The extracellular matrix and insulin resistance - PubMed (original) (raw)
Review
The extracellular matrix and insulin resistance
Ashley S Williams et al. Trends Endocrinol Metab. 2015 Jul.
Abstract
The extracellular matrix (ECM) is a highly-dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggests that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. In addition, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review addresses what is currently known about the ECM, integrins, and insulin action in the muscle, liver, and adipose tissue. Understanding how ECM remodeling and integrin signaling regulate insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes (T2D).
Keywords: extracellular matrix; glucose homeostasis; insulin resistance; integrins; liver; muscle.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Figures
Figure 1
A link between extracellular matrix remodeling and insulin resistance. A diet high in fat generates a state of chronic inflammation. This inflammatory response leads to increased ECM synthesis and decreased ECM degradation, resulting in increased deposition and remodeling of ECM. Increased levels of ECM lead to increased physical barriers for insulin and glucose transport, decreased vascular insulin delivery and decreased insulin signaling. The combination of all of these factors then culminates in insulin resistance.
Figure 2
The role of integrin α2β1 diet-induced muscle insulin resistance. In the HF-fed state, capillary density and endothelial function are impaired. This results in decreased potential for glucose and insulin transport into the interstitial space despite hyperglycemia and hyperinsulinemia. Moreover, increased ECM deposition in the interstitial space also provides a physical barrier to glucose and insulin transport to the myocyte. Insulin signaling within the myocyte is impaired and this may be attributed to increased integrin α2β1 signaling as a consequence of increased deposition of the ECM. This results in impaired Glut4 translocation and decreased glucose transport into the myocyte. In contrast, the genetic deletion of the integrin α2 subunit results in improved insulin-stimulated muscle glucose uptake.
Figure 3
The role of integrin α1β1 in diet-induced hepatic insulin resistance. In the HF-fed state, sinusoidal capillarization occurs and this, in addition to increased ECM buildup in the space of Disse, results in decreased insulin transport to the hepatocyte despite hyperinsulinemia. Protein expression of the integrin α1 subunit is increased and this leads to increased α1β1 cell signaling. Upon insulin stimulation, the combination of both insulin and integrin α1β1 signaling results in some insulin signaling and the partial suppression of hepatic glucose output. In contrast, the genetic deletion of the integrin α1 subunit results in severe hepatic insulin resistance and no insulin-mediated suppression of hepatic glucose output. This is attributed to decreased insulin signaling. It is possible that this effect is mediated by integrin α5β1, the only other known integrin expressed on the hepatocyte, however this is currently unknown.
Figure 4
Proposed model whereby integrins regulate insulin action. In the presence of insulin, integrin signaling through both integrin linked kinase (ILK) and focal adhesion kinase (FAK) promotes insulin action. Canonical insulin signaling occurs, however it is possible that other mechanisms exist whereby insulin exerts its actions within the cell. Several studies show that FAK is an important regulator of insulin action in both the muscle and liver. Less is known about ILK. However, Nck2 is an adaptor protein shared by both the insulin receptor and ILK. This suggests that there may be a physical link between the insulin receptor and integrins through Nck2 and ILK, allowing the centralization of signaling through this complex. Akt, a critical insulin signaling molecule, is a known binding partner of ILK. Additionally, integrin signaling has been shown to modulate the assembly of the cytoskeleton and this may have effects on both mitochondrial function and insulin action.
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