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The chromogranins and the counter-regulatory hormones: do they make homeostatic sense?

Johan H. Koeslag, Peter T. Saunders * and Jabus A. Wessels

MS 8872 Received 19 October 1998; accepted after revision 16 March 1999.

	ABSTRACT

Top Abstract Introduction Methods Results Discussion References

1. The chromogranins are ubiquitous proteins which are co-stored and co-secreted with many peptide hormones. All appear to be powerful inhibitors of endocrine secretions. This poses a problem.

2. When endocrine glands are involved in the efferent limbs of homeostatic loops, they are message transmitters. The self-inhibition caused by the co-secretion of a chromogranin will, on the face of it, erase the message.

3. Pairs of counter-regulatory homeostatic hormones also present a problem.

4. If both members of the pair have clearly defined set points, as suggested by their 'time integral' (or 'growth with time') responsiveness to deviations from set point, then, if the two set points are not exactly the same, one or other member will always register an error, leading, eventually, to an overwhelmingly large and unnecessary response.

5. Our model eliminates both paradoxes, and emphasizes the importance of counter-regulation and the co-secretion of chromogranins in 'zero steady-state error' (ZSSE) homeostasis.

6. If hormone A is secreted into the blood in progressively increasing amounts when [Q], the plasma concentration of substance Q, is low, and in decreasing amounts when [Q] is high; and hormone B responds in the opposite manner, then there will be a [Q], designated [Q]_p, at which the secretory rate increase, or decrease, of the two hormones is exactly the same.

7. If, in addition, the secretion of both hormones is stimulated by low plasma chromogranin levels, [Cg], but inhibited by high [Cg] then there will be a different [Q]_p for every chromogranin concentration in the blood.

8. At one of these points (at a unique [Q] and [Cg]) the concentration of neither hormone will increase or decrease. This is the equilibrium point to which, according to our model, the system always returns regardless of disturbances within physiological limits.

9. This is robust ZSSE control.

	INTRODUCTION

Top Abstract Introduction Methods Results Discussion References

The chromogranins were first discovered in adrenal medullary tissue by Blaschko et al. (1967). Early studies soon revealed that the chromogranins comprised a complex mixture of proteins. It is now recognized that this is the result of the existence of at least three proproteins, known as chromogranin-A, chromogranin-B and secretogranin-II, and their proteolytic products (Winkler & Fischer-Colbrie, 1992). These highly acidic proteins occur in a wide variety of particularly endocrine and neuroendocrine tissues (Winkler & Fischer-Colbrie, 1992). Processing of the proproteins occurs within the endocrine secretory granules by endoproteases (Laslop et al. 1998). The proteolytic products are then co-stored (constituting up to 40 % of the contents of the secretory granules), and co-secreted with most resident peptide hormones and neurotransmitters (Cohn & Elting, 1983; Cohn et al. 1984, 1995; Efendic et al. 1987; Winkler & Fischer-Colbrie, 1992; Helle & Angeletti, 1994; O'Connor et al. 1994; Zhang et al. 1994; Huttner & Natori, 1995; Lewin et al. 1995). Their role in endocrine physiology remains enigmatic (Laslop et al. 1998).

