Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids

To elucidate the mechanism of the basal hyperinsulinemia of obesity, we perfused pancreata from obese Zucker and lean Wistar rats with substimulatory concentrations of glucose. Insulin secretion at 4.2 and 5.6 mM glucose was approximately 10 times that of controls, whereas beta-cell volume fraction...

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Bibliographic Details
Published in:The Journal of biological chemistry 1995-01, Vol.270 (3), p.1295
Main Authors: Milburn, Jr, J L, Hirose, H, Lee, Y H, Nagasawa, Y, Ogawa, A, Ohneda, M, BeltrandelRio, H, Newgard, C B, Johnson, J H, Unger, R H
Format: Article
Language:English
Subjects:
Animals
Bromodeoxyuridine
DNA - metabolism
Fasting
Fatty Acids - metabolism
Female
Glucose - pharmacology
Hexokinase - metabolism
Insulin - metabolism
Insulin Secretion
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
Islets of Langerhans - pathology
Male
Obesity - metabolism
Obesity - pathology
Rats
Rats, Wistar
Rats, Zucker
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Summary:To elucidate the mechanism of the basal hyperinsulinemia of obesity, we perfused pancreata from obese Zucker and lean Wistar rats with substimulatory concentrations of glucose. Insulin secretion at 4.2 and 5.6 mM glucose was approximately 10 times that of controls, whereas beta-cell volume fraction was increased only 4-fold and DNA per islet 3.5-fold. We therefore compared glucose usage at 1.4, 2.8, and 5.6 mM. Usage was 8-11.4 times greater in Zucker islets at 1.4 and 2.8 mM and 4 times greater at 5.6 mM; glucose oxidation at 2.8 and 5.6 mM glucose was > 12 times lean controls. To determine if the high free fatty acid (FFA) levels of obesity induce these abnormalities, normal Wistar islets were cultured with 0, 1, or 2 mM long chain FFA for 7 days. Compared to islets cultured without FFA insulin secretion by FFA-cultured islets (2 mM) perifused with 1.4, 3, or 5.6 mM glucose was increased more than 2-fold, bromodeoxyuridine incorporation was increased 3-fold, and glucose usage at 2.8 and 5.6 mM glucose was increased approximately 2-fold (1 mM FFA) and 3-fold (2 mM FFA). We conclude that hypersecretion of insulin by islets of obese Zucker fatty rats is associated with, and probably caused by, enhanced low Km glucose metabolism and beta-cell hyperplasia, abnormalities that can be induced in normal islets by increased FFA.
ISSN:0021-9258
DOI:10.1074/jbc.270.3.1295