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Diabetes. 2014 Nov;63(11):3856-67. doi: 10.2337/db13-1794. Epub 2014 Jun 10.

Tissue-specific differences in the development of insulin resistance in a mouse model for type 1 diabetes.

Author information

1
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany German Center for Diabetes Research, Partner Düsseldorf, Germany.
2
German Center for Diabetes Research, Partner Düsseldorf, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
3
German Center for Diabetes Research, Partner Düsseldorf, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
4
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany German Center for Diabetes Research, Partner Düsseldorf, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
5
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
6
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.
7
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany German Center for Diabetes Research, Partner Düsseldorf, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany Department of Endocrinology and Diabetology, Heinrich-Heine University, Düsseldorf, Germany.
8
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany German Center for Diabetes Research, Partner Düsseldorf, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany Department of Endocrinology and Diabetology, Heinrich-Heine University, Düsseldorf, Germany michael.roden@ddz.uni-duesseldorf.de.

Abstract

Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic 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 activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C θ 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.

PMID:
24917575
DOI:
10.2337/db13-1794
[Indexed for MEDLINE]
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