Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM.

The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1␣. Overexpression of PGC-1␣ rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1␣ expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone upregulates PGC-1␣ in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1␣ and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1␣. Moreover, PGC-1␣ is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.Understanding the pathophysiology initiating the development of insulin resistance should augment our capacity to identify novel therapeutic targets for the prevention and treatment of type 2 diabetes. This biology remains incompletely characterized in part due to the complexity of the interaction of multiple organ systems and the multiplicity of intracellular perturbations within these organs governing the development of insulin resistance. The major peripheral organ systems implicated in insulin resistance include skeletal muscle, adipose tissue, liver, and the immune system. The enhancement of our understanding of this biology will require the combination of reductionist and systems biological approaches.The complexity of the effects of insulin resistance in a single organ is exemplified in skeletal muscle where disruption in glucose uptake (1), insulin signaling (2, 3), glycogen synthesis (4) and in mitochondrial biology (5-7) are evident in insulin-resistant subjects up to two decades before their developing diabetes. A fundamental question arising is whether disruption of skeletal muscle mitochondria is a primary component in this disease pathophysiology or whether it is a consequence of reduced aerobic activity in response to alternate metabolic perturbations associated with insulin resistance and diabetes (8). Although this question has not been definitively answered, increasing mitocho...

Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-B⌬KC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP-but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-B⌬KC expression selectively reduced NPR-B but not NPR-A signaling. NPR-B⌬KC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.C-type natriuretic peptide ͉ knockdown