Journal
DIABETES
Volume 63, Issue 11, Pages 3856-3867Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db13-1794
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Funding
- Schmutzler Stiftung
- Skroder Stiftung
- German Research Foundation [SFB575]
- German Federal Ministry of Education and Research
- Ministry of Science and Research of the State of North Rhine-Westphalia
- German Federal Ministry of Health
- U.S. Public Health Service [R01-DK-40936, P30-DK-45735]
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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 theta 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.
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