title: 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.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Goh
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Mason
authors.forename: Neehar
authors.initials: N
authors.lastname: Gupta
authors.forename: Abby
authors.initials: A
authors.lastname: So
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
authors.forename: Loretta
authors.initials: L
authors.lastname: Lam
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology*; D008055:Lipids / Q000097:blood / Q000494:pharmacology*; D010182:Pancreatic Diseases / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008055:Lipids