Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role ofPGC1andNRF1

Abstract

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic ␤ cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR␥ coactivator 1-␣ and-␤ (PGC1-␣͞PPARGC1 and PGC1-␤͞PERC), coactivators of NRF-1 and PPAR␥-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.I nsulin resistance precedes and predicts the development of type 2 diabetes mellitus (DM) (1, 2). Defects in insulin signal transduction, gene expression, and muscle glycogen synthesis, and accumulation of intramyocellular triglycerides have all been identified as potential mediators of insulin resistance in high-risk individuals (1, 3-7). However, the molecular pathogenesis of DM remains unknown. Mouse data highlight the importance of glucose uptake into muscle but suggest a role for novel mechanisms, distinct from insulin signaling pathways (8). The importance of genetic risk factors is exemplified by the high concordance of DM in identical twins, the strong influence of family history and ethnicity on risk, and the identification of DNA sequence alterations in both rare and common forms of DM (9). Environmental factors, including obesity, inactivity, and aging, also play critical roles in DM risk. Because both genotype and environment converge to influence cellular function via gene and protein expression, we hypothesize that alterations in expression define a phenotype that parallels the metabolic evolution of DM and provides potential clues to pathogenesis. We used high-density oligonucleotide arrays to identify genes differentially expressed in skeletal muscle from nondiabetic and type 2 diabetic subjects. Because hyperglycemia per se can modulate expression, we also evaluated gene expression in insulin-resistant subjects at high risk for DM (''prediabetes'') on the basis of family history of DM and Mexican-American ethnicity (10). We demonstrate that prediabetic and diabetic muscle is characterized by decreased expressi...

T3-mediated gene expression is independent of PGC-1α

“…Consistent with this observation, we detected reduced expression levels of mitochondrial biogenesis marker genes cytochrome c, cytochrome c oxidase and mitochondrial transcription factor A 270 ( Figure 2C, and not shown). Moreover, investigations in non-diabetic but insulin resistant patients detected reduced expression rates of PGC-1α in muscle, correlating with reduced expression rates of mitochondria-associated genes (Mootha et al, 2003;Patti et al, 2003).…”

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

“…Heilbronn et al (13) have demonstrated that different biomarkers of mitochondrial biogenesis and metabolism are reduced in overweight and obese insulin-resistant subjects. Two other studies using cDNA microarrays have reported that mitochondrial metabolism in both muscle and adipocytes is disturbed in subjects with insulin resistance, type 2 diabetes and even in subjects with family history for diabetes (28,32). Both trials found a decrease in the expression of a subset of genes involved in mitochondrial oxidative metabolism, suggesting that impaired regulation of mitochondrial function could be an important mechanism linked to obesity and the metabolic syndrome.…”

Increased susceptibility to oxidative damage in post-diabetic human myotubes

“…Glycogen deficit may therefore be an early marker of dysfunctional metabolism in muscle of individuals prone to obesity-associated diabetes or perhaps an imprint left in the satellite cells of individuals who have had type 2 diabetes, despite reversal of clinical symptoms of the disease via weight loss. It has been previously shown that genes involved in oxidative metabolism and mitochondrial biogenesis are downregulated in skeletal muscle of individuals with type 2 diabetes, in individuals who are insulin-resistant and in healthy offspring of type 2 diabetes patients [16]. Functional impairment of skeletal muscle mitochondria has also been shown in these populations [18,44].…”

“…These may thus be diverted from the tricarboxylic acid cycle into other lipid metabolites such as ceramides, diacylglycerol and/or acylcarnitines, which in turn can interfere with the insulin signalling pathway [10,11], as discussed in reviews [12][13][14]. Indeed, decreased mitochondrial content and impaired oxidative capacity are correlated with insulin resistance and associated with obesity [15][16][17][18], but effects can be mitigated by weight loss and physical activity [19,20].…”