In the introduction to Chapter 15, we noted that the same hormone often acts on several types of body cells to coordinate specific physiological responses. And each cell in the body has multiple types of hormone receptors on its surface and in its cytosol; different hormones binding to these receptors can induce similar or dissimilar cellular responses. In this section, we consider how multiple hormones and signal transduction pathways interact, focusing on one of the most important physiological control systems: regulation of the body’s needs for the metabolites glucose and fatty acids. Defects in these pathways lead to major diseases, including diabetes and cardiovascular disease; obesity itself can lead to these and other diseases, with dire consequences for the individual and increasingly for public health.
Cellular responses to changes in other nutrients, which are largely reflected in alterations in gene expression, are covered in Chapter 9.
Insulin and Glucagon Work Together to Maintain a Stable Blood Glucose Level
During normal daily living, the maintenance of normal blood glucose concentrations depends on the balance between two peptide hormones, insulin and glucagon, which are made in distinct pancreatic islet cells and elicit different cellular responses. Insulin, which lowers blood glucose, contains two polypeptide chains linked by disulfide bonds and is synthesized by the β cells in the islets. Glucagon, a monomeric peptide, is produced by the α islet cells and raises blood glucose. The availability of blood glucose is regulated during periods of abundance (following a meal) or scarcity (following fasting) by the adjustment of insulin and glucagon concentrations in the blood.
Our focus here will be on the key hormone insulin, which acts in several ways to reduce the level of blood glucose:
● Within seconds, insulin induces an increase in the uptake of glucose from the blood into muscle and fat cells, primarily by increasing the number of GLUT4 glucose transporters on the plasma membrane (see Figure 1 below).
● Within seconds to minutes, insulin stimulates glycogen synthesis from glucose in the liver.
● Over a longer time frame, insulin acts on the liver to inhibit synthesis of enzymes that catalyze the synthesis of glucose from smaller metabolites, a process termed gluconeogenesis.
● Insulin enhances the formation of adipocytes from pro genitor cells, increasing the body’s storage of fatty acids as triglycerides.
● Insulin acts on the nearby α cells in the pancreatic islets to inhibit glucagon synthesis.
Fig1. Insulin stimulation of fat cells induces translocation of GLUT4 from intracellular vesicles to the plasma mem brane. (a) Cultured adipose cells engineered to express a chimeric protein comprising GLUT4 with a green fluorescent protein (GFP) fused to its C-terminus were visualized with a confocal fluorescence microscope. In the absence of insulin, virtually all of the GLUT4 is in intracellular mem branes. Treatment with insulin triggers fusion of the GLUT4 containing membranes with the plasma membrane. Arrows highlight GLUT4 present at the plasma membrane; N indicates the position of the nucleus. (b) In fat and muscle cells, insulin signaling acts in multiple steps to increase the level of GLUT4 at the plasma membrane. In resting cells, the majority of the GLUT4 protein is localized to specialized GLUT4 storage vesicles (GSVs), tethered to Golgi matrix proteins by the TUG protein. Binding of insulin to the insulin receptor leads to activation of a protease (step 1) that cleaves the TUG protein, releasing GLUT4-containing vesicles (step 2), which then move along microtubules, powered by a kinesin motor (see Chapter 18), to the cell surface. Insulin also activates PKB (step 3; see Figure 16-29). PKB then phosphorylates the Rab GAP protein AS160 (step 4), inhibiting its ability to accelerate GTP hydrolysis by Rab8, Rab10, and Rab14. These Rab proteins accumulate in their active GTP-bound states (step 5) and allow the GLUT4 storage vesicles to move along microtubules to the cell surface (steps 6a and 6b). Finally, these GSVs fuse with the plasma membrane (step 7). This step is catalyzed by the exocyst and also by another monomeric GTP-binding protein, RALA. PKB stimulates this membrane fusion event by phosphorylating and thus inactivating the RALA GAP protein RGC (step 8), allowing RALA to accumulate in its active GTP-bound state (step 9). The resultant increase in plasma membrane GLUT4 allows the cell to incorporate glucose from the extracellular fluids at a rate about 10 times that of unstimulated cells (step 10). Following removal of insulin, the plasma membrane GLUT4 is internalized by endocytosis (step 11) and eventually transported to GSVs (step 12). Many other proteins, not shown here, participate in these signaling and vesicle budding and fusion events. See J. Bogan, 2012, Annu. Rev. Biochem. 81:507, D. Leto and A. Saltiel, 2012, Nat. Rev. Mol. Cell Biol. 13:383, and J. Belman et al., 2014, Rev. Endocr. Metab. Disord. 15:55. [Part (a) C. Yu et al., 2007, J. Biol. Chem 282:7710; ©2007 American Society for Biochemistry and Molecular Biology.]
A lowering of blood glucose stimulates glucagon release from pancreatic α cells. Like the epinephrine receptor, the glucagon receptor, found primarily on liver cells, is coupled to the Gαs protein, whose effector protein is adenylyl cyclase. The binding of glucagon to this receptor induces a rise in cAMP, leading to activation of protein kinase A, which inhibits glycogen synthesis and promotes glycogenolysis, yielding glucose 1-phosphate. Liver cells convert glucose 1-phosphate into glucose, which is released into the blood, thus raising blood glucose back toward its normal fasting level.
A Rise in Blood Glucose Triggers Insulin Secretion from the
