FATTY ACID-INDUCED BETA-CELL APOPTOSIS - A LINK BETWEEN OBESITY AND DIABETES

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early beta cell compensation for insulin resistance (4-fold beta cell hyperplasi a) followed by decompensation (>50% loss of beta cells. In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is incre ased 3- and >7-fold, respectively, compared with lean ZDF controls. Ce ramide, a fatty acid-containing messenger in cytokine-induced apoptosi s, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabe tic and diabetic ZDF rats; therefore, we cultured prediabetic islets i n 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islet s, preceded by an 82% increase in ceramide. C-2-Ceramide without FFA i nduced DNA laddering, but fumonisin B-1, a ceramide synthetase inhibit or, completely blocked FFA-induced DNA laddering in cultured ZDF islet s. [H-3] Palmitate incorporation in [H-3]ceramide in ZDF islets was tw ice that of controls, but [H-3]palmitate oxidation was 77% less. Triac sin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA an d NO production, which are involved in FFA-induced apoptosis. In ZDF o besity, beta cell apoptosis is induced by increased FFA via de novo ce ramide formation and increased NO production.