ReferenceID 85
Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B
Diabetologia
AIM/HYPOTHESIS: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the
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Record Fields
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- Reference Id
- 85
- Evidence Id
- 16675
- Core Evidence Id
- 16675
- Source Reference Id
- 141
- Herb2 Reference Id
- HBREF000308
- Subject Paper Key
- HBIN037294_24985145
- Pubmed Id
- 24985145
- Doi
- 10.1007/s00125-014-3315-8
- Paper Title
- Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B
- Paper Abstract
- AIM/HYPOTHESIS: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B. METHODS: The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests. RESULTS: Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 μmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity. CONCLUSIONS/INTERPRETATION: Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.
- Journal
- Diabetologia
- Publish Year
- 2014
- Experiment Subject
- mouse
- Experiment Type
- Animal Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B
- Bilingual Status
- semi_complete