The cell biology of systemic insulin function

Abstract

Insulin is the paramount anabolic hormone, promoting carbon energy deposition in the body. Its synthesis, quality control, delivery, and action are exquisitely regulated by highly orchestrated intracellular mechanisms in different organs or "stations" of its bodily journey. In this Beyond the Cell review, we focus on these five stages of the journey of insulin through the body and the captivating cell biology that underlies the interaction of insulin with each organ. We first analyze insulin's biosynthesis in and export from the β-cells of the pancreas. Next, we focus on its first pass and partial clearance in the liver with its temporality and periodicity linked to secretion. Continuing the journey, we briefly describe insulin's action on the blood vasculature and its still-debated mechanisms of exit from the capillary beds. Once in the parenchymal interstitium of muscle and adipose tissue, insulin promotes glucose uptake into myofibers and adipocytes, and we elaborate on the intricate signaling and vesicle traffic mechanisms that underlie this fundamental function. Finally, we touch upon the renal degradation of insulin to end its action. Cellular discernment of insulin's availability and action should prove critical to understanding its pivotal physiological functions and how their failure leads to diabetes.

Circulating Spexin Decreased and Negatively Correlated with Systemic Insulin Sensitivity and Pancreatic β Cell Function in Obese Children

“…Nevertheless, Sassek et al [28] reported that insulin secretion from cultured cells and isolated islets was reduced by SPX, and insulin secretion decreased after injection with SPX in obese rats. These results suggest that SPX may suppress over-secretion of insulin, which in turn may contribute to the improvement of insulin sensitivity [29].…”

The insulin‐PI3K‐Rac1 axis contributes to terminal adipocyte differentiation through regulation of actin cytoskeleton dynamics

“…Arp2/3 is thought to act downstream of Rac1 (Chauhan, Lou, Zheng, & Lang, ; Ridley, ). Insulin‐induced activation of Rac1 in muscle cells was found to result in dynamic actin remodeling with the formation of cortical F‐actin structures that was mediated by Arp2/3‐dependent branching of F‐actin and led to the translocation of the glucose transporter GLUT4 (encoded by Slc2a4 ) from the cytoplasm to the plasma membrane (Chiu, Patel, Shaw, Bamburg, & Klip, ; Tokarz, MacDonald, & Klip, ). Arp2/3 has been also found to regulate adipocyte differentiation through control of the formation of cortical F‐actin structures in 3T3‐L1 preadipocytes (Yang et al, ).…”

Rac1 supports muscle glucose uptake independently of Akt

“…Furthermore, downstream of PI3K, and in parallel with Akt activation, PI3K also phosphorylates/activates the Rho‐family GTPase Rac1, which promotes GLUT4 translocation by initiating cortical actin filaments remodelling (Tokarz et al . ). Rac1 plays an important role in the reorganization of the actin cytoskeleton and is also essential for insulin‐stimulated glucose transport.…”

“…This reorganization of the cytoskeleton allows for the translocation of GLUT4 transporters to the plasma membrane, which increases glucose uptake into the cell (Tokarz et al . ). However, it is important to state, that this has not been shown in vivo (Madsen et al .…”

“…Insulin-stimulated glucose uptake in skeletal muscle is achieved by increased translocation of intracellular stored GLUT4 glucose transporters to the plasma membrane through the phosphatidylinositol-3 kinase (PI3K) and Akt signalling pathway (Tokarz et al 2018). Furthermore, downstream of PI3K, and in parallel with Akt activation, PI3K also phosphorylates/activates the Rho-family GTPase Rac1, which promotes GLUT4 translocation by initiating cortical actin filaments remodelling (Tokarz et al 2018). Rac1 plays an important role in the reorganization of the actin cytoskeleton and is also essential for insulin-stimulated glucose transport.…”