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Lipid-induced beta-cell dysfunction in vivo in models of progressive beta-cell failure.

Abstract
We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive beta-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of beta-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in beta-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired beta-cell function. In conclusion, 1) the FFA-induced impairment in beta-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the beta-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing.
AuthorsTracy T Goh, Timothy M Mason, Neehar Gupta, Abby So, Tony K T Lam, Loretta Lam, Gary F Lewis, Andrea Mari, Adria Giacca
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 292 Issue 2 Pg. E549-60 (Feb 2007) ISSN: 0193-1849 [Print] United States
PMID17003242 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • Lipids
Topics
  • Animals
  • Blood Glucose (analysis)
  • Body Weight
  • Disease Models, Animal
  • Fatty Acids, Nonesterified (blood)
  • Female
  • Glucose Clamp Technique
  • Hyperglycemia (etiology)
  • Insulin (blood)
  • Insulin Resistance
  • Insulin-Secreting Cells (drug effects, pathology)
  • Lipids (blood, pharmacology)
  • Pancreatic Diseases (blood, etiology, physiopathology)
  • Rats
  • Rats, Wistar
  • Rats, Zucker

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