling pathway
ko04950  Maturity onset diabetes of the young
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