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J Biol Chem, Vol. 273, Issue 6, 3547-3550, February 6, 1998
§,§,§, and§
From the The thiazolidinedione compound troglitazone,
which is used to treat non-insulin-dependent diabetes
mellitus (NIDDM) in man, is also effective in the adipogenic NIDDM of
Zucker diabetic fatty (ZDF) rats. To test the "lipotoxicity
hypothesis," which attributes the beta cell dysfunction of adipogenic
NIDDM to an excessive accumulation of fat in the pancreatic islets, we
sought to determine if troglitazone-mediated amelioration of beta cell
function in islets of ZDF rats might be associated with a reduction in
their elevated triglyceride (TG) content. Troglitazone (10 µM) in the culture medium reduced the TG content of
ZDF rats by 52%; this was reflected by decreased esterification and
increased oxidation of [3H]palmitate.
Glycerol-3-phosphate acyltransferase mRNA fell by 57% and
acyl-CoA synthetase mRNA by 67% (brain isoform) and 38% (liver
isoform), all consistent with the effects of troglitazone on TG
metabolism. The 52% decrease in islet TG was accompanied by >30- and
2-fold improvements in glucose- and arginine-stimulated insulin
secretion, respectively. We conclude that troglitazone exerts direct
lipopenic activity in normal islets and in islets of obese
prediabetic ZDF rats; in the latter, this correlated with improvement
in beta cell function. The results are consistent with the lipotoxicity
hypothesis for adipogenic diabetes.
Gifford Laboratories, Center for Diabetes
Research and the Department of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75235 and the
§ Veterans Affairs Medical Center, Dallas, Texas 75216
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