General Information:

Id: 5,410 (click here to show other Interactions for entry)
Diseases: Cancer
Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Garcia-Jimenez C et al.(2013) A new link between diabetes and cancer: enhanced WNT/beta-catenin signaling by high glucose J Mol Endocrinol 52: R51-R66 [PMID: 24049067]

Interaction Information:

Comment High glucose enhances cancer-associated WNT signaling by allowing nuclear retention and accumulation of transcriptionally active beta-catenin independently of hyperinsulinemia, adipokines, or inflammation. Beta-catenin is a potent transcriptional coactivator targeted to genes involved in proliferation and senescence bypass, among others. Nuclear beta-catenin is a well-known tumor marker of bad prognosis, and therefore the requirement for high glucose by WNT signaling to promote nuclear accumulation of beta-catenin is likely to have a major impact on cancer biology.
Formal Description
Interaction-ID: 52803

phenotype

hyperglycemia

increases_activity of

Comment The WNTs comprise a large family of secreted cys-rich glycoprotein ligands that coordinate cell fate decision-making in a broad range of developmental and homeostatic contexts. WNT proteins bind to their membrane receptors and activate a number of pathways, including planar cell polarity pathway, Ca+ signaling, and the canonical WNT/beta-catenin pathway which is the best known and the most deeply involved in cancer. Notably, aberrant WNT signaling is present in 40–90% gastrointestinal cancers, which are the specific cancer sites more tightly associated with diabetes.
Formal Description
Interaction-ID: 52806

affects_activity of

disease

Cancer

Comment WNT signaling is also tightly associated with diabetes. Indirect links are illustrated by WNT-regulated control of adipocyte differentiation and obesity a major risk factor for diabetes.
Formal Description
Interaction-ID: 52808

affects_activity of

Comment WNT signaling is also tightly associated with diabetes. Indirect links are illustrated by WNT-regulated control of adipocyte differentiation and obesity a major risk factor for diabetes.
Formal Description
Interaction-ID: 52809

affects_activity of

disease

Obesity

Comment Direct links between WNT signaling and diabetes are illustrated by the mutations reported in its effector, the transcription factor TCF7L2 (previously known as TCF4), which represent the strongest genetic link with diabetes in all ethnicities. The role of the TCF7L2 intronic mutations associated with diabetes has remained elusive, but since their discovery, WNT/beta-catenin signaling has been shown to increase the expression of incretin hormones that are global regulators of metabolism and are required for normal glucose-dependent insulin secretion. As such, WNT-mediated induction of incretin production established a new link between WNT and diabetes.
Formal Description
Interaction-ID: 52810

gene/protein

TCF7L2

affects_activity of

Comment Direct links between WNT signaling and diabetes are illustrated by the mutations reported in its effector, the transcription factor TCF7L2 (previously known as TCF4), which represent the strongest genetic link with diabetes in all ethnicities. The role of the TCF7L2 intronic mutations associated with diabetes has remained elusive, but since their discovery, WNT/beta-catenin signaling has been shown to increase the expression of incretin hormones that are global regulators of metabolism and are required for normal glucose-dependent insulin secretion. As such, WNT-mediated induction of incretin production established a new link between WNT and diabetes.
Formal Description
Interaction-ID: 52811

increases_activity of

process

incretin hormone biosynthetic process

Comment WNT signaling induces incretin receptor expression and signaling in the pancreas as well as insulin expression and secretion.
Formal Description
Interaction-ID: 52813

increases_expression of

gene/protein

GIPR

Comment WNT signaling induces incretin receptor expression and signaling in the pancreas as well as insulin expression and secretion.
Formal Description
Interaction-ID: 52814

increases_activity of

process

incretin hormone signaling

Comment WNT signaling induces incretin receptor expression and signaling in the pancreas as well as insulin expression and secretion.
Formal Description
Interaction-ID: 52815

increases_expression of

gene/protein

INS

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Comment WNT signaling induces incretin receptor expression and signaling in the pancreas as well as insulin expression and secretion.
Formal Description
Interaction-ID: 52816

increases_activity of

Comment WNT induces the expression of the receptors for insulin and IGF1.
Formal Description
Interaction-ID: 52817

increases_expression of

gene/protein

INSR

Drugbank entries Show/Hide entries for INSR
Comment WNT induces the expression of the receptors for insulin and IGF1.
Formal Description
Interaction-ID: 52818

increases_expression of

gene/protein

IGF1R

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Comment WNT stimulation alone is not enough to promote nuclear accumulation of beta-catenin, but this process requires and depends on high glucose to increase its nuclear retention in a variety of human tumor-derived cell lines related to cancers associated with hyperglycemia and diabetes. As nuclear accumulation of beta-catenin is a well-known tumor marker of bad prognosis, constitutive WNT signaling in cancer on one side, and increased glucose uptake by tumor cells on the other, reveals a previously unrecognized requisite for WNT signaling in cancer, namely its amplification by high glucose. The ability of high glucose to amplify WNT/beta-catenin signaling provides a link between cancer and hyperglycemia which is independent of inflammation, hyperinsulinemia, or ROS induced mutations.
Formal Description
Interaction-ID: 52822

increases_transport of

gene/protein

CTNNB1

into the nucleus; amplified by hyperglycemia
Drugbank entries Show/Hide entries for CTNNB1