CommentaryProtein tyrosine phosphatase-1B in diabetes
Section snippets
Is PTP-1B insulin receptor specific?
PTPs display very little substrate specificity when assayed in vitro either in the test tube or by overexpression in cell lines. This has led to the erroneous concept that PTPs are promiscuous and have multiple unrelated cellular substrates. Only recently, with the generation of mice having targeted mutations in various PTP genes, has the in vivo specificity of these enzymes been demonstrated. This is illustrated by the unique phenotypes in mice in which a particular PTP gene has been mutated.
PTP-1B in diabetes
DM2 is characterized by a resistance of insulin-sensitive tissues, such as muscle, liver, and fat, to insulin action 32, 33, 34, 35, 36. Although the mechanism of the insulin resistance is unknown, it is tightly associated with obesity. Approximately three-quarters of obese individuals will develop DM2. PTP-1B is involved in dephosphorylation of the activated IR and consequently in termination of the insulin signal. Therefore, any changes in expression levels or activity of PTP-1B relative to
Obesity-resistant phenotype of PTP-1B−/− mice
One of the more surprising phenotypes of the PTP-1B-deficient mice is their resistance to diet-induced obesity. Insulin is a powerful anabolic hormone that stimulates the storage of carbohydrates and fat. If PTP-1B−/− mice are so insulin-sensitive, why are they resistant to storing fat? One possible explanation is that PTP-1B−/− mice display tissue-specific insulin sensitivity. Muscle and liver appear to have increased insulin sensitivity, whereas adipose tissue is unchanged or has a slightly
PTP-1B inhibitors
The development of selective PTP-1B inhibitors would certainly help in clarifying the role of PTP-1B in diabetes. This will be a daunting challenge due to the large number of PTP family members and the conservation of the PTP catalytic domain 13, 61. Progress in developing selective PTP inhibitors is being made, although most inhibitors described to date are non-selective. One of the best characterized is vanadate, which is a reversible non-selective inhibitor of PTP with affinity in the
Conclusion
PTP-1B-deficient mice are resistant to both diabetes and obesity. Drugs that inhibit PTP-1B activity have the potential to be important new therapies in the treatment of these prevalent metabolic disorders. Much more work will be required to better understand the role of PTP-1B in insulin signaling and its potential involvement in insulin resistance in DM2. Furthermore, the development of selective, potent, and bioavailable inhibitors of PTP-1B will be a formidable challenge, although some of
Acknowledgements
Scientific contributions from the Merck Frosst phosphatase group and Dr. Michel Tremblay (McGill University) are gratefully acknowledged.
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