Adaptations in Mitochondrial Function Parallel, but Fail to Rescue, the Transition to Severe Hyperglycemia and Hyperinsulinemia: A Study in Zucker Diabetic Fatty Rats

Abstract

Cross‐sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6‐, 12‐, and 19‐week‐old ZDF (fa/fa) and fa/+ control rats (n = 8–10 per group) using respirometry with pyruvate, glutamate, and palmitoyl‐CoA as substrates. Six‐week‐old normoglycemic–hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)‐driven state 3 and carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP)‐stimulated state uncoupled (state u) respiration on palmitoyl‐CoA were lower compared to controls (62.3 ± 9.5 vs. 119.1 ± 13.8 and 87.8 ± 13.3 vs. 141.9 ± 14.3 nmol O2/mg/min.). Pyruvate oxidation in 6‐week‐old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6‐week‐old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 ± 11.2 and 57.7 ± 9.8 nmol O2/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 ± 0.6 and 16.1 ± 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein‐3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance.

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

“…Although this seems paradoxical, acute elevations in circulating free fatty acid levels are correlated with increased mitochondrial biogenesis in glycolytic skeletal muscle, possibly due to increased lipid availability (15,21). Our results are consistent with earlier studies showing enhanced mitochondrial function (30,46) and density (47) in insulin-resistant monoge- Fig. 3.…”

Skeletal Muscle Mitochondrial Function/Dysfunction and Type 2 Diabetes

“…All these results showed how T2DM develops in line with increased intra-myocellular lipid accumulation but without a decrease in skeletal muscle mitochondrial function, again showing a clear divergence between T2DM and skeletal muscle mitochondrial function (De Feyter et al, 2008). These observations were corroborated in later studies by the same research group where mitochondrial respiratory capacity was measured by high-resolution respirometry (Lenaers et al, 2010). A similar analytical approach was also performed in mice fed with a HFD for 4 weeks (Bonnard et al, 2008) with similar results to those reported by De Feyter and coworkers (De Feyter et al, 2008), highlighting that mitochondrial dysfunction did not precede insulin resistance.…”

Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: Impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter

“…28 Similar results have been shown to occur in skeletal muscle until the development of IR. 29 However, when IR is established, the decrease in mtDNA content is a common finding, even in leukocytes. 6 Finally, despite an inability to establish a cause and effect relationship between liver DNA methylation of PPARGC1A and IR, this study has novel findings with potentially important implications.…”