Chromogranin-A (CgA), the most widely studied of the chromogranins, and a wide variety of its proteolytic products have powerful statin-like characteristics, and are capable, as a group, of inhibiting the secretion of most peptide hormones (Drees et al. 1991; Fasciotto et al. 1993; Drees & Hamilton, 1994). Thus, pancreastatin, the proteolytic fragment of CgA found in pancreatic -cells (Schmidt et al. 1988; Winkler & Fischer-Colbrie, 1992) is a powerful paracrine inhibitor of insulin secretion. Pancreastatin (although probably not formed in the parathyroid glands), -granin and the newly discovered parastatin are all strong inhibitors of parathyroid hormone (PTH) secretion (Fasciotto et al. 1993; Zhang et al. 1994; Cohn et al. 1995; Lewin et al. 1995). The 26 kDa N-terminal fragment of CgA, known as CgA_(1-40), which is co-stored and co-secreted with PTH and with calcitonin, inhibits both PTH and calcitonin secretion (Deftos et al. 1990; Fasciotto et al. 1990; Drees et al. 1991, 1994; Zhang et al. 1994; Cohn et al. 1984, 1995). Other CgA-derived peptides have been found in the myoendocrine cells of the heart storing atrial natriuretic peptide (Steiner et al. 1990). The chromogranins are also known to inhibit catecholamine secretion by the adrenal medulla (Galindo et al. 1991; Mahata et al. 1997), pro-opiomelanocortin secretion in neuroendocrine tissue (Wand et al. 1991), cholecystokinin-induced amylase secretion by the exocrine pancreas (Funakoshi et al. 1988), and acid secretion by parietal cells in the stomach (Lewis et al. 1988). They are also present in the anterior pituitary gland, enterochromaffin cells of the gut, and the placenta (Syversen et al. 1996).

The CgA-derived peptides are powerfully active at physiological concentrations and are presumed, therefore, to play a role in the regulation of peptide hormone secretion (Cohn et al. 1995; Mahata et al. 1997). Since they are co-secreted with the resident hormone, they probably have endocrine functions, although what that function is, is not known. They are also generally believed to have paracrine or autocrine functions within endocrine glands. But once again, the physiological significance is unknown (Winkler & Fischer-Colbrie, 1992; Zhang et al. 1994; Cohn et al. 1995; Laslop et al. 1998). Why a message transmitter, such as an endocrine gland, should attempt to inhibit itself, and thus blunt its message, by co-secreting powerful endocrine, paracrine or autocrine statins together with its main messenger molecules, remains unexplained.

The problem

Here we concentrate on the problems posed by the co-secretion of powerful statins (in the form of the chromogranin-derived peptides) with the hormones involved in homeostasis. These are in particular the insulin/glucagon, the PTH/calcitonin, and the atrial natriuretic peptide (ANP)/renin-angiotensin-aldosterone counter-regulatory systems, involved in the regulation of the plasma glucose, plasma ionized calcium, and plasma sodium ion concentrations, respectively.

Information theory (Shannon & Weaver, 1949; Rucker, 1987) tells us that changelessness and periodicity contain no information. On the other hand, a message that appears to consist of a random, patternless set of data cannot be summarized and therefore contains a maximum of information. The information content of an endocrinological message is conveyed in two forms: the chemical structure of the hormone and its plasma concentration. Since the chemical structure of a hormone cannot be changed it serves only as a destination determiner, in the same way that the anatomical course of an efferent nerve specifies the destination of certain nervous messages. The true messenger function, or information content, of a hormone therefore resides in the variability of its plasma concentration. The more highly varied and unpredictable (from the point of view of the target tissue) the plasma concentration of a hormone, the greater is its information content. On the face of it, therefore, any endocrinological self-inhibition (which tends to promote secretory uniformity), be it via the resident hormone itself, or via a chromogranin-derived peptide which is co-secreted with the resident hormone, is self-defeating.

A second problem arises from the fact that the hormones which constitute the efferent limbs of negative feedback loops generally operate in counter-regulatory pairs. In simple proportional controllers (Riggs, 1963, 1970; Milsum, 1966; Guyton & Hall, 1996) this would not cause any problems, and may even impart some advantages (Clynes, 1969) in addition to the fact that the two hormones act as back-ups of one another. If this is so, however, then failure of either member of a given pair (e.g. an isolated inability to secrete insulin) would cause no major pathophysiology.

