Insulin oscillations

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].

Glucagon Gonadotropic hormones Gonadotropin-releasing hormone Growth hormone (GH) Insulin oscillations Insulin pulsatile secretion Luteinizing hormone (LH) Hypothalamus, and circadian rhythms, 461, 521... 

Oscillating unbridged catalysts, 16 109 Oscillatory flowmeters, 11 667-669 Oscillatory insulin delivery, 9 71 Oscillatory temperature changes, 14 616-617... 

Glycolytic oscillations in yeast cells provided one of the first examples of oscillatory behavior in a biochemical system. They continue to serve as a prototype for cellular rhythms. This oscillatory phenomenon, discovered some 40 years ago [36, 37] and still vigorously investigated today [38], was important in several respects First, it illustrated the occurrence of periodic behavior in a key metabolic pathway. Second, because they were soon observed in cell extracts, glycolytic oscillations provided an instance of a biochemical clock amenable to in vitro studies. Initially observed in yeast cells and extracts, glycolytic oscillations were later observed in muscle cells and evidence exists for their occurrence in pancreatic p-cells in which they could underlie the pulsatile secretion of insulin [39]. 

Studied in both an experimental and theoretical manner. The link between glycolytic oscillations and the pulsatile secretion of insulin in pancreatic p cells [53] is another topic of current concern. Models for the latter phenomenon rely on the coupling between intracellular metabolic oscillations and an ionic mechanism generating action potentials. Such coupling results in bursting oscillations of the membrane potential, which are known to accompany insulin secretion in these cells [54, 55]. 

K. Tomheim, Are metabolic oscillations responsible for normal oscillatory insulin secretion Diabetes 46, 1375-1380 (1997). 

For example, the oscillatory change in intracellular [Ca2+] shown above was observed in pancreatic insulin-secreting P cells responding to stimulation by the agonist carbamoylcholine. The free [Ca2+] was evaluated from fluorescence measurements using the Ca2+ indicator dye fura 2 (From Prentki et alss). Oscillations in [Ca2+] have been observed... 

Let us try to illustrate the mechanism-based modeling approach through the process of formulating a model of the ultradian oscillations in human insulin secretion [9], A better understanding of the role and underlying mechanisms of these oscillations is clearly of interest in the design of an optimal treatment of diabetes. 

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.

With such independently determined parameters, the model must now be able to reproduce the experimentally observed characteristics of ultradian oscillations in human insulin secretion, e.g. the observed period, the oscillation amplitudes and phase relations, and the ringing of the insulin secretion in response to a meal. If the model can only produce the desired behavior after minor adjustments of the parameters, such adjustments may be performed. In most cases, however, the model either produces temporal variations in qualitative and semi-quantitative agreement with the empirical results or it does not produce anything that resembles them at all. In the latter case we conclude that the model structure is incorrect, and that a new hypothesis must be formulated. 

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. 

Are the oscillations associated with conditions characteristic for type II diabetic patients, e.g. insulin resistance or reduced pancreatic activity ... 

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 ... 

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

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. 

T. R. Chay Effects of extracellular calcium on electrical bursting and intracellular and luminal calcium oscillations in insulin secreting pancreatic jS-cells. Biophys.J. 1997, 73 1673-1688. 

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. 

Contributions of Aromatic Side Chains to the Far UV CD of Proteins. Numerous theoretical studies of the effects of aromatic groups on both the far and near UV CD spectra of proteins have been conducted by Hooker and co-workers [143-154], While the calculations on larger proteins were limited in scope, they do provide the only comprehensive attempt to include these chromophores into CD calculations (see below). Other researchers have attempted coupled-oscillator calculations on proteins such as insulin [155, 156], to assess the effects of tertiary structure on near UV CD spectra. More recent work by Woody and co-workers expanded the matrix method to include more elaborate descriptions of... 

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). 

S. Thore, O. Dyachok, and A. Tengholm. Oscillations of phospholipase c activity triggered by depolarization and Ca " influx in insulin-secreting cells. J. Biol. Chem., 279 19396-19400, 2004. 

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