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.
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Authors | Tracy T Goh, Timothy M Mason, Neehar Gupta, Abby So, Tony K T Lam, Loretta Lam, Gary F Lewis, Andrea Mari, Adria Giacca |
Journal | American 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 |
PMID | 17003242
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Blood Glucose
- Fatty Acids, Nonesterified
- Insulin
- Lipids
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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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