The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes

Diabetes. 2001 Jun;50(6):1425-31. doi: 10.2337/diabetes.50.6.1425.


HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.

MeSH terms

  • 3T3 Cells
  • Adipocytes / drug effects*
  • Adipocytes / physiology*
  • Animals
  • Biological Transport / drug effects
  • Glucose / metabolism
  • Glucose Transporter Type 4
  • HIV Protease Inhibitors / pharmacology*
  • Insulin Resistance*
  • Lipolysis / drug effects*
  • Mice
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins*
  • Nelfinavir / pharmacology*
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt


  • Glucose Transporter Type 4
  • HIV Protease Inhibitors
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Proto-Oncogene Proteins
  • Slc2a4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Nelfinavir
  • Glucose