From Cellular Mechanisms to Physiological Responses: Functional Signal Integration Across Multiple Biological Levels

The environmental and nutritional landscapes encountered by organisms are in constant flux. To survive in such an environment, organisms must continuously sense changes in their surroundings and mount a coordinated functional response that spans several levels of biological organization, including the cellular level, the tissue level, and the organismal level. Failure to properly integrate functional responses at any of these levels—due to mutation and/or disruption of endogenous signaling processes by pharmacological/toxicological agents—underlies pathological disorders such as diabetes, cancer and cardiovascular disease. In the previous chapter, we examined the molecular properties of key signaling receptors, enzymes and small-molecule second messengers. We then discussed some of the ways in which select signaling molecules can be organized into discrete signaling modules inside the cell. In this chapter, we will build on this discussion by exploring specific mechanisms by which cellular signaling modules—and, ultimately, the larger signaling networks of which they are a part—convert environmental cues into integrated functional responses. While our discussion will focus primarily on signal integration at the cellular level, we will also touch upon some of the ways in which signaling processes can be further coordinated at both the tissue and the organismal levels. Our discussion will be centered around three fundamental questions: 1) how do individual cells sense and respond to changes in their environment (i.e., cellular information processing); 2) how are individual signaling modules and, by extension cellular signaling networks, regulated in cellular time and space; and 3) why do different cell types respond differently to the same signal? To help illustrate these concepts, we will examine the mechanisms by which various types of cells respond to elevations in blood glucose and how these responses are integrated across multiple tissues and organs to elicit a coordinated, systemic response. In this context, we will also discuss how dysregulation of these mechanisms contributes to the etiology of type 2 diabetes mellitus (T2D) and its complications.