Insulin resistance is a complex metabolic defect that most likely has several etiologies dependent on the pathophysiologic state. In humans, there is a genetic component to decreased insulin sensitivity in patients with T2DM and it has been suggested that inherited defects in mitochondrial function with a decreased capacity to oxidize fatty acids is a contributory factor [64
]. In addition, obesity is a major cause of insulin resistance in T2DM and recent information demonstrates that chronic, low-grade inflammation associated with obesity is an important etiologic mechanism in decreasing insulin signaling. In this regard, inflammation causes cell-autonomous insulin resistance in muscle, liver and adipose cells and activated tissue macrophages can underlie tissue-autonomous inflammatory processes. What remains to be defined, however, is the sequence of events by which obesity initiates this cascade, and which tissue(s) are the primary effectors in this process versus those that are secondarily involved. Based on the evidence summarized in this review, we highlight a process of gradual progression to insulin resistance in obese states. In this model, obesity causes excessive growth of adipose depots with adipocyte hypertrophy and hyperplasia. This fat overload results in the activation of stress/inflammatory pathways and subsequent paracrine/autocrine-mediated cellular insulin resistance. This in turn increases adipocyte FFA release which stimulates resident macrophages and adipocytes, at least partly through Toll-like receptors, causing increased expression of Tnf
and other pro-inflammatory cytokines. Additionally, these hypertrophied unstable adipocytes eventually die and release their lipid content causing additional migration of macrophages to clear dead or dying adipocytes. The resulting internal environment of this adipose tissue is lipotoxic and pro-inflammatory, favoring the M2 to M1 conversion of resident macrophages or of newly recruited Ly-6Chi
“inflammation-primed” monocytes. All of these events culminate in adipose tissue inflammation and insulin resistance. This can be envisioned as a two step process in which the inflammatory pathway is activated in a tissue resident macrophage which leads to paracrine activation of inflammatory pathway components in neighboring insulin target cells, causing impaired insulin signaling. The resulting efflux of FFA and increased secretion of cytokines can lead to secondary insulin resistance in other tissues.
In addition to inflammation and insulin resistance within adipose tissue, the same process most likely occurs in the liver. Thus, the liver contains a large pool of tissue-resident macrophages, (i.e. Kupffer cells) and disabling the inflammatory pathway within these cells prevents hepatic insulin resistance [65
]. There may be similarities in the triggers for hepatic inflammation, since increased lipid content and steatosis are common findings in insulin resistant states. Such inflammation in the liver, besides causing localized insulin resistance, would also contribute to systemic inflammation and secondary insulin resistance in other tissues, such as skeletal muscle.
Although chronic inflammation can cause skeletal muscle insulin resistance, the precise sequence and the connections between inflammation and decreased insulin signaling in myocytes remains poorly elucidated. It is possible that increased circulating FFAs or altered cytokine/adipokine levels cause secondary insulin resistance in muscle. Extramyocellular adipose deposits could also contribute to this process in a paracrine fashion. Finally, increased macrophage content has been reported in insulin resistant muscle, raising the possibility of macrophage-mediated tissue autonomous insulin resistance, as in liver and fat [66
]. Of course, these possibilities are not mutually exclusive.
Clearly, much progress has been made in this area in recent years, and it is now clear that chronic low-grade tissue inflammation is an important contributor to the etiology of obesity and high fat diet-induced insulin resistance. Resident tissue macrophages play a key role in orchestrating this tissue inflammatory response, and future studies will undoubtedly shed much light on the underlying mechanisms.