Progression of type 2 diabetes in GK rats affects muscle and liver mitochondria differently: pronounced reduction of complex II flux is observed in liver only

Abstract

Impaired mitochondrial function is implicated in the development of type 2 diabetes mellitus (T2DM). This was investigated in mitochondria from skeletal muscle and liver of the Goto-Kakizaki (GK) rat, which spontaneously develops T2DM with age. The early and the manifest stage of T2DM was studied in 6- and 16-wk-old GK rats, respectively. In GK16 compared with GK6 animals, a decrease in state 3 respiration with palmitoyl carnitine (PC) as substrate was observed in muscle. Yet an increase was seen in liver. To test the complex II contribution to the state 3 respiration, succinate was added together with PC. In liver mitochondria, this resulted in an ∼50% smaller respiratory increase in the GK6 group compared with control and no respiratory increase at all in the GK16 animals. Yet no difference between groups was seen in muscle mitochondria. RCR and P/O ratio was increased (P < 0.05) in liver but unchanged in muscle in both GK groups. We observed increased lipid peroxidation and decreased Akt phosphorylation in liver with the progression of T2DM but no change in muscle. We conclude that, during the progression of T2DM in GK rats, liver mitochondria are affected earlier and/or more severely than muscle mitochondria. Succinate dehydrogenase flux in the presence of fatty acids was reduced severely in liver but not in muscle mitochondria during manifest T2DM. The observations support the notion that T2DM pathogenesis is initiated in the liver and that only later are muscle mitochondria affected.

Genetic Control of Differential Acetylation in Diabetic Rats

“…Our results are consistent with a report showing that flux through Complex II with palmitoylcarnitine substrate is reduced in GK liver, but not in GK muscle [28]. We observe lower Sirt3 transcript abundance with concomitant increased Sdh acetylation in liver, but no change of Sirt3 transcription in muscle.…”

Insulin Resistance Is Not Associated with an Impaired Mitochondrial Function in Contracting Gastrocnemius Muscle of Goto-Kakizaki Diabetic Rats In Vivo

“…Considering that ATP generation is mainly aerobic at rest [ 50 ], these findings might suggest an impaired mitochondrial ATP generation. However, neither of the results we obtained in vivo ( 31 P-MRS) or in vitro (citrate synthase activity assays) support any reduction in mitochondrial capacity, which is consistent with the unaffected mitochondrial respiration reported in isolated mitochondria from GK rat quadriceps muscle [ 51 ]. On that basis, the reduced basal PCr content would not be linked to an impaired mitochondrial function.…”

The loss of hemoglobin and myoglobin does not minimize oxidative stress in Antarctic icefishes

“…Mitochondria from the liver, in general, have a lower respiratory control ratio than those from muscle (e.g. Jørgensen et al, 2012), and mitochondria from skeletal muscle have a lower RCR than those from cardiac muscle (Park et al, 2014). Thus, high levels of oxidized macromolecules in the pectoral adductor may be driven, in part, by greater rates of mitochondrial ROS production compared with those in the liver.…”