Mitochondrial Dysfunction Might Underlie Type 2 Diabetes

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Increased deposition of lipids in muscle and liver is a marker of insulin resistance [10], but whether this is causal in the development of insulin resistance is less clear. More recently, it has been hypothesized that impaired mitochondrial function leads to the accumulation of lipid metabolites and alters insulin signaling [4,11,16,42]. Recent experiments have shown that insulin resistance in the elderly could be attributed to intramyocellular lipid content, which in turn is linked to a reduction in mitochondrial oxidative-phosphorylation activity [3]. The reduction in mitochondrial function and lipid accumulation in muscle can probably be ascribed to an age-related reduction in mitochondrial content caused by accumulated mutations in mtDNA, which are known to occur with aging [43]. Furthermore, recent studies have shown that a reduction in mitochondrial activity is associated with an increase in intramyocellular lipid content in young, lean, insulin-resistant offspring of parents with type 2 diabetes, a group of individuals that has a strong tendency to develop diabetes later in life [4]. Taken together, these data suggest that alterations in nuclear encoded genes that regulate mito-chondrial function and biogenesis may establish the genetic basis for inheritance of type 2 diabetes.

Mitochondria are the site of oxidative energy production in eukaryotic cells. Mitochondrial biogenesis involves the coordinated action of both nuclear and mitochondrial encoded genomes. Peroxisome proliferator-acti-vated receptor a coactivator a (PGC-1a), an inducible transcriptional coac-tivator, has been implicated as a major regulator of the mitochondrial biogenic program. PGC-1a interacts with nuclear respiratory factor 1 (NRF-1), stimulating transcription of many mitochondrial genes as well as mito-chondrial transcription factor A (TFAM), a direct regulator of mitochondrial DNA replication and transcription. A coordinated reduction of PGC-1a-responsive genes involved in oxidative phosphorylation was found in vastus lateralis muscle biopsies from non-diabetic relatives of subjects with type 2 diabetes and in subjects with overt type 2 diabetes compared with glucose-tolerant controls [16, 44]. Additional investigations have also shown reduced mitochondrial function in non-diabetic relatives of subjects with type 2 diabetes and in subjects with overt type 2 diabetes. This mitochon-drial impairment has been assessed by multiple methods including ATP phosphorylation, mitochondrial size, citrate synthase (CS) activity, rotenone-sensitive nicotinamide adenine dinucleotide:oxygen (NADH:O2) oxidore-ductase, and mitochondrial copy number [4,7,45,46]. An important question is whether mitochondrial dysfunction is an inherent property of insulin-resistant subjects or whether it is acquired and can be reversed by exercise training. Aerobic exercise training is sufficient to increase mitochondrial enzyme activity and the expression of nuclear-encoded genes involved in regulating mitochondrial transcription, including PGC-1a, NRF-1, and TFAM, in young and old lean individuals [47,48].

Most of these investigations have not evaluated training levels and have not adequately matched groups for gender and other physical characteristics that may have a substantial impact on mitochondrial metabolism. A recent study on individuals characterized by similar VO2max and body fat percentage has shown that insulin-resistant obese subjects had significantly reduced expression of PGC-1a and COX1, indicating reduced mitochondr-

ial biogenesis. Furthermore, CS activity, a marker of mitochondrial content and function, was also reduced [49]. Taken together, these data lead to the hypothesis that mitochondrial dysfunction could be causal in the development of insulin resistance.

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