Abstract
To determine if underleptinization of islets of Zucker diabetic fatty (ZDF) rats is the proximal cause of their inability to compensate for obesity, we compared the proinsulin/beta-actin mRNA ratio in heterozygous (fa/+) ZDF rats with that of wild-type (+/+) and homozygous (fa/fa) ZDF rats. In +/+ islets cultured with 2 mM free fatty acids (FFA) the proinsulin mRNA ratio rose 2.4-fold at 12 h. In fa/+ islets, the ratio rose only 65% above normal. There was no change in fa/fa islets. The presence of leptin (20 ng/ml) in the culture medium increased the FFA-induced response of proinsulin mRNA of fa/+ islets to that of +/+ islets while reducing FFA incorporation into triglycerides. The leptin-induced improvement in the proinsulin mRNA response was independent of any changes in glucose usage. These findings support a causal relationship between diminished leptin action on islets and the impaired beta-cell response to FFA in ZDF rats.
Highlights
To determine if underleptinization of islets of Zucker diabetic fatty (ZDF) rats is the proximal cause of their inability to compensate for obesity, we compared the proinsulin/-actin mRNA ratio in heterozygous ZDF rats with that of wild-type (؉/؉) and homozygous ZDF rats
We compared the effect of leptin upon free fatty acids (FFA)-induced up-regulation of proinsulin mRNA in islets of lean wild-type ZDF rats (ϩ/ϩ), of obese prediabetic ZDF rats, which are homozygous for the mutation in the leptin receptor, and of lean heterozygous ZDF rats
We determined if the failure of islets of ZDF rats to increase insulin production in response to FFA was associated with impairment of the response of the proinsulin mRNA/-actin mRNA ratio
Summary
Vol 272, No 41, Issue of October 10, pp. 25648 –25651, 1997 Printed in U.S.A. Leptin Normalizes the Impaired Response of Proinsulin mRNA to Long Chain Fatty Acids in Heterozygous Zucker Diabetic Fatty Rats*. The leptin-induced improvement in the proinsulin mRNA response was independent of any changes in glucose usage These findings support a causal relationship between diminished leptin action on islets and the impaired -cell response to FFA in ZDF rats. In leptin-resistant obese Zucker diabetic fatty (ZDF) rats with defective leptin receptors (5, 6), there is a marked increase in the triglyceride (TG) content in islets during the developement of the -cell defects of adipo-. “underleptinization” might be the proximal cause of the -cell dysfunction that results in the noninsulin-dependent diabetes mellitus of ZDF rats To test this hypothesis, we compared the effect of leptin upon FFA-induced up-regulation of proinsulin mRNA in islets of lean wild-type ZDF rats (ϩ/ϩ), of obese prediabetic ZDF rats, which are homozygous for the mutation in the leptin receptor (fa/fa), and of lean heterozygous ZDF rats (fa/ϩ).
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