HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db08-0079v1 57/11/2924    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Bugger, H. Articles by Abel, E. D. PubMed PubMed Citation Articles by Bugger, H. Articles by Abel, E. D. Social Bookmarking                What's this?

Type 1 Diabetic Akita Mouse Hearts are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria that Remain Coupled Despite Increased Uncoupling Protein 3

¹Division of Endocrinology, Metabolism and Diabetes, and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112
²Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah 84112

Objective: Fatty acid (FA)-induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita).

Research Design and Methods: Cardiac function and substrate utilization was determined in isolated working hearts, and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers and proton leak kinetics in isolated mitochondria. H₂O₂ production and aconitase activity were measured in isolated mitochondria, and total ROS in heart homogenates.

Results: Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, MVO₂ was not increased and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress and despite a 2-fold increase in UCP3 content, ATP/O ratios and proton leak kinetics were unchanged, even following perfusion of Akita hearts with 1mM palmitate.

Conclusions: Insulin-deficient Akita hearts do not exhibit FA-induced mitochondrial uncoupling, indicating important differences in the basis for mitochondrial dysfunction between insulin-responsive type 1 versus insulin resistant type 2 diabetic hearts. Increased UCP3 levels do not automatically increase mitochondrial uncoupling in the heart, which supports the hypothesis that FA-induced mitochondrial uncoupling as exists in type 2 diabetic hearts requires a concomitant increase in ROS generation.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?