There is ample evidence that the counter-regulatory pairs of hormones do not operate as 'proportional', but as 'integral' controllers (Koeslag et al. 1997; Saunders et al. 1998). This means that during any steady-state disturbance, the controller always brings the controlled variable back to 'set point'. It does so by responding to the time integral of a disturbance-induced error (i.e. the error multiplied by the time that it persists) (Milsum, 1966; Koeslag et al. 1997; Saunders et al. 1998). Thus, the insulin output from the pancreas during a glucose-clamp experiment is not a fixed increase which is proportional to the hyperglycaemic challenge, but a progressively increasing insulin output with time (Grodsky, 1972; Gerich et al. 1974; Tsuchiyama et al. 1992; Koeslag et al. 1997). Such time integral responses are the basis of all 'perfect', or 'zero steady-state error' (ZSSE) homeostasis. (Guyton & Hall (1996) refer to ZSSE control as 'homeostasis with infinite gain'.) However, a pair of independent ZSSE homeostats duplicating each others' efforts presents a problem. This stems from the fact that the two set points are unlikely ever to be exactly the same. If the set points differ by even an infinitesimally small amount, then at least one counter-regulatory homeostat will always register an error, which, when multiplied by the time that it persists, leads to an overwhelmingly large and unnecessary response. Thus, since there is likely to be a time delay between the effect on the controlled variable induced by one member of the counter-regulatory pair, and the subsequent response of the other, the controlled variable will oscillate temporarily between the two set points. During this time, the response of both controllers escalates (each in response to the other's previous effort to return the controlled variable to its specific set point), until at least one of them is working at maximum capacity.

Since integral controllers generally work best on their own, loss of one member of a counter-regulatory pair should improve homeostasis, and not cause disease.

A proposed role for the chromogranins and the pairs of counter-regulatory hormones in ZSSE homeostasis

We have previously proposed a model, inspired by James Lovelock's Daisyworld Parable (Watson & Lovelock, 1983; Saunders, 1994), in which the insulin/glucagon counter-regulatory pair of hormones produces ZSSE control of the arterial blood glucose concentration (Koeslag et al. 1997; Saunders et al. 1998). The model is, however, critically dependent on intercellular connections between the - and -cells of the islets of Langerhans (Orci et al. 1973, 1975; Orci & Unger, 1975; Meda et al. 1986). This allows small functional syncytial units within the pancreatic islets to operate as flip-flop mechanisms which secrete either insulin or glucagon. Each functional unit secretes one or other hormone maximally or not at all (Schuit et al. 1988; Pipeleers et al. 1994). Clearly this mechanism could only work for the insulin/glucagon counter-regulatory pair of hormones. The other counter-regulatory pairs of hormones are secreted by glands that are functionally connected only via the blood. The flip-flop mechanism of counter-regulatory hormone secretion (in ZSSE homeostasis) is therefore clearly a special case.

Here we propose a more general model of counter-regulatory hormone ZSSE control which would operate between anatomically remote pairs of endocrine glands (e.g. the C cells of the thyroid and the chief cells of the parathyroid glands; or between the ANP-secreting myoendocrine cells of the atria and the renin-secreting cells of the juxtaglomerular apparatus).

We use the PTH/calcitonin system as a generic model of counter-regulatory ZSSE control, in this case of the plasma ionized calcium concentration, [Ca²⁺]. Thus, we use the names (and basic physiology) of this system instead of generic terms. This is for ease of explanation. The reader is therefore relieved of the necessity constantly to convert unfamiliar terminology into familiar examples in order to follow the reasoning. The term 'CgA' is also used in a generic sense, to represent the particular species of chromogranin-derived peptide (probably CgA_(1-40) in the case of the PTH/calcitonin pair) which endocrinologically inhibits the secretion of both hormones in the given counter-regulatory system.

Low [Ca²⁺] values stimulate PTH secretion from the parathyroid glands, while inhibiting calcitonin secretion from the C cells of the thyroid gland. The rate of PTH secretion decreases, and that of calcitonin increases, both almost linearly, with increasing [Ca²⁺] values (Nordin, 1990; Copp, 1994). The secretion of both hormones is inhibited by CgA, in a dose-dependent fashion (Deftos et al. 1989, 1990; Fasciotto et al. 1990; Drees et al. 1991; Zhang et al. 1994; Cohn et al. 1995).

