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Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Pointe-Claire - Dorval, Quebec, Canada H9R 4P8
Type 2 diabetes
is increasing at an alarming rate worldwide, and there has been a
considerable effort in several laboratories to identify suitable
targets for the design of drugs against the disease. To this end, the
protein tyrosine phosphatases that attenuate insulin signaling by
dephosphorylating the insulin receptor (IR) have been actively pursued.
This is because inhibiting the phosphatases would be expected to
prolong insulin signaling and thereby facilitate glucose uptake and,
presumably, result in a lowering of blood glucose. Targeting the IR
protein tyrosine phosphatase, therefore, has the potential to be a
significant disease-modifying strategy. Several protein tyrosine
phosphatases (PTPs) have been implicated in the dephosphorylation of
the IR. These phosphatases include PTP
, LAR, CD45, PTP
, SHP2, and
PTP1B. In most cases, there is evidence for and against the involvement
of the phosphatases in insulin signaling. The most convincing data,
however, support a critical role for PTP1B in insulin action. PTP1B
knockout mice are not only insulin sensitive but also maintain
euglycemia (in the fed state), with one-half the level of insulin
observed in wild-type littermates. Interestingly, these mice are also
resistant to diet-induced obesity when fed a high-fat diet. The
insulin-sensitive phenotype of the PTP1B knockout mouse is reproduced
when the phosphatase is also knocked down with an antisense
oligonucleotide in obese mice. Thus PTP1B appears to be a very
attractive candidate for the design of drugs for type 2 diabetes and obesity.
insulin receptor; protein tyrosine phosphatase; type 2 diabetes
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