ABSTRACT
Address for all correspondence: Barry J.Goldstein, M.D., Ph.D., Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College, Room 349 Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107. Phone: (215) 503-1272; Fax: (215) 923-7932; E-mail: Barry.Goldstein@mail.tju.edu
INTRODUCTION
Over the past few years, protein-tyrosine phosphatases (PTPases) have been shown to play an integral role in the regulation of cellular insulin action. More recently animal models deficient in the expression of specific PTPases have been generated to test the potential involvement of individual PTPase enzymes in insulin signalling and glucose metabolism in intact animals. To date, knock-out models for a three PTPases, LAR, PTP1B and SHP-2, have been generated and carefully evaluated with respect to insulin signalling. LAR and PTP1B have been shown to act as negative regulators of insulin receptor activation in cellular models, and the knock-out mouse models indicate that they both play an important role in insulin action and glucose homeostasis. In contrast, SHP-2 has been shown to have an important role as a positive regulator of post-receptor signalling in the insulin action pathway, affecting mitogenic pathways. Mice deficient in SHP-2 expression did not exhibit major abnormalities in insulin signalling, confirming that this PTPase does not regulate the metabolic effects of insulin. These powerful animal models have provided new insight into the physiological role of specific PTPases in the insulin signalling pathway. The results in knock-out mice with PTP1B and LAR have provided further impetus for the development of targeted pharmaceuticals that can modulate the activity of these PTPases in order to enhance insulin action in type 2 diabetes and insulin resistant states.
