Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria

Abstract

Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The association between mitochondrial changes and insulin resistance is well known. More recently, there is growing evidence of a relationship between inflammation, extracellular remodeling, and insulin resistance. The intent of this review is to propose a potentially novel mechanism for the development of insulin resistance, focusing on the underappreciated connections among inflammation, extracellular remodeling, cytoskeletal interactions, mitochondrial function, and insulin resistance in human skeletal muscle. Several sources of inflammation, including expansion of adipose tissue resulting in increased lipolysis and alterations in pro- and anti-inflammatory cytokines, contribute to the insulin resistance observed in obesity and type 2 diabetes. In the experimental model of lipid oversupply, an inflammatory response in skeletal muscle leads to altered expression extracellular matrix-related genes as well as nuclear encoded mitochondrial genes. A similar pattern also is observed in "naturally" occurring insulin resistance in muscle of obese nondiabetic individuals and patients with type 2 diabetes mellitus. More recently, alterations in proteins (including α-actinin-2, desmin, proteasomes, and chaperones) involved in muscle structure and function have been observed in insulin-resistant muscle. Some of these cytoskeletal proteins are mechanosignal transducers that allow muscle fibers to sense contractile activity and respond appropriately. The ensuing alterations in expression of genes coding for mitochondrial proteins and cytoskeletal proteins may contribute to the mitochondrial changes observed in insulin-resistant muscle. These changes in turn may lead to a reduction in fat oxidation and an increase in intramyocellular lipid, which contributes to the defects in insulin signaling in insulin resistance.

Lipid Overload: Trigger or Consequence of Mitochondrial Oxidative Stress in Ventilator-induced Diaphragmatic Dysfunction?

“…In other models of lipid overload (e.g., models of insulin resistance in skeletal muscle), it has been postulated that mitochondrial abnormalities lead to the accumulation of ectopic lipids (9), in contrast to the hypothesis presented by Picard and coworkers, in which lipid accumulation seems to precede mitochondrial dysfunction in the animal model. Further limitations of the study include the lack of information with respect to body composition, the presence of metabolic syndrome, and the mode of mechanical ventilation.…”

“…Over several years just prior to the 2008 Olympics, epidemiological studies reported that patterns of associations between fine particulate air pollution and cause-specific mortality were consistent with the hypothesis that air pollution exposure contributes to pulmonary and systemic oxidative stress, inflammation, and associated increased risk of atherosclerosis and ischemic cardiovascular and obstructive pulmonary diseases (2, 7). Recent reviews of the expanding literature (8) and emerging evidence from the Multi-Ethnic Study of Atherosclerosis (9) suggest that there are likely multiple, complex, interdependent mechanistic pathways linking air pollution to cardiopulmonary disease, but also provide growing evidence that pulmonary and systemic oxidative stress and inflammation play important roles.…”

Air Pollution and Insulin Resistance: Do All Roads Lead to Rome?

“…A variety of extracellular and intracellular biological components has been implicated in impairment of insulin signaling. These include free fatty acids (15), branched-chain amino acids (16), steroid and stress hormones (17), cytokines (18), diacylglycerol, ceramides (15), and intracellular free radicals derived from mitochondria (19). Although many studies have supported the contribution of oxidatively modified biological molecules, nonoxidized metabolites have also been implicated in insulin resistance (15,20).…”

Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood

“…1 Individuals with obesity show chronic low-grade inflammation. 2,3 The expansion of white adipose tissue in obesity has been associated with increased proinflammatory cytokines, such as tumor necrosis factor-a (TNFa) and interleukin 6 (IL-6). 2 These inflammatory cytokines circulate in the blood and can have negative effects on peripheral inulin responsive tissues, such as skeletal muscle and liver.…”