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-Reference-Cited by-同舟云学术

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:2013-01-01 Issue:1 Volume:154 Page:89-101
ISSN:0013-7227
Container-title:Endocrinology
language:en
Short-container-title:

Author:

Tang Christine¹,Naassan Anthony E.¹,Chamson-Reig Astrid²³,Koulajian Khajag¹,Goh Tracy T.¹,Yoon Frederick¹,Oprescu Andrei I.⁴,Ghanim Husam⁵,Lewis Gary F.¹⁶,Dandona Paresh⁵,Donath Marc Y.⁷⁸,Ehses Jan A.⁹,Arany Edith²³,Giacca Adria⁶⁴

Affiliation:

1. Departments of Physiology (C.T., A.E.N., K.K., T.T.G., F.Y., G.F.L., A.G.), University of Toronto, Toronto, Ontario, Canada M5S 1A8

2. Department of Medicine and Pathology (A.C.-R., E.A.), University of Western Ontario, London, Ontario, Canada N6A 5C1

3. Lawson Health Research Institute (A.C.-R., E.A.), University of Western Ontario, London, Ontario, Canada N6C 2R5

4. Institute of Medical Sciences (A.I.O., A.G.), University of Toronto, Toronto, Ontario, Canada M5S 1A8

5. Division of Endocrinology, Diabetes, and Metabolism (H.G., P.D.), State University of New York at Buffalo, Kaleida Health, Buffalo, New York 14221

6. Medicine (G.F.L., A.G.), University of Toronto, Toronto, Ontario, Canada M5S 1A8

7. Division of Endocrinology, Diabetes, and Nutrition (M.Y.D.), University Hospital Zurich, University of Zurich, Zurich, Switzerland 8091

8. Center for Integrative Human Physiology (M.Y.D.), University of Zurich, Zurich, Switzerland 8006

9. Department of Surgery (J.A.E.) and Child and Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4

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.

Publisher

The Endocrine Society

Subject

Endocrinology

Link

http://academic.oup.com/endo/article-pdf/154/1/89/10386270/endo0089.pdf

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