Protein tyrosine phosphatase 1B: a novel target for type 2 diabetes and obesity.
The identification of autophosphorylation of the insulin receptor as a pivotal component in the signal transduction induced by insulin, initiated the hunt to identify the tyrosine phosphatase(s) that were responsible for regulating dephosphorylation, and thus inactivation of the receptor. Compelling evidence for the existence of an insulin receptor specific PTP has come from the remarkable phenotype of the PTP1B deficient mouse. PTP1B deficient mice display an insulin sensitive phenotype and are able to maintain glucose homeostasis with about half the level of circulating insulin. In response to insulin administration PTP1B deficient mice have a significant increase in insulin receptor phosphorylation in liver and muscle compared to wild type controls. Unexpectedly these animals were also resistant to diet induced obesity. These observations strongly support PTP1B as a negative regulator of insulin action, thereby making it an ideal therapeutic target for intervention in type 2 diabetes and obesity.
Ramachandran
Chidambaram
C
Department of Biochemistry and Molecular Biology, Merck Frosst Canada & Co, Pointe-Claire, Quebec, Canada. chidambaram_ramachandran@merck.com
Kennedy
Brian P
BP
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D011972:Receptor, Insulin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D005947:Glucose