Previous studies implicate
protein-tyrosine phosphatase 1B (PTP1B) and leukocyte
antigen-related
phosphatase (LAR) as negative regulators of
insulin signaling. The expression and/or activity of PTP1B and LAR are increased in muscle of
insulin-resistant rodents and humans. Overexpression of LAR selectively in muscle of transgenic mice causes whole body
insulin resistance. To determine whether overexpression of PTP1B also causes
insulin resistance, we generated transgenic mice overexpressing human PTP1B selectively in muscle at levels similar to those observed in
insulin-resistant humans.
Insulin-stimulated
insulin receptor (IR) tyrosyl phosphorylation and
phosphatidylinositol 3'-kinase activity were impaired by 35% and 40-60% in muscle of PTP1B-overexpressing mice compared with controls.
Insulin stimulation of
protein kinase C (
PKC)lambda/zeta activity, which is required for
glucose transport, was impaired in muscle of PTP1B-overexpressing mice compared with controls, showing that PTP1B overexpression impairs activation of these PKC
isoforms. Furthermore, hyperinsulinemic-euglycemic clamp studies revealed that whole body
glucose disposal and muscle
glucose uptake were decreased by 40-50% in PTP1B-overexpressing mice. Overexpression of PTP1B or LAR alone in muscle caused similar impairments in
insulin action; however, compound overexpression achieved by crossing PTP1B- and LAR-overexpressing mice was not additive.
Antibodies against specific IR phosphotyrosines indicated overlapping sites of action of PTP1B and LAR. Thus, overexpression of PTP1B in vivo impairs
insulin sensitivity, suggesting that overexpression of PTP1B in muscle of obese humans and rodents may contribute to their
insulin resistance. Lack of additive impairment of
insulin signaling by PTP1B and LAR suggests that these
PTPs have overlapping actions in causing
insulin resistance in vivo.