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

• Published in: Endocrinology (Philadelphia) 2013-01, Vol.154 (1), p.89-101
• Main Authors: Tang, Christine, Naassan, Anthony E, Chamson-Reig, Astrid, Koulajian, Khajag, Goh, Tracy T, Yoon, Frederick, Oprescu, Andrei I, Ghanim, Husam, Lewis, Gary F, Dandona, Paresh, Donath, Marc Y, Ehses, Jan A, Arany, Edith, Giacca, Adria
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Animals; Autoimmune diseases; Beta cells; Biological and medical sciences; Cell culture; Chemokine CCL2 - blood; Cytokines; Diabetes; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diabetes. Impaired glucose tolerance; Emulsions - pharmacology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Heparin; Immunohistochemistry; Inflammation; Insulin; Insulin resistance; Insulin secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulitis; Interleukin-10 - blood; Islets of Langerhans - drug effects; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Lipids; Medical sciences; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; mRNA; Phospholipids - pharmacology; Prediabetic State - immunology; Prediabetic State - metabolism; Rats; Rats, Inbred BB; Real-Time Polymerase Chain Reaction; Soybean Oil - pharmacology; Toxicity; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2012-1720

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.