Liver adapts mitochondrial function to insulin resistant and diabetic states in mice

J Hepatol. 2014 Apr;60(4):816-23. doi: 10.1016/j.jhep.2013.11.020. Epub 2013 Nov 28.


Background & aims: To determine if diabetic and insulin-resistant states cause mitochondrial dysfunction in liver or if there is long term adaptation of mitochondrial function to these states, mice were (i) fed with a high-fat diet to induce obesity and T2D (HFD), (ii) had a genetic defect in insulin signaling causing whole body insulin resistance, but not full blown T2D (IR/IRS-1(+/-) mice), or (iii) were analyzed after treatment with streptozocin (STZ) to induce a T1D-like state.

Methods: Hepatic lipid levels were measured by thin layer chromatography. Mitochondrial respiratory chain (RC) levels and function were determined by Western blot, spectrophotometric, oxygen consumption and proton motive force analysis. Gene expression was analyzed by real-time PCR and microarray.

Results: HFD caused insulin resistance and hepatic lipid accumulation, but RC was largely unchanged. Livers from insulin resistant IR/IRS-1(+/-) mice had normal lipid contents and a normal RC, but mitochondria were less well coupled. Livers from severely hyperglycemic and hypoinsulinemic STZ mice had massively depleted lipid levels, but RC abundance was unchanged. However, liver mitochondria isolated from these animals showed increased abundance and activity of the RC, which was better coupled.

Conclusions: Insulin resistance, induced either by obesity or genetic manipulation and steatosis do not cause mitochondrial dysfunction in mouse liver. Also, mitochondrial dysfunction is not a prerequisite for liver steatosis. However, severe insulin deficiency and high blood glucose levels lead to an enhanced performance and better coupling of the RC. This may represent an adaptation to fuel overload and the high energy-requirement of an unsuppressed gluconeogenesis.

Keywords: Insulin receptor; Liver metabolism; Mitochondrial biogenesis; Mitochondrial gene expression; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Animals
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Diet, High-Fat / adverse effects
  • Fatty Liver / etiology
  • Fatty Liver / physiopathology
  • Gene Expression
  • Insulin Receptor Substrate Proteins / deficiency
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / physiology*
  • Ion Channels / metabolism
  • Liver / metabolism
  • Liver / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Liver / physiology*
  • Mitochondrial ADP, ATP Translocases / metabolism
  • Mitochondrial Proteins / metabolism
  • Obesity / etiology
  • Obesity / physiopathology
  • Oxidative Phosphorylation
  • Proton-Motive Force
  • Receptor, Insulin / deficiency
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Signal Transduction
  • Uncoupling Protein 2


  • Insulin Receptor Substrate Proteins
  • Ion Channels
  • Irs1 protein, mouse
  • Mitochondrial Proteins
  • Uncoupling Protein 2
  • Mitochondrial ADP, ATP Translocases
  • Receptor, Insulin