Oscillation insulin-glucose

Before we can start to develop a model we also have to decide how to interpret the behavior observed in Fig. 2.1. The variations in insulin and glucose concentrations could be generated by a damped oscillatory system that was continuously excited by external perturbations (e.g. through interaction with the pulsatile release of other hormones). However, the variations could also represent a disturbed self-sustained oscillation, or they could be an example of deterministic chaos. Here, it is important to realize that, with a sampling period of 10 min over the considered periods of 20-24 h, the number of data points are insufficient for any statistical analysis to distinguish between the possible modes. We need to make a choice and, in the present case, our choice is to consider the insulin-glucose regulation to operate... 

Fig. 2.2 Simulation of a mechanism-based model of ultradian insulin-glucose oscillations. Using independently determined parameters and nonlinear relations, the model displays self-sustained oscillations of the correct period with proper amplitudes and phase relationships. The model also responds correctly to a meal as well as to changes in the rate of glucose infusion.

Figure 2.2 presents the results obtained with our mechanism-based model of the ultradian insulin-glucose oscillations [9], Although clearly only a preliminary model of the phenomenon, the applied model passes all of the above tests. The model produces self-sustained oscillations of the correct period and proper amplitudes, and the model also responds correctly both to a meal and to changes in the rate of glucose infusion. The next step is to use the model to predict the outcome of experiments that have not previously been performed. To the extent that the model is successful in such predictions, the hypothesis underlying the model structure gains additional support. 

If the oscillations derive from an instability in the insulin-glucose feedback regulation, where do we find the delay that can produce such an instability ... 

J. Sturis, C. Knudsen, N. M. O Meara,). S. Thomsen, E. Mosekilde, E. Van Cauter, and K. S. Polonsky Phase-locking regions in a forced model of slow insulin glucose oscillations. Chaos 1995, 5 193-199. 

We conclude that the ultradian insulin oscillations cannot be related to an intermittent supply of glucose. Neither do the oscillations appear to be generated through interaction with counter-regulatory hormones, since analysis of simulta-... 

Fig. 2.1 Examples of ultradian oscillations in human insulin secretion and blood glucose concentration (a) during continuous enteral nutrition and (b) during constant glucose infusion. Closer inspection shows that the glucose oscillations lead the insulin oscillations by a few minutes. Redrawn from [39, 40].

E. Van Cauter The mechanisms underlying ultradian oscillations of insulin and glucose a computer simulation approach. Am.]. Physiol. 1991, 260 E801-E809. 

C. Simon, G. Brandenberger, and M. Fol-lenius Ultradian oscillations of plasma glucose, insulin and C-peptide in man. J. Clin. Endocrinol. Metab. 1987, 64 669-675. 

Van Cauler Oscillations in insulin secretion during constant glucose infusion in normal man relationship to changes in phasma glucose. J. Clin. Endocrinol. Metab. 1988, 67 307-314. 

Oscillations of [Ca2+][ have been reported following initiation of insulin release by nutrients and sulphonylureas (Heilman etal., 1992). The frequency of these large-amplitude oscillations corresponds to 0.2-0.5 min-1 in mouse B-cells, which is similar to the slow cyclic variations in burst activity recorded with intracellular microelectrodes in intact islets and also the periodicity of insulin release. However, this oscillatory pattern of the electrical and [Ca2+]j responses induced by glucose is not accompanied by, and thus probably not due to, similar oscillations in metabolism (Gilon and Henquin, 1992). However, Longo et al. (1991) reported oscillations with similar periods in insulin secretion, oxygen consumption and [Ca2+]j. Since oscillations appear in vivo as well as in vitro there must be a pacemaker in the islet tissue itself (Goodner et al., 1991). 

Goodner, C.J., B.C. Walike, D.J. Koerker, J.W. Ensinck, A.C. Brown, E.W. Chideckel, J. Palmer L. Kalnasy. 1977. Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. Science 195 177-9. 

Lang, D.A., D.R. Matthews, J. Peto R.C. Turner. 1979. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. New Engl. J. Med. 301 1023-7. 

Longo, E.A., K. Tornheim, J.T. Deeney, B.A. Varnum, D. Tillotson, M. Prentki B.E. Corkey. 1991. Oscillations in cytosolic free Ca, oxygen consumption, and insulin secretion in glucose-stimulated rat pancreatic islets. J. Biol. Chem. 266 9314-19. 

When polymeric matrices containing insulin and magnetic beads were implanted in diabetic rats, glucose levels could be repeatedly decreased on demand by application of an oscillating magnetic field, and the blood glucose levels were additionally lowered by approximately 30% (Kost et al,... 

Applepolscher has designed a Smith predictor with proportional control for a control loop that regulates blood glucose concentration with insulin flow. Based on simulation results for a FOPTD model, he tuned the controller so that it will not oscillate. However, when the controller was implemented, severe oscillations occurred. He has verified through numerous step tests that the process model is linear. What explanations can be offered for this anomalous behavior ... 

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