In Vitro Insulin Resistance Model: A Recent Update

Abstract

Insulin resistance, which affects insulin-sensitive tissues, including adipose tissues, skeletal muscle, and the liver, is the central pathophysiological mechanism underlying type 2 diabetes progression. Decreased glucose uptake in insulin-sensitive tissues disrupts insulin signaling pathways, particularly the PI3K/Akt pathway. An in vitro model is appropriate for studying the cellular and molecular mechanisms underlying insulin resistance because it is easy to maintain and the results can be easily reproduced. The application of cell-based models for exploring the pathogenesis of diabetes and insulin resistance as well as for developing drugs for these conditions is well known. However, a comprehensive review of in vitro insulin resistance models is lacking. Therefore, this review was conducted to provide a comprehensive overview and summary of the latest in vitro insulin resistance models, particularly 3T3-L1 (preadipocyte), C2C12 (skeletal muscle), and HepG2 (liver) cell lines induced with palmitic acid, high glucose, or chronic exposure to insulin.

Figure 1

The insulin signaling pathway in adipocytes (mature 3T3-L1 cell lines). Insulin binds to the insulin receptor (IR) and activates the downstream molecules, including IRS1/2, PI3-kinase (PI3K), and Akt. The activated-Akt phosphorylates AS160 and inhibits its activation in stabilizing GLUT4, followed by GLUT4 translocation. It also enhances lipogenesis and adipogenesis via sterol regulatory element binding protein 1c (SREBP-1c) and PPARγ related to mTORC1 activation. Moreover, the activated- Akt inhibits lipolysis by suppressing hormone-specific lipase (HSL).

Figure 2

The insulin signaling pathway in skeletal muscles (C2C12 cell lines). The PI3K/Akt activation in skeletal muscle is triggered by insulin binding to its receptor. Activated Akt will promote glucose uptake as well as glycogen synthesis through the inhibition of GSK-3β and AS160, respectively.

Figure 3

The insulin signaling pathway in hepatocytes (HepG2 cell lines). Insulin binds to the insulin receptor (IR) and activates the downstream molecules, including IRS1/2, PI3-kinase (PI3K), and Akt. The activated Akt will inhibit GSK-3β and allow glycogen synthase (GS) to be in an active state to facilitate glycogen synthesis. It also suppresses the transcriptional activity of FOXO1, which will downregulate PEPCK and reduce hepatic glucose production. Insulin enhances de novo lipogenesis via sterol regulatory element binding protein 1c (SREBP-1c) to produce triacylglycerol (TAG).