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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-1368

Handschin, C; Choi, C S; Chin, S; Kim, S; Kawamori, D; Kurpad, A J; Neubauer, N; Hu, J; Mootha, V K; Kim, Y B; Kulkarni, R N; Shulman, G I; Spiegelman, B M (2007). Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. Journal of Clinical Investigation, 117(11):3463-3474.

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Abstract

The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1alpha and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1alpha expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1alpha knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic beta cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.

Item Type:Journal Article, refereed
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
Language:English
Date:November 2007
Deposited On:11 Feb 2008 12:22
Last Modified:27 Nov 2013 20:06
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
Publisher DOI:10.1172/JCI31785
PubMed ID:17932564
Citations:Web of Science®. Times Cited: 137
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