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 humans and rodents remain normoglycemic because of compensatory hyperinsulinemia. This has been attributed to beta-cell hyperplasia and increased low Km glucose metabolism of islets. Since free fatty acids (FFA) can induce these same beta-cell changes in normal islets of Wistar rats and since plasma FFA are increased in obesity, FFA could be the signal from adipocytes that elicits beta-cell compensation sufficient to prevent diabetes. To determine if FFA-induced compensation is impaired in islets of rats with a diabetogenic mutation, the Zucker diabetic fatty (ZDF) rat, we cultured islets from 6-week-old obese (fa/fa) rats that had compensated for obesity and apparently normal islets from lean ZDF rats (fa/+) in 0, 1, or 2 mM FFA. Low Km glucose usage rose 2.5-fold in FFA-cultured control islets from age-matched Wistar rats, but failed to rise in either the precompensated islets of ZDF rats or in islets of lean ZDF rats. Bromodeoxyuridine incorporation increased 3.2-fold in Wistar islets but not in islets from obese or lean ZDF rats. Insulin secretion doubled in normal islets cultured in 2 mM FFA (p < 0.01) but increased only slightly in islets from lean ZDF rats (not significant) and declined in islets from obese ZDF rats (p < 0.05). We conclude that, unlike the islets of age-matched Wistar rats, islets of 6-week-old heterozygous and homozygous ZDF rats lack the capacity for FFA-induced enhancement of beta-cell function.
Hirose
H
H
Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75235, USA.
Lee
Y H
YH
Inman
L R
LR
Nagasawa
Y
Y
Johnson
J H
JH
Unger
R H
RH
D000818:Animals; D001973:Bromodeoxyuridine; D002470:Cell Survival; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D006946:Hyperinsulinism / Q000503:physiopathology; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009765:Obesity; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D012016:Reference Values; D012727:Sex Characteristics; D012737:Sex Factors; D013045:Species Specificity; D013997:Time Factors
D005230:Fatty Acids, Nonesterified; D001973:Bromodeoxyuridine; D005947:Glucose