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.

Fig. 1.

The distribution of the M values (mg·kg⁻¹·min⁻¹), measured by insulin-stimulated glucose disposal during the euglycemic clamp in 45 normal, glucose-tolerant, healthy subjects. Data were obtained during an 80 mU·m⁻²·min⁻¹ insulin infusion and were taken from unpublished (Mandarino LJ) and published (14, 23, 32) sources.

Fig. 2.

Sources of inflammation associated with insulin resistance in skeletal muscle. IRS-1, insulin receptor substrate-1.

Fig. 3.

mRNA expression levels from 7 subjects for collagens (COL), lumican (LUM), fibronectin (FN1), and connective tissue growth factor (CTGF) following a 48-h lipid infusion in normal, glucose-tolerant, healthy subjects normalized to 18S ribosomal RNA and shown as means ± SE of fold increase compared with a 48-h saline infusion in the same participants. *P < 0.05, lipid infusion vs. saline. Data are redrawn from Richardson et al. (49).

Fig. 4.

A: hydroxyproline content of acid hydrolysates of biopsies of vastus lateralis muscle from lean (n = 10), obese (n = 10), and diabetic (n = 10) subjects. Data are shown as means ± SE. *P < 0.05 vs. lean control values. Data are redrawn from Berria et al. (4). B: immunofluorescence staining of 5-μm sections of biopsies of vastus lateralis muscle from lean, obese, and diabetic subjects for types I (top) and III (bottom) collagen. Data are redrawn from Berria et al. (4).

Fig. 5.

Proposed model of the relationships among inflammation, changes in the extracellular matrix, cytoskeletal elements and mechanosignal transduction, and mitochondrial function in insulin-resistant muscle.