Abstract
Insulin resistance, altered lipid metabolism and mitochondrial dysfunction in skeletal muscle would play a major role in type 2 diabetes mellitus (T2DM) development, but the causal relationships between these events remain conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in Goto-Kakizaki (GK) rats, a non-obese T2DM model developing peripheral insulin resistant without abnormal level of plasma non-esterified fatty acids (NEFA). Wistar rats were used as controls. Mechanical performance and energy metabolism were assessed strictly non-invasively using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Compared with control group, plasma insulin and glucose were respectively lower and higher in GK rats, but plasma NEFA level was normal. In resting GK muscle, phosphocreatine content was reduced whereas glucose content and intracellular pH were both higher. However, there were not differences between both groups for basal oxidative ATP synthesis rate, citrate synthase activity, and intramyocellular contents for lipids, glycogen, ATP and ADP (an important in vivo mitochondrial regulator). During a standardized fatiguing protocol (6 min of maximal repeated isometric contractions electrically induced at a frequency of 1.7 Hz), mechanical performance and glycolytic ATP production rate were reduced in diabetic animals whereas oxidative ATP production rate, maximal mitochondrial capacity and ATP cost of contraction were not changed. These findings provide in vivo evidence that insulin resistance is not caused by an impairment of mitochondrial function in this diabetic model.
Highlights
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia leading to long-term damage, dysfunction and failure of various organs, especiallyPLOS ONE | DOI:10.1371/journal.pone.0129579 June 9, 2015Unaltered Mitochondrial Function in Goto-Kakizaki Rats pancreas, heart, skeletal muscle and blood vessels
On the basis of biochemical [14,15,16], gene expression [17, 18] and in vivo 31-phosphorus magnetic resonance spectroscopy (31P-MRS) [7, 8, 19, 20] measurements, it has been initially proposed that mitochondrial capacity reduction contributes to intramyocellular lipids (IMCL) accumulation thereby leading to insulin signaling failure and insulin resistance development
The GK model is of interest in order to address this issue given that it is a non-obese T2DM model displaying a normal non-esterified fatty acids (NEFA) plasmatic level and an insulin-resistance [28,29,30,31,32]
Summary
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia leading to long-term damage, dysfunction and failure of various organs, especiallyPLOS ONE | DOI:10.1371/journal.pone.0129579 June 9, 2015Unaltered Mitochondrial Function in Goto-Kakizaki Rats pancreas, heart, skeletal muscle and blood vessels. Lipid metabolism alteration and mitochondrial dysfunction in skeletal muscle have been implicated in the etiology of T2DM but the causal relationships with insulin resistance development are still unclear [5,6,7,8]. On the basis of biochemical [14,15,16], gene expression [17, 18] and in vivo 31-phosphorus magnetic resonance spectroscopy (31P-MRS) [7, 8, 19, 20] measurements, it has been initially proposed that mitochondrial capacity reduction contributes to IMCL accumulation thereby leading to insulin signaling failure and insulin resistance development. Mitochondrial density and structure were abnormal only in the HFHSD model but not in the KKAγ strain, thereby suggesting a direct link between the increased plasmatic NEFA level and the mitochondrial number and integrity [21]
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