Abstract
BackgroundIt has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis.Methodology/Principal FindingsRats were made severely iron deficient, by means of an iron-deficient diet. Iron deficiency results in decreases of the iron containing mitochondrial respiratory chain proteins without affecting the enzymes of the fatty acid oxidation pathway. Insulin resistance was induced by feeding iron-deficient and control rats a high fat diet. Skeletal muscle insulin resistance was evaluated by measuring glucose transport activity in soleus muscle strips. Mitochondrial proteins were measured by Western blot. Iron deficiency resulted in a decrease in expression of iron containing proteins of the mitochondrial respiratory chain in muscle. Citrate synthase, a non-iron containing citrate cycle enzyme, and long chain acyl-CoA dehydrogenase (LCAD), used as a marker for the fatty acid oxidation pathway, were unaffected by the iron deficiency. Oleate oxidation by muscle homogenates was increased by high fat feeding and decreased by iron deficiency despite high fat feeding. The high fat diet caused severe insulin resistance of muscle glucose transport. Iron deficiency completely protected against the high fat diet-induced muscle insulin resistance.Conclusions/SignificanceThe results of the study argue against the hypothesis that a deficiency of the electron transport chain (ETC), and imbalance between the ETC and β-oxidation pathways, causes muscle insulin resistance.
Highlights
There has been much interest in the possibility that the insulin resistance in obese individuals and patients with type 2 diabetes is mediated by mitochondrial deficiency in skeletal muscle [1,2,3,4,5,6,7,8,9,10]
There are a number of reasons why this hypothesis is unlikely to be correct, including the fact that diabetic muscle can increase fat oxidation many-fold in response to exercise, indicating that a 30% decrease in mitochondria is not limiting for fat oxidation at rest [11]
It was found that high fat diets induce an increase in the ability of skeletal muscle to oxidize fatty acids [20,21,22], In the present study, the rate of oleate oxidation by triceps muscles was 60% higher in the high fat, normal iron, than in the low fat, normal iron control group (Fig. 3A)
Summary
There has been much interest in the possibility that the insulin resistance in obese individuals and patients with type 2 diabetes is mediated by mitochondrial deficiency in skeletal muscle [1,2,3,4,5,6,7,8,9,10]. Ritov et al [12] have proposed the new concept that insulin resistance is not due to a decrease in skeletal muscle mitochondria per se but to a selective decrease in the components of the mitochondrial electron transport chain, with no decrease in the enzymes of the mitochondrial fatty acid oxidation pathway They proposed that, because of this discrepancy, toxic products of incomplete fatty acid oxidation accumulate and mediate skeletal muscle insulin resistance [12]. It has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
