Entry |
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Name |
Type II diabetes mellitus - Homo sapiens (human)
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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.
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Class |
Human Diseases; Endocrine and metabolic disease
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Pathway map |

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Disease |
H00409 | Type 2 diabetes mellitus |
H00410 | Maturity onset diabetes of the young (MODY) |
H01228 | Insulin-resistant diabetes mellitus with acanthosis nigricans |
H01267 | Familial hyperinsulinemic hypoglycemia |
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Drug |
D00219 | Acetohexamide (JP17/USP/INN) |
D00271 | Chlorpropamide (JP17/USP/INN) |
D00379 | Tolazamide (JAN/USP/INN) |
D00380 | Tolbutamide (JP17/USP/INN) |
D00593 | Glimepiride (JP17/USP/INN) |
D00594 | Repaglinide (JAN/USP/INN) |
D01111 | Nateglinide (JP17/USP/INN) |
D01356 | Glymidine sodium (JAN/USAN/INN) |
D01799 | Glyclopyramide (JAN/INN) |
D01854 | Mitiglinide calcium hydrate (JP17) |
D02427 | Glibornuride (USAN/INN) |
D03230 | Insulin human (USP/INN) |
D03250 | Insulin glargine (USAN/INN) |
D04050 | Ertiprotafib (USAN/INN) |
D04475 | Insulin aspart (USP/INN) |
D04477 | Insulin lispro (USP/INN) |
D04539 | Insulin detemir (USAN/INN) |
D04540 | Insulin glulisine (USAN/INN) |
D04740 | Linogliride fumarate (USAN) |
D06177 | Tolbutamide sodium, sterile |
D09727 | Insulin degludec (USAN/INN) |
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Organism |
Homo sapiens (human) [GN: hsa]
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Gene |
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] |
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] |
6517 | SLC2A4; solute carrier family 2 member 4 [KO:K07191] |
9370 | ADIPOQ; adiponectin, C1Q and collagen domain containing [KO:K07296] |
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] |
3651 | PDX1; pancreatic and duodenal homeobox 1 [KO:K07594] |
6514 | SLC2A2; solute carrier family 2 member 2 [KO:K07593] |
3767 | KCNJ11; potassium inwardly rectifying 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] |
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Compound |
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Reference |
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Authors |
Stumvoll M, Goldstein BJ, van Haeften TW. |
Title |
Type 2 diabetes: principles of pathogenesis and therapy. |
Journal |
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Reference |
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Authors |
Gual P, Le Marchand-Brustel Y, Tanti JF. |
Title |
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. |
Journal |
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Reference |
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Authors |
Henquin JC. |
Title |
Triggering and amplifying pathways of regulation of insulin secretion by glucose. |
Journal |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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Authors |
Robertson RP. |
Title |
Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. |
Journal |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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Authors |
Yang SN, Berggren PO. |
Title |
Beta-cell CaV channel regulation in physiology and pathophysiology. |
Journal |
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Related pathway |
hsa04920 | Adipocytokine signaling pathway |
hsa04950 | Maturity onset diabetes of the young |
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KO pathway |
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LinkDB |
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