Saturated fatty acid-induced insulin resistance
in rat adipocytes.

Hunnicutt JW, Hardy RW, Williford J, McDonald JM

Palmitate has been shown to stimulate glucose transport, translocation
of GLUT4 and insulin receptor autophosphorylation in isolated rat
adipocytes (Biochem Biophys Res Commun 177:343-49, 1991). Here
we further characterize the ability of short-term treatment with free
fatty acids to stimulate glucose transport in isolated rat adipocytes and
demonstrate that prolonged treatment induces insulin resistance.
Treatment of adipocytes for 15 min with 1 mM myristate (14:0),
palmitate (16:0), or stearate (18:0) stimulates glucose transport by 119
+/- 33, 89 +/- 29, and 114 +/- 30%, respectively. In contrast, oleate
(cis 18:1), 1), elaidate (trans 18:1), and linoleate (cis 18:2) do not
stimulate glucose transport. Palmitate stimulates glucose transport in a
concentration-dependent manner, demonstrating saturation at 1 mM
and half-maximal stimulation at 0.25-0.5 mM. Prolonged treatment
(4 h) of rat adipocytes with 1 mM palmitate induces insulin resistance.
After a 4-h preincubation with palmitate (1 mM), insulin stimulates
glucose transport in rat adipocytes by 4.4-fold +/- 0.8, vs. 8.8-fold +/-
0.8 in controls (n = 3). Palmitate-induced resistant cells demonstrated
a 40% inhibition in maximal insulin responsiveness with little change
in insulin sensitivity. Insulin binding is only slightly decreased (8%) in
palmitate-pretreated cells. These studies indicate that saturated fatty
acids stimulate glucose transport acutely and on prolonged exposure
induce insulin resistance via a post-insulin binding defect. The
underlying molecular mechanisms of insulin resistance induced by
prolonged treatment with saturated fatty acids may now be
investigated using this unique cellular model.