Tissue-specific differences in the development of insulin resistance in a mouse model for type 1 diabetes
- Tomas Jelenik1,#,
- Gilles Séquaris1,#,
- Kirti Kaul1,
- D. Margriet Ouwens2,3,
- Esther Phielix1,
- Jörg Kotzka2,
- Birgit Knebel2,
- Jürgen Weiß2,
- Anna Lena Reinbeck1,
- Linda Janke1,
- Peter Nowotny1,
- Hans-Joachim Partke1,2,
- Dongyan Zhang4,6,
- Gerald I. Shulman4,5,6,
- Julia Szendroedi1,7 and
- Michael Roden1,7,*
- 1 Institute for Clinical Diabetology, German Diabetes Center, 40225, Düsseldorf, Germany;
- 2 Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, 40225, Düsseldorf, Germany;
- 3 Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
- 4 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA;
- 5 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA;
- 6 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA;
- 7 Department of Endocrinology and Diabetology, Heinrich-Heine University, D-40225, Düsseldorf, Germany
- *Corresponding Author: Dr. Michael Roden, E-mail:
While insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes is gaining increasing interest more recently. In a model of type 1 diabetes, the non-obese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in liver of pre-diabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration, followed by increased production of lipid peroxides and c-jun N-terminal kinase (JNK) activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C theta (PKCθ) activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset, but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.
# Both authors contributed equally.
- Received November 24, 2013.
- Accepted June 5, 2014.
- © 2014 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.