Nonlinear Dynamic Properties of the Pancreas and Liver

Abstract

Early models of mammalian metabolism were relatively simple, and frequently linear (1, 2). In many cases simplification required the lumping of two or more morphologically distinct organ level unit processes as a single, quasi-linear process, thus making physiological interpretation of simulation results difficult. With the introduction of versatile digital simulation tools during the last decade, models appeared which were increasingly isomorphic with in vivo system (3,4), and which included some of the simpler nonlinearities (e.g., thresholds, saturations) which govern the dynamic range of the system components.Several groups have reported that the stable, relaxation character that has been ascribed to the behavior of the metabolic system (i.e., the homeostatic concept) may not apply. Court et al., reported that the concentration of free fatty acids in the plasma of resting children oscillates powerfully (5), and this phenomenon has been confirmed by us in dogs (unpublished observations). Also, although the fasting blood sugar level has been reported by some to oscillate (6,7), but not others (8), large amplitude oscillations have definitely been provoked by moderate, constant infusions of glucose (9), and by large oral doses of glucose (9).The oscillatory behavior of the metabolic system which has been observed in vivo has not been predicted by even the most complex models available (A. Foster, A. Camfield, personal communications). One possible reason is that the representations chosen for the most significant system components do not reflect many of the important nonlinearities of those components. Sustained oscillations would not occur except for the existence of nonlinearities within the system (10). Therefore, it is necessary to define more precisely the dynamic characteristics of the most relevant unit processes of the metabolic system. Functionally lumped, these include those tissues which store or process energetic compounds: liver, muscle and adipose tissue, and the elements which control the production, utilization and storage of energy: α and β-cells of the pancreas, possibly anterior pituitary, and the autonomic nervous system including the hypothalamus. I have chosen two of the components of the metabolic system most responsible for the determination of system behavior, the pancreas and the liver, and performed dynamic tests on the whole organs which will hopefully reveal their most significant nonlinearities.