The response of the parathyroid gland to the plasma ionized calcium, [Ca²⁺], and CgA concentrations, [CgA], can therefore be represented on a 3-dimensional graph (Fig. 1A). On the x-axis is the ionized calcium concentration, and on the y-axis is the CgA concentration. The vertical z-axis depicts the rate of growth in number of cells (or groups of cells) in the parathyroid gland which are actively secreting PTH. Zero growth rate (the horizontal yellow plane) means that the rate of PTH secretion is neither increasing nor decreasing. Positive growth rates indicate that the number of actively secreting cells is increasing with time. Negative growth rates imply that that number is decreasing with time. The red surface gives the growth rate of the number of active cells in the parathyroid gland as a function of the plasma calcium and CgA concentrations. It slopes downwards to the right because the growth rate decreases (and eventually becomes negative) as [Ca²⁺] increases. It also slopes downwards to the back because the growth rate also decreases as [CgA] increases. In the diagram the red surface is a plane (i.e. not curved). This is purely for representational simplicity. It could be, and probably is, curved. The only important attribute, in terms of our model, is that the slope of the red surface should be negative both to the right and to the back. The red surface therefore intersects the yellow surface (zero growth rate) to form a horizontal curve (in Fig. 1A, a straight line) from the front right (high [Ca²⁺]/low [CgA]) to the back left (low [Ca²⁺]/high [CgA]).

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Figure 1 Diagrammatic representations of the response of the parathyroid gland (A, red surface) and of the C cells of the thyroid gland (B, blue surface) to different concentrations of ionized calcium (x-axis) and chromogranin-A (CgA) (y-axis) in the plasma. The vertical z-axis denotes the rate of increase (+) or decrease (-) in the number of actively secreting endocrine cells in the parathyroid gland (A) and parafollicular cells in the thyroid gland (B). See text for further details.

The calcitonin response to different plasma [CgA] and [Ca²⁺] values is depicted by means of the blue surface in Fig. 1B. The axes are the same as in Fig. 1A, except that growth rate on the vertical z-axis now refers to the rate of increase (or decrease) in numbers of active C cells in the thyroid gland. The blue surface is once again a plane purely for representational simplicity. It could be curved, as long as the slope remains negative to the left and to the back. It intersects the zero growth rate surface to form a horizontal curve (in Fig. 1B, again a straight line) from the front left (low [Ca²⁺]/low [CgA]) to the back right (high [Ca²⁺]/high [CgA]).

The combined response of the pair of counter-regulatory hormones to different plasma [CgA] and [Ca²⁺] values is depicted in Fig. 2A and B, from the combination of Fig. 1A and B, using the same colour code and axes labelling. Figure 2A and B view the same graph from two slightly different perspectives. It will be noticed, especially in Fig. 2B, that the three planes intersect at only one point (labelled X). This is the only point of equilibrium. Here the rates of increase in the number of active cells in both glands are zero. At all other combinations of plasma [Ca²⁺] and [CgA] the number of active cells in one or both glands is changing, thereby changing the PTH/calcitonin ratio in the blood. At calcium concentrations in the blood to the left of [Ca²⁺]_X the PTH/calcitonin ratio will increase, progressively raising the plasma ionized calcium level with time; to the right of [Ca²⁺]_X the ratio will decrease, progressively lowering the plasma ionized calcium level with time.

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Figure 2 The combination of Fig. 1A and B, depicting the response of the counter-regulatory pair of hormones concerned with zero steady-state error (ZSSE) control of the plasma ionized calcium level. Point X (where the red, blue and yellow planes intersect) is the only equilibrium point of the system. A and B are different perspectives of the same diagram. See text for further details.

