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Published on: July 17, 2020
A novel protein tyrosine phosphatase 1B inhibitor with therapeutic potential for insulin resistance
Xiaolin Zhang1, Jinying Tian1, Juan Li1
1Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Background And Purpose:
Insulin-sensitizing drugs are currently limited, and identifying new candidates is a challenge. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling, and its inhibition is anticipated to improve insulin resistance. Here, the pharmacological properties of CX08005, a novel PTP1B inhibitor, were investigated.
Experimental Approach:
Recombinant hPTP1B protein was used to study enzyme activity and mode of inhibition. Docking simulation explored the interactions between CX08005 and PTP1B. Insulin sensitivity was evaluated by glucose tolerance test (GTT) in diet-induced obese (DIO) and KKAy mice; glucose-stimulated insulin secretion (GSIS), homeostasis model assessment of insulin resistance index (HOMA-IR) and whole-body insulin sensitivity (ISWB ) were also determined. A hyperinsulinaemic-euglycaemic clamp was performed to evaluate insulin-stimulated glucose disposal in both whole-body and insulin-sensitive tissues. Furthermore, CX08005's effects on muscle, fat and liver cells were determined in vitro.
Key Results:
CX08005 competitively inhibited PTP1B by binding to the catalytic P-loop through hydrogen bonds. In DIO mice, CX08005 ameliorated glucose intolerance dose-dependently (50-200 mg·kg(-1) ·day(-1) ) and decreased the HOMA-IR. In KKAy mice, CX08005 (50 mg·kg(-1) ·day(-1) ) improved glucose intolerance, GSIS, ISWB and hyperglycaemia. CX08005 also enhanced insulin-stimulated glucose disposal, increased glucose infusion rate and glucose uptake in muscle and fat in DIO mice (hyperinsulinaemic-euglycaemic clamp test). CX08005 enhanced insulin-induced glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes, and increased phosphorylation of IRβ/IRS1 and downstream molecules in hepatocytes in a dose- and insulin-dependent manner respectively.
Conclusions And Implications:
Our results strongly suggest that CX08005 directly enhances insulin action in vitro and in vivo through competitive inhibition of PTP1B.
Insights
A novel drug, CX08005, effectively inhibits protein tyrosine phosphatase 1B (PTP1B), improving insulin sensitivity and glucose tolerance in preclinical models of insulin resistance.
Area of Science:
- Pharmacology
- Metabolic Diseases
- Biochemistry
Background:
- Limited therapeutic options exist for insulin-sensitizing drugs.
- Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling.
- Targeting PTP1B offers a potential strategy to combat insulin resistance.
Purpose of the Study:
- To investigate the pharmacological properties of CX08005, a novel PTP1B inhibitor.
- To evaluate the efficacy of CX08005 in improving insulin sensitivity and glucose metabolism.
- To elucidate the mechanism of action of CX08005.
Main Methods:
- Enzyme activity assays and docking simulations were used to characterize CX08005 inhibition of PTP1B.
- In vivo studies utilized diet-induced obese (DIO) and KKAy mice to assess glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion.
- In vitro studies involved cell-based assays with adipocytes, myotubes, and hepatocytes to examine insulin signaling pathways.
Main Results:
- CX08005 competitively inhibited PTP1B by binding to its catalytic P-loop.
- CX08005 demonstrated dose-dependent amelioration of glucose intolerance and reduced insulin resistance markers (HOMA-IR) in DIO mice.
- In KKAy mice, CX08005 improved glucose intolerance, insulin secretion, and overall insulin sensitivity.
- In vivo and in vitro studies confirmed enhanced insulin-stimulated glucose uptake and signaling pathway activation by CX08005.
Conclusions:
- CX08005 directly enhances insulin action both in vitro and in vivo.
- The mechanism involves competitive inhibition of PTP1B.
- CX08005 represents a promising therapeutic candidate for managing insulin resistance and related metabolic disorders.
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