Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk
Christoph Handschin, … , Gerald I. Shulman, Bruce M. Spiegelman
Christoph Handschin, … , Gerald I. Shulman, Bruce M. Spiegelman
Published October 11, 2007
Citation Information: J Clin Invest. 2007;117(11):3463-3474. https://doi.org/10.1172/JCI31785.
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Research Article Metabolism

Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk

Abstract

The transcriptional coactivator PPARγ coactivator 1α (PGC-1α) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1α 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-1α expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle–specific PGC-1α knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic β 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-1α in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.

Authors

Christoph Handschin, Cheol Soo Choi, Sherry Chin, Sheene Kim, Dan Kawamori, Amarnath J. Kurpad, Nicole Neubauer, Jiang Hu, Vamsi K. Mootha, Young-Bum Kim, Rohit N. Kulkarni, Gerald I. Shulman, Bruce M. Spiegelman

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Figure 6

Islet morphology, insulin content, and glucose-stimulated insulin secretion.

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Islet morphology, insulin content, and glucose-stimulated insulin secret...
(A) Fixed pancreatic sections were immunostained for insulin (blue), glucagon (red), and somatostatin (green). Islets pictured are representative of control mice and MKOs shown at the same scale (original magnification, ×40). Scale bars: 50 μM. (B) Quantitative analysis of β cell and non–β cell mass. Mass was measured by quantifying islets sections stained with markers for the different islet cell types. (C) β-Catenin staining of islet sections. Islet sections were stained with antibodies against insulin (red) and β-catenin (green) as well as DAPI (blue) to visualize nuclei. Original magnification, ×100. (D) Quantification of β cell size. The cellular area outlined by cell membrane stained for β-catenin was measured as the size of individual cells. (E) Insulin content of isolated islets was determined and normalized to the amount of DNA. (F) Insulin secretion normalized to the amount of DNA from isolated islets was determined under low-glucose (3.3 mM) and high-glucose (16.7 mM) conditions. Values are mean ± SEM. *P < 0.05, MKO versus control.