DEFECTIVE FATTY ACID-MEDIATED BETA-CELL COMPENSATION IN ZUCKER DIABETIC FATTY RATS - PATHOGENIC IMPLICATIONS FOR OBESITY-DEPENDENT DIABETES

Although obesity is associated with insulin resistance, most obese hum ans and rodents remain normoglycemic because of compensatory hyperinsu linemia, This has been attributed to beta-cell hyperplasia and increas ed low K-m glucose metabolism of islets, Since free fatty acids (FFA) can induce these same beta-cell changes in normal islets of Wistar rat s and since plasma FFA are increased in obesity, FFA could be the sign al hom adipocytes that elicits beta-cell compensation sufficient to pr event diabetes, To determine if FFA-induced compensation is impaired i n islets of rats with a diabetogenic mutation, the Zucker diabetic fat ty (ZDF) rat, we cultured islets from g-week-old obese (fa/fa) rats th at had compensated for obesity and apparently normal islets from lean ZDF rats (fa/+) in 0, 1, or 2 mM FFA. Low K-m glucose usage rose 2.5-f old in FFA-cultured control islets from age-matched Wistar rats, but f ailed to rise in either the precompensated islets of ZDF rats or in is lets of lean ZDF rats. Bromodeoxyuridine incorporation increased 3.2-f old in Wistar islets but not in islets from obese or lean ZDF rats. In sulin secretion doubled in normal islets cultured in 2 mM FFA (p < 0.0 1) but increased only slightly in islets from lean ZDF rats (not signi ficant) and declined in islets from obese ZDF rats (p < 0.05). We conc lude that, unlike the islets of age-matched Wistar rats, islets of 6-w eek-old heterozygous and homozygous ZDF rats lack the capacity for FFA -induced enhancement of beta-cell function.