Metabolic Disease

Protein tyrosine phosphatase inhibitor reverses diabetes

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The development of oral insulin-sensitizing agents to minimize the need for injectable insulin remains a major unmet need in the treatment of diabetes. Now, writing in Nature Chemical Biology, Bottini and colleagues report the identification of the first orally available small-molecule inhibitor of the low-molecular-weight phosphotyrosine protein phosphatase (LMPTP), which enhances liver insulin signalling and reverses type 2 diabetes in mice.

Insulin signalling is countered by protein tyrosine phosphatases (PTPs) that dephosphorylate and inactivate the insulin receptor. Inhibition of PTPs has therefore emerged as a promising therapeutic strategy for the treatment of insulin resistance. Knockdown of expression of LMPTP (which is encoded by Acp1) had previously been shown to improve the glycaemic profile and decrease insulin resistance in diet-induced obese (DIO) mice. Several LMPTP inhibitor series have been described since then, but these are non-specific and also target other PTPs. Stanford et al. therefore set out to further explore the potential of LMPTP as a therapeutic target.

Previously, the authors the generated of the first whole-body Acp1-deficient mouse model. Now, they report that when these mice are fed a high-fat diet for 3 months to induce obesity, although they gain similar weight compared with wild-type mice, they exhibit considerably improved glucose tolerance and reduced fasting insulin levels.

Next, the authors generated mice with Acp1 deleted specifically in insulin target tissues. Liver-specific Acp1 deletion recapitulated the diabetes-protective phenotype observed in Acp1-deficient DIO mice. Furthermore, they observed an increase in both tyrosine phosphorylation of the liver insulin receptor kinase domain activation loop and activation of downstream signalling pathways.

A high-throughput screen of 364,168 small-molecule compounds from the US National Institutes of Health Molecular Libraries Small Molecule Repository, followed by structure–activity relationship studies, led to the development of a small-molecule selective LMPTP inhibitor series. Further studies revealed that the inhibitors were acting through a novel uncompetitive mechanism: they bound to the LMPTP phosphocysteine intermediate, blocked hydrolysis of the covalent intermediate and hindered the final release of the phosphate product.

In human HepG2 hepatocytes, the LMPTP inhibitors increased insulin receptor phosphorylation after insulin stimulation. In mice, the most potent inhibitor (compound 23) was orally available, and when administered to diabetic DIO mice in the food for 2 weeks, it significantly improved glucose tolerance. It also decreased fasting insulin levels without affecting body weight, in conjunction with increased activation of liver insulin receptor signalling. Notably, compound 23 had no effect in liver-specific Acp1-deleted DIO mice.

These findings suggest that LMPTP activity plays a key part in the development of insulin resistance, and that LMPTP inhibitors should be further explored for the treatment of type 2 diabetes.

References

  1. 1

    Stanford, S. M. et al. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Nat. Chem. Biol. http://dx.doi.org/10.1038/nchembio.2344 (2017)

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Crunkhorn, S. Protein tyrosine phosphatase inhibitor reverses diabetes. Nat Rev Drug Discov 16, 312–313 (2017). https://doi.org/10.1038/nrd.2017.73

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