KEGG   PATHWAY: hsa04930Help
Entry
hsa04930                    Pathway                                

Name
Type II diabetes mellitus - Homo sapiens (human)
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
hsa04930

All organismsOrtholog table
Disease
H00409  
Type II diabetes mellitus
H00410  
Maturity onset diabetes of the young (MODY)
H00512  
Permanent neonatal diabetes mellitus (PNDM)
H00513  
Transient neonatal diabetes mellitus (TNDM)
H00719  
Leprechaunism
H00861  
Pancreatic agenesis
H00942  
Rabson-Mendenhall syndrome
H00967  
Adiponectin deficiency
H01228  
Insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN)
H01267  
Familial hyperinsulinemic hypoglycemia (HHF)
Drug
D00085  
Insulin (JAN/USP)
D00219  
Acetohexamide (JP17/USP/INN)
D00271  
Chlorpropamide (JP17/USP/INN)
D00335  
Glipizide (USP/INN)
D00336  
Glibenclamide (JP17/INN)
D00379  
Tolazamide (JP17/USP/INN)
D00380  
Tolbutamide (JP17/USP/INN)
D00593  
Glimepiride (JP17/USP/INN)
D00594  
Repaglinide (JAN/USP/INN)
D01111  
Nateglinide (JP17/USAN/INN)
D01356  
Glymidine sodium (JAN/USAN/INN)
D01599  
Gliclazide (JP17/INN)
D01799  
Glyclopyramide (JAN/INN)
D01854  
Mitiglinide calcium hydrate (JP17)
D02425  
Carbutamide (INN)
D02427  
Glibornuride (USAN/INN)
D02430  
Gliquidone (INN)
D03230  
Insulin human (genetical recombination) (JP17)
D03250  
Insulin glargine (genetical recombination) (JP17)
D04475  
Insulin aspart (genetical recombination) (JAN)
D04477  
Insulin lispro (genetical recombination) (JAN)
D04539  
Insulin detemir (genetical recombination) (JAN)
D04540  
Insulin glulisine (genetical recombination) (JAN)
D04541  
Insulin human, isophane (USP)
D04542  
Insulin human zinc (USP)
D04543  
Insulin human zinc, extended (USP)
D04544  
Insulin I 125 (USAN)
D04545  
Insulin I 131 (USAN)
D04546  
Insulin, dalanated (USAN)
D04547  
Isophane insulin injection (aqueous suspension) (JAN)
D04548  
Insulin, neutral (USAN)
D04549  
Insulin zinc, extended (USP)
D04550  
Insulin zinc, prompt (USP)
D04551  
Insulin zinc (USP)
D05622  
Proinsulin human (USAN)
D06177  
Tolbutamide sodium, sterile
D07117  
Metahexamide (INN)
D07118  
Glisoxepide (INN)
D08080  
Insulin injection, biphasic isophane (BAN)
D08970  
Piragliatin (USAN)
D09727  
Insulin degludec (genetical recombination) (JAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3630  
INS; insulin [KO:K04526]
3643  
INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
3667  
IRS1; insulin receptor substrate 1 [KO:K16172]
8660  
IRS2; insulin receptor substrate 2 [KO:K07187]
8471  
IRS4; insulin receptor substrate 4 [KO:K17446]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
6517  
SLC2A4; solute carrier family 2 member 4 [KO:K07191]
9370  
ADIPOQ; adiponectin, C1Q and collagen domain containing [KO:K07296]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
2475  
MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
5590  
PRKCZ; protein kinase C zeta [KO:K18952] [EC:2.7.11.13]
8651  
SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
8835  
SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
9021  
SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
122809  
SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
3551  
IKBKB; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
5599  
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
7124  
TNF; tumor necrosis factor [KO:K03156]
5580  
PRKCD; protein kinase C delta [KO:K06068] [EC:2.7.11.13]
5581  
PRKCE; protein kinase C epsilon [KO:K18050] [EC:2.7.11.13]
3651  
PDX1; pancreatic and duodenal homeobox 1 [KO:K07594]
389692  
MAFA; MAF bZIP transcription factor A [KO:K07595]
6514  
SLC2A2; solute carrier family 2 member 2 [KO:K07593]
3101  
HK3; hexokinase 3 [KO:K00844] [EC:2.7.1.1]
3098  
HK1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
3099  
HK2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
80201  
HKDC1; hexokinase domain containing 1 [KO:K00844] [EC:2.7.1.1]
2645  
GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
5315  
PKM; pyruvate kinase, muscle [KO:K00873] [EC:2.7.1.40]
5313  
PKLR; pyruvate kinase, liver and RBC [KO:K12406] [EC:2.7.1.40]
3767  
KCNJ11; potassium voltage-gated channel subfamily J member 11 [KO:K05004]
6833  
ABCC8; ATP binding cassette subfamily C member 8 [KO:K05032]
775  
CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  
CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
773  
CACNA1A; calcium voltage-gated channel subunit alpha1 A [KO:K04344]
774  
CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849]
777  
CACNA1E; calcium voltage-gated channel subunit alpha1 E [KO:K04852]
8913  
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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