Premium
In vitro and in vivo prevention of HIV protease inhibitor‐induced insulin resistance by a novel small molecule insulin receptor activator
Author(s) -
Cheng Mingshan,
Chen Seiyu,
Schow Steven R.,
Manchem Vara Prasad,
Spevak Wayne R.,
Cristobal Cristina P.,
Shi Songyuan,
Macsata Robert W.,
Lum Robert T.,
Goldfine Ira D.,
Keck James G.
Publication year - 2004
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20150
Subject(s) - insulin , insulin resistance , insulin receptor , glut4 , medicine , in vivo , activator (genetics) , endocrinology , pharmacology , protease inhibitor (pharmacology) , in vitro , insulin receptor substrate , indinavir , receptor , biology , human immunodeficiency virus (hiv) , biochemistry , virology , viral load , antiretroviral therapy , microbiology and biotechnology
Abstract Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin‐stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non‐peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin‐stimulated GLUT4 at the plasma membrane, and enhanced insulin‐stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs. © 2004 Wiley‐Liss, Inc.