The peptide hormone insulin is secreted from pancreatic β cells, and exerts a broad spectrum of anabolic effects in multiple tissues. In response to a meal, insulin stimulates uptake and storage of carbohydrate, fat, and amino acids, while, at the same time, antagonizing the catabolism of these fuel reserves. During periods of fasting, a fall in circulating insulin combined with increased secretion of counterregulatory hormones leads to breakdown of stored fuels and increased availability of metabolic substrates for cellular energy. In particular, insulin plays a key role in maintaining blood glucose level within a narrowly defined range despite large fluctuations in food intake. After a meal, insulin returns the organism to postabsorptive homeostasis by promoting uptake and storage of glucose as glycogen in skeletal muscle and liver, and by inhibiting hepatic glucose production via decrements in glycogenolysis and gluconeogenesis. Insulin also promotes triglyceride storage by suppressing fatty acid oxidation, increasing lipid synthesis in liver and adipose tissues, and via an antilipolytic effect in fat cells. Insulin’s actions extend to protein accretion through a diminution in protein catabolism and an increase in translation, to cell growth and differentiation, and to cell survival as a consequence of mitogenicity and anti-apoptosis.
Changing perspectives of insulin action
In mediating its pleiotropic actions, insulin engages multiple networks of signal transduction molecules and a wide array of effector systems. Insulin alters activity of enzymatic pathways, subcellular localization of enzymes, and activation state of membrane transport systems by regulating the posttranslational modification, translation, and degradation of proteins in cells and by affecting gene transcription and expression. The classical approach to the review of insulin action is to describe a linear cascade of sequentially-interacting signal transduction molecules, which then engage specific effector systems, such as membrane transport proteins or the activities of rate-limiting enzymes (e.g. glycogen synthase). This narrow perspective is myopic for three reasons. First, signal transduction and effector functions are not clearly distinct. For example, phosphatidylinositide-3 kinase (PI-3 kinase), which is a component of linear signal transduction from insulin receptor to activation of Akt/protein kinase B (Akt/PKB) and protein kinase C (PKC) isoforms, is integrally involved in glucose transport system effector functions such as vesicle trafficking and the actin cytoskeleton .
Secondly, it has become clear, partly through the study of genetic disruption and hyperexpression in mice, that insulin activates numerous systems of signal transduction. These systems are at least partially redundant and are able to interact in modulating signal transduction and ultimate biologic effects. One example is the ability of Akt/PKB, activated through the PI-3 kinase “metabolic” signaling pathway, to impact mitogenic responses through regulation of gene transcription factors. Furthermore, signal transduction systems and effector systems must work in concert to mediate a given biologic effect. For example, stimulation of glucose transport requires parallel activation of PI-3 kinase and CAP/Cbl/TC10 signal pathways, as well as interaction between two effector systems, the glucose transport system (i.e., trafficking of GLUT4-containing vesicles) and effects on the cellular cytoskeleton. Thus, promulgation of insulin action is most accurately viewed as a changing pattern of network interactions involving a web of signal molecule cascades and effector systems. The final biologic action represents the net synergism of the combined facilitative, inhibitory, and complementary signaling pathways that interact with more terminal functional systems in cell biology. Certain aspects of linear insulin signal transduction are evolutionarily conserved and are quite similar in mammals and invertebrates. However, complex patterns of interactions between signal and effector systems are more pronounced in mammals and allow for greater plasticity in adaptive responses.
Thirdly, the classic descriptions of insulin signaling pathways emphasize insulin action mechanisms within certain target cells, especially fat cells. However, these actions at the level of cells and tissues affect substrate flux and release of hormones and tissue factors resulting in the coordinated function of multiple organs as whole organisms adapt to the nutritional environment. The reader is encouraged to think about insulin action in the context of systems biology and integrative physiology. This chapter will emphasize insulin action involving stimulation of glucose transport and glucose metabolism, for reasons outlined later. However, this information will complement other chapters depicting insulin’s ability to regulate protein metabolism (Chapter 16), fat metabolism (Chapter 17), and intermediary metabolism (Chapter 13).
Interest in defining molecular mechanisms mediating insulin action has accelerated with the recognition that insulin resistance is both a primary abnormality in the evolution of type 2 diabetes (T2DM) and is also associated with a cluster of risk factors predisposing to cardiovascular disease (the metabolic syndrome) . The cardinal clinical manifestations of insulin resistance include hyperinsulinemia in conjunction with normoglycemia or hyperglycemia. Investigators have used various in vivo metabolic techniques that assess glucose uptake during insulin infusions to demonstrate that insulin resistance was due to impaired insulin action in peripheral tissues. These conclusions were subsequently confirmed with the demonstration that insulin-stimulated glucose transport was diminished in fat and muscle tissues removed from insulin-resistant subjects and studied ex vivo. Therefore, while insulin resistance could apply to any of insulin’s pleiotropic effects, the term generally applies to insulin’s ability to stimulate tissue glucose uptake and suppress hepatic glucose production since these actions are most directly relevant to its clinical manifestations (hyperinsulinemia and impaired glucose tolerance). This chapter will primarily focus on mechanisms of insulin action related to the regulation of glucose transport and metabolism. While many key aspects remain to be elucidated, this field is rapidly advancing. Over the past decade, the application of new and improved methodologies in molecular biology have facilitated the study of insulin action, resulting in new knowledge and new ways to conceptualize the effects of this powerful and interesting hormone.