Insulin stimulates
glucose uptake by myocytes and adipocytes, a process crucial for
maintaining glucose, and ultimately, metabolic homeostasis. Insulin
resistance occurs when insulin fails to stimulate sufficient glucose
uptake. This results in persistent hyperglycemia with the eventual
development of Type II (non-insulin dependent) diabetes mellitus.
People undergoing potent antiretroviral therapy (ART) for the treatment
of Human Immunodeficiency Virus type I (HIV-1) very often develop
metabolic abnormalities that include insulin resistance. The correlation
between metabolic abnormalities and ART has been the subject of
intense investigation. However, alterations in resting energy expenditure,
lipid levels including cholesterol, lipogenesis and triglyceride
clearance have been documented before the ART era, indicating that
HIV-1 itself contributes to metabolic abnormalities as well.
Nef is a viral,
non-structural myristoylated phosphoprotein essential for HIV-1
replication and propagation. It has a role in evasion from host
immune responses, and significantly contributes to the pathogenesis
of HIV-1 infection. Nef is a pleiotropic modulator of cell function.
It downregulates cell surface expression of CD4 and MHC-I molecules
by interfering with intracellular trafficking pathways. It also
alters signal transduction pathways, and interacts directly with
the cytoskeleton and proteins involved in actin polymerization.
Nef is also secreted into the extracellular environment, is measurable
in the sera of HIV-infected people, and extracellular Nef can influence
function of normal cells, even those not competent for HIV-1 infection.
It is possible
that Nef contributes to the development of insulin resistance in
HIV-1 infected people. We have sought to determine whether Nef may
alter adipocyte function in the context of insulin resistance and
glucose homeostasis. We first found that Nef-treated 3T3L1 adipocytes
take in less glucose in response to insulin when compared to control
cells. We also foundthat the surface expression of the facilitative
glucose transporter Glut4 is significantly reduced after Nef treatment
of adipocytes versus control cells. We observed that adipocytes
treated with Nef have disrupted cortical actin rings relative to
control cells, although the insulin signal transduction cascade
was not appreciably altered after Nef treatment. Our data indicates
that Nef inhibits glucose uptake by adipocytes at an early step
by preventing Glut4 translocation to and fusion with the plasma
membrane via disruption of actin dynamics. This identifies an important
mechanism whereby HIV-1 itself contributes to insulin resistance,
disruption of glucose homeostasis and possibly morbidity of HIV-1
disease.
Poster:
L., Chirch, L., Cheney, S., Morrison, R., Steigbigel.
HIV-specific Immunity and Lipoatrophy. Poster to be presented at
Infectious Disease Society of America, October 12, 2006.
