Glycemia Regulation: From Feedback Loops to Organizational Closure

Abstract

Endocrinologists apply the idea of feedback loops to explain how hormones regulate certain bodily functions such as glucose metabolism. In particular, feedback loops focus on the maintenance of the plasma concentrations of glucose within a narrow range. Here, we put forward a different, organicist perspective on the endocrine regulation of glycaemia, by relying on the pivotal concept of closure of constraints. From this perspective, biological systems are understood as organized ones, which means that they are constituted of a set of mutually dependent functional structures acting as constraints, whose maintenance depends on their reciprocal interactions. Closure refers specifically to the mutual dependence among functional constraints in an organism. We show that, when compared to feedback loops, organizational closure can generate much richer descriptions of the processes and constraints at play in the metabolism and regulation of glycaemia, by making explicit the different hierarchical orders involved. We expect that the proposed theoretical framework will open the way to the construction of original mathematical models, which would provide a better understanding of endocrine regulation from an organicist perspective.

Keywords: feedback loop; functional constraints; glycemia regulation; organicism; organizational closure; proof of concept (POC).

FIGURE 1

Representation of glycemia regulation in terms of a feedback loop. The regulated variable (glycemia) is represented by the bold circle. The functional components involved in the feedback loop are represented by rectangular boxes indicating their localization in the organism. Blue arrows indicate interactions between components. Red arrows indicate interactions (signals and metabolic processes) that, triggered by low glycemia, produce an increase in glucose concentration. Green arrows decrease the glucose concentration as a response to high glycemia. The system feeds back into itself by sensing the value of glycemia, which is the target of its regulatory activity. The feedback loop maintains the value of glycemia as homeostatic by modulating the release of insulin and glucagon on the basis of the difference between the actual value and the normal range.

FIGURE 2

Representation of glycemia regulation in terms of organizational closure. (A) Represents the first-order functional regime, in which a set of functional parts (rectangular boxes) constrain (blue arrows) processes and transformations (dotted blue arrows) involving glucose as a product or metabolite. Metabolic substrates and products are in dotted circles. Constraints and processes in red and green are those that affect glucose and glucagon concentrations. Organizational closure is realized by the fact that each part acting as a constraint is also the product of a metabolic process within the system. As a result, the system self-maintains. (B) Includes second-order regulatory functions to organizational closure. The regulatory subsystem comprises parts which play the role of constraints that are sensitive to glycemia (sensitivity to x is marked by <x>above the pertinent box) and second-order constraints (double arrows), which modulate the activity of first-order ones. Regulatory constraints marked in red are sensitive to low glycemia and accelerate glycogenolysis; regulatory constraints marked in green are sensitive to high glycemia and accelerate glycogenesis. The overall result of regulation is the homeostasis of glycemia, which is not represented as a separate ‘component’ in this figure, but constitutes an effect of the biological dynamics controlled and regulated by different orders of organized constraints. (C) Adds third-order regulatory functions. The regulatory subsystem includes parts that play the role of constraints sensitive to food (either by ingestion or perception) and exert third-order constraints (triple arrows) on second-order constraints. The inhibitory action of insulin on alpha-cells is also interpreted as a third-order constraint. Second- and third-order regulatory constraints are also the target of metabolic processes, which contribute to their maintenance: therefore, the whole hierarchical system realizes organizational closure.