In vitro and in vivo prevention of HIV protease inhibitor-induced insulin resistance by a novel small molecule insulin receptor activator.
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.
Cheng
Mingshan
M
Telik, Inc., 3165 Porter Drive, Palo Alto, California 94304, USA.
Chen
Seiyu
S
Schow
Steven R
SR
Manchem
Vara Prasad
VP
Spevak
Wayne R
WR
Cristobal
Cristina P
CP
Shi
Songyuan
S
Macsata
Robert W
RW
Lum
Robert T
RT
Goldfine
Ira D
ID
Keck
James G
JG
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D066246:ErbB Receptors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D066298:In Vitro Techniques; D019469:Indinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007333:Insulin Resistance; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism; D013425:Sulfanilic Acids / Q000008:administration & dosage / Q000494:pharmacology*
D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009281:Naphthalenes; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D013425:Sulfanilic Acids; C497773:TLK 19781; D019469:Indinavir; D066246:ErbB Receptors; D011972:Receptor, Insulin; D005947:Glucose