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Review
. 2018 Jul 2;217(7):2273-2289.
doi: 10.1083/jcb.201802095. Epub 2018 Apr 5.

The cell biology of systemic insulin function

Victoria L Tokarz  1   2 , Patrick E MacDonald  3 , Amira Klip  4   2   5
Affiliations
Review

The cell biology of systemic insulin function

Victoria L Tokarz et al. J Cell Biol. .

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.

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Figures

Figure 1.
Figure 1.
Journey of insulin in the body. Insulin is transcribed and expressed in the β-cells of the pancreas, from whence it is exported through the portal circulation to the liver. During this first pass, over 50% of insulin is cleared by the hepatocytes in the liver. The remaining insulin exits the liver via the hepatic vein, where it follows the venous circulation to the heart. Insulin is distributed to the rest of the body through the arterial circulation. Along the arterial tree, insulin promotes vasodilation. Arterially delivered insulin exerts its metabolic actions in the liver and is further cleared (second pass). Insulin exits the circulation at the level of the microvasculature, reaching muscle and fat cells, where it stimulates GLUT4 translocation and glucose uptake. Remaining circulating insulin is delivered to and finally degraded by the kidney. This review analyzes the cellular processes at each stage of this journey. This figure was created using Servier Medical Art (available at https://smart.servier.com/).
Figure 2.
Figure 2.
Insulin biosynthesis and secretion. (A) Insulin maturation along the granule secretory pathway. Preproinsulin mRNA is transcribed from the INS gene and translated to preproinsulin peptide. As this transits through the RER and TGN, the prepropeptide is processed to its mature form and ultimately stored as hexameric insulin/Zn2+ crystals within mature secretory granules. (B) Glucose sensing and metabolic signals leading to insulin granule secretion. The release of insulin via exocytosis of secretory granules from pancreatic β-cells is controlled by a series of metabolic and electrical signals arising as a result of glucose entry through GLUTs, phosphorylation by GK, and entry into the TCA cycle. The closure of ATP-dependent K+ (KATP) channels triggers electrical events that culminate in Ca2+ entry through voltage-dependent Ca2+ channels (VDCCs), which triggers exocytosis mediated by SNARE complex proteins. The overall secretory response is modulated by numerous receptors, channels, intracellular Ca2+ stores, metabolic signals, and cytoskeletal elements. (C) Islet communication for coordinated pulsatile insulin secretion. Within an islet, β-cells communicate with each other and with glucagon-producing α-cells and somatostatin (SST)–producing δ-cells to coordinate their activity. Many putative intraislet messengers have been implicated, including ATP, Zn2+, γ-aminobutyric acid (GABA), glucagon-like peptide-1 (GLP-1), acetylcholine (ACh), and others. These, along with electrical coupling via gap junctions, are likely important for the physiological coordination of pulsatile insulin secretion.
Figure 3.
Figure 3.
Insulin clearance in the liver. (A) Insulin is delivered to the hepatic sinusoid, where it freely accesses the liver hepatocytes through the fenestrated sinusoidal endothelium. (B) Proposed mechanism for insulin degradation in hepatocytes. Insulin binds to the IR and forms a complex with CEACAM1. Prior to internalization, extracellular IDE begins to degrade receptor-bound insulin. After internalization, endosomal IDE degrades receptor-bound insulin and, once the endosome acidifies and the complex dissociates, also frees insulin. Any remaining insulin or insulin fragments progress toward lysosomes for their complete proteolytic degradation.
Figure 4.
Figure 4.
Insulin interactions with the vasculature. (A) Endothelial insulin signaling leading to vasodilation in the macrovasculature. The endothelial cell IR engages its major substrate in these cells, IRS2, leading downstream to activation of Akt. Akt phosphorylates endothelial NO synthase (eNOS), which catalyzes the production of NO from l-arginine. NO freely diffuses to the underlying vascular smooth muscle layer, where it leads to cyclic guanosine monophosphate production to induce vasorelaxation. (B) Possible routes for insulin exit across microvascular endothelial cells toward the interstitial space in muscle and fat tissue. Insulin may cross the microvascular capillary endothelium either paracellularly (between adjacent endothelial cells) or transcellularly (through individual endothelial cells). For the transcellular route, both receptor-mediated and fluid-phase mechanisms of transport have been proposed.
Figure 5.
Figure 5.
Insulin signaling in muscle and adipose cells leading to recruitment of GLUT4 to the plasma membrane. Insulin binds to its receptor on the surface of muscle or fat cells and activates the canonical insulin-signaling cascade to PI3K and Akt. Downstream of Akt, phosphorylation of AS160 allows for the full activation of Rab8A and Rab13 (in muscle cells) and Rab10 (in adipocytes). In the perinuclear region, Rab8A engages with its effector, MyoVa, and Rab10 with its effector, Sec16A, to promote outward vesicle traffic. Near the plasma membrane, Rab13 engages with MICAL-L2 and Actinin-4, whereas Rab10 engages with RalA, Myo1c, and Exocyst components. Simultaneously, downstream of PI3K, insulin leads to activation of Rac1 that promotes a dynamic cycle of cortical actin remodeling. Together, these actions tether GLUT4 vesicles to the actin cytoskeleton near the plasma membrane. Inset: Docked GLUT4 vesicle ready to fuse with the plasma membrane. Immobilized GLUT4 vesicles fuse with the membrane through formation of a SNARE complex between vesicular VAMP2 and syntaxin4 and SNAP23 on the plasma membrane.
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References

    1. Abdul-Hay S.O., Kang D., McBride M., Li L., Zhao J., and Leissring M.A.. 2011. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS One. 6:e20818 10.1371/journal.pone.0020818 - DOI - PMC - PubMed
    1. Ader M., Stefanovski D., Kim S.P., Richey J.M., Ionut V., Catalano K.J., Hucking K., Ellmerer M., Van Citters G., Hsu I.R., et al. . 2014. Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog. Obesity (Silver Spring). 22:1238–1245. 10.1002/oby.20625 - DOI - PMC - PubMed
    1. Alenkvist I., Gandasi N.R., Barg S., and Tengholm A.. 2017. Recruitment of Epac2A to Insulin Granule Docking Sites Regulates Priming for Exocytosis. Diabetes. 66:2610–2622. 10.2337/db17-0050 - DOI - PubMed
    1. Andrali S.S., Sampley M.L., Vanderford N.L., and Ozcan S.. 2008. Glucose regulation of insulin gene expression in pancreatic beta-cells. Biochem. J. 415:1–10. 10.1042/BJ20081029 - DOI - PubMed
    1. Arnold W.P., Mittal C.K., Katsuki S., and Murad F.. 1977. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc. Natl. Acad. Sci. USA. 74:3203–3207. 10.1073/pnas.74.8.3203 - DOI - PMC - PubMed

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