At blood CgA concentrations lower than [CgA]_X the number of actively secreting cells in both glands increases. Since CgA is co-secreted with the two counter-regulatory hormones, its level in the blood will rise progressively (together with the total amount of PTH and calcitonin). This rising level of CgA will eventually inhibit secretion by both endocrine glands. Blood CgA concentrations higher than [CgA]_X will strongly inhibit the production of the total amount of hormone (calcitonin plus PTH), thereby simultaneously inhibiting its own secretion. Once again the only equilibrium point is X. While we have represented the surfaces as planes to make the situation easier to visualize, replacing the planes with curved surfaces does not materially affect our conclusions.

The equilibrium point, X, occurs at a unique plasma ionized calcium concentration, [Ca²⁺]_X, as well as at a unique blood CgA concentration, [CgA]_X (Fig. 2). The unique plasma ionized calcium concentration value imparts ZSSE control to the counter-regulatory pair of hormones, whose concentration ratios in the blood are the only things that differ, under different stresses, whenever the system returns to X (and thus to [Ca²⁺]_X). Thus, although the plasma ionized calcium level during lactation and postprandially (in the non-lactating state) might both be tightly maintained at exactly 1·25 mmol l^-1, the PTH/calcitonin ratio in the blood will be high in the first case, but low in the second. (The classical dogma suggests that at a plasma ionized calcium concentration of 1·25 mmol l^-1 there is no stimulus for a higher or lower than resting PTH/calcitonin ratio in the blood.)

Consider the prolonged input of calcium into the blood after a meal. The plasma ionized calcium concentration shifts to the right of [Ca²⁺]_X. This causes a progressive increase (with time) in the number of actively secreting C cells in the thyroid gland, while the number of actively secreting parathyroid cells decreases progressively. This progressively lowers the PTH/calcitonin ratio in the blood. The change (downwards) in PTH/calcitonin ratio stops only when the plasma ionized calcium concentration reaches [Ca²⁺]_X again. Thus, during the postprandial period, normocalcaemia will be rapidly restored, and will then remain associated with a lowered PTH/calcitonin ratio in the blood (despite the normocalcaemia) for as long as the input of calcium is higher than in the fasting state.

Feedforward, or anticipatory rises (Koeslag et al. 1997) in the calcitonin level of the blood during the cephalic and gastric phases of digestion would be the result of a temporary autonomic or gut hormone-induced shift of the calcitonin surface (blue) to the left (Fig. 1B). This would drag the equilibrium point to the left, thereby increasing the vigour of the hormone response to the postprandial influx of calcium. Depending on the magnitude and duration of the feedforward stimulus, the plasma ionized calcium concentration could therefore, in fact, temporarily, tend towards a lower than normal equilibrium point during the early postprandial period.

Model assumptions

The model is critically dependent on a pair of counter-regulatory effectors (not necessarily hormonal). If the system operates via hormones, these hormones must, according to the model, be functionally linked by the co-secretion of a common blood-borne (i.e. endocrinological) statin which inhibits the secretion of both members of the pair of counter-regulatory hormones in a dose-dependent fashion. However, the inhibition of one need not be a near mirror image of the other when displayed in diagrams such as Fig. 1A and B. Indeed, if the above general assumptions are met then the model is extremely robust and detail insensitive. The two response surfaces (red and blue planes in Figs 1 and 2) will create a single point attractor (or equilibrium point where their line of intersection crosses the horizontal zero-growth surface), whether they are flat or curved, whether one is gradually sloped and the other steeply sloped, or whether they are moved, singly or together, to the left, right, front or back (within the physiological range).

We assume that the 'growth', or the 'time integral' responsiveness (Grodsky, 1972; Gerich et al. 1974; Tsuchiyama et al. 1992; Koeslag et al. 1997; Saunders et al. 1998) of the hormone secretions in our model probably relies on a number of inhibitory paracrine secretions (e.g. GABA and paracrine chromogranin secretions) in the manner described previously (Koeslag et al. 1997). This would then account for the wide variety of paracrine CgA-derived peptides found in endocrine (and other) glands, whose functions, we believe, are distinct from those of the endocrine CgA species which are co-secreted with the resident peptide hormones.

