IRS1-Independent Defects Define Major Nodes of Insulin Resistance

Abstract

Insulin resistance is a common disorder caused by a wide variety of physiological insults, some of which include poor diet, inflammation, anti-inflammatory steroids, hyperinsulinemia, and dyslipidemia. The common link between these diverse insults and insulin resistance is widely considered to involve impaired insulin signaling, particularly at the level of the insulin receptor substrate (IRS). To test this model, we utilized a heterologous system involving the platelet-derived growth factor (PDGF) pathway that recapitulates many aspects of insulin action independently of IRS. We comprehensively analyzed six models of insulin resistance in three experimental systems and consistently observed defects in both insulin and PDGF action despite a range of insult-specific defects within the IRS-Akt nexus. These findings indicate that while insulin resistance is associated with multiple deficiencies, the most deleterious defects and the origin of insulin resistance occur independently of IRS.

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

“…It is possible that any subtle diet-and genotypedependent effects present after 1 week cannot be detected upon the injection of a bolus of maximal insulin, as we used here. Our results are, however, in agreement with previous work showing that defects in proximal insulin signalling are only observed after several weeks of high-fat feeding and may not be the initial cause of insulin resistance, which may lie downstream of Akt [38]. We have been able to demonstrate diet-induced inhibition of insulin signalling in the liver after 16 weeks of fat feeding [9], but this was not reversed by Prkce deletion, suggesting that PKCε-independent mechanisms are more important in the maintenance of insulin resistance in the longer term.…”

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

“…Additionally, a report that palmitate induces insulin resistance without a defect in insulin-stimulated Akt phosphorylation in the soleus muscle (Alkhateeb et al, 2007) suspects a role for impairment of the insulin signaling pathway in PIIR. In particular, Cleasby et al reported that reduced IRS-1 levels in muscle did not severely impair insulin action (Cleasby et al, 2007) and Hoehn et al revealed that upstream elements of the insulin signaling cascade are not a central feature of the origin of insulin resistance (Hoehn et al, 2008). Although our data showed that palmitate treatment reduced Fig.…”

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

“…showing that only a small percentage of total Akt activation is required for a full insulin‐stimulated glucose transport response (Hoehn et al. 2008). Together these findings suggest that an early component of insulin resistance may be membrane/cytoskeletal abnormalities that exercise, possibly via AMPK stimulation, improves.…”

“…While a surprising finding that enhanced proximal insulin signaling is not a feature of the exercise effect, this corresponds well with an emerging appreciation that defects in proximal insulin signaling may not represent a major node of insulin resistance (Hoehn et al. 2008; Hoy et al. 2009).…”