title: Susceptibility to fatty acid-induced β-cell dysfunction is enhanced in prediabetic diabetes-prone biobreeding rats: a potential link between β-cell lipotoxicity and islet inflammation.
abstract: β-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, β-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on β-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased β-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced β-cell dysfunction in the BB rat, which suggests a link between β-cell lipotoxicity and islet inflammation.
authors.affiliation: Department of Physiology, University of Toronto, Room 3336, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Christine
authors.initials: C
authors.lastname: Tang
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Naassan
authors.forename: Astrid
authors.initials: A
authors.lastname: Chamson-Reig
authors.forename: Khajag
authors.initials: K
authors.lastname: Koulajian
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Goh
authors.forename: Frederick
authors.initials: F
authors.lastname: Yoon
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Oprescu
authors.forename: Husam
authors.initials: H
authors.lastname: Ghanim
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
authors.forename: Paresh
authors.initials: P
authors.lastname: Dandona
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
authors.forename: Edith
authors.initials: E
authors.lastname: Arany
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D004655:Emulsions / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D016753:Interleukin-10 / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010743:Phospholipids / Q000494:pharmacology; D011236:Prediabetic State / Q000276:immunology* / Q000378:metabolism*; D051381:Rats; D011913:Rats, Inbred BB; D060888:Real-Time Polymerase Chain Reaction; D013024:Soybean Oil / Q000494:pharmacology
chemical_list: D018932:Chemokine CCL2; D004655:Emulsions; D005227:Fatty Acids; D010743:Phospholipids; C545823:soybean oil, phospholipid emulsion; D016753:Interleukin-10; D013024:Soybean Oil