Conclusion

The interaction between a pair of counter-regulatory hormones, which are co-secreted into the blood with a common statin capable of inhibiting both members of the pair of counter-regulatory hormones, produces a single physiological equilibrium point. This means that starting from any point away from the equilibrium point, the system automatically, very simply, and extremely robustly, always returns to that equilibrium point. This results in ZSSE homeostasis. It is achieved without complex neuronal circuitry.

The model not only explains why counter-regulatory hormone control is so common in homeostasis, but also, for the first time, suggests a crucial physiological role for the CgA-derived peptides. The model also explains why the absence (or excess, or unvarying, 'adenomatous' secretion) of just one member of a counter-regulatory pair of hormones has such disastrous effects. If the members of the pair were mere back-ups of one another (as is implied by the classical model) then loss of one of them should have no major physiological consequences. In our model, loss of one member of a counter-regulatory pair of hormones causes the single equilibrium point (X in Fig. 2) to be replaced by an equilibrium line (see the equilibrium lines caused by the intersection of either the red or the blue plane, each on their own, with the yellow horizontal plane in Fig. 1A and B), along which the controlled variable (e.g. the blood sugar or plasma calcium concentration) is driven in the direction of the hypo-CgA effects. This means that homeostasis is lost. It also means that the equilibrium point of the counter-regulatory system cannot be recreated, even approximately, by hormone replacement therapy. In most clinical settings, therefore, the clinician has to be satisfied with an adequate, but by no means ideal, maintenance range of levels of the controlled variable (blood sugar, etc.), whose 'boundaries' are set by the effectiveness of the behavioural homeostat.

If the specific hypochromograninaemia, caused by the loss of one member of a pair of counter-regulatory hormones together with its co-secreted CgA, could be replaced with a therapeutic chromogranin clamp (i.e. a constant plasma chromogranin concentration of the right magnitude), then homeostasis of the controlled variable could be restored if the other member of the counter-regulatory pair was still operational (and could both raise and lower the controlled variable). This is because fixing the CgA concentration determines a particular point on the equilibrium line in either Fig. 1A or B as unique as point X in Fig. 2. Whether, in practice, it will be easier to clamp the chromogranin concentration than, for instance, the blood sugar concentration, remains to be seen. If a chromogranin clamp is a feasibility, then the controlled variable would always tend towards a well-defined set point; whereas insulin replacement therapy, for instance, tends to pull the controlled variable away from (to the left of) the equilibrium line (Fig. 1A). The therapeutic effort, in classical hormone replacement therapy, therefore tends to create a fundamentally unstable situation, which might explain why attempts at maintaining the average blood sugar concentration around 5-6 mmol l^-1 is nearly always accompanied by a disturbing degree of glycaemic lability.

In both physiological and type II diabetic 'insulin resistance' (insulin receptor down-regulation, or second messenger failure), the effectiveness of insulin is curtailed. The model predicts not only that for a given physiological effect the blood insulin concentration will be higher than normal (as predicted by the classical model), but it also predicts that while there is still unused insulin secretory capacity, coupled with some remaining target tissue responsiveness, the blood glucose set point remains unchanged. After a glucose challenge, however, it merely takes much longer than normal to return to set point. In a person consuming three meals a day the time between meals might thus be too short to return to set point, and the person presents as a frank diabetic. A short period of relative starvation will, however, correct the hyperglycaemia, and apparently 'cure' the diabetes. Unlike type I diabetes mellitus, therefore, type II diabetes responds extremely well (certainly in the initial phases) to dietary restriction.

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Acknowledgements

We gratefully acknowledge the very helpful comments of an anonymous referee, who, amongst other helpful suggestions, pointed out the therapeutic possibilities of a chromogranin clamp. We thank Kay Stead for constructing and drawing the illustrations.

Corresponding author

J. H. Koeslag: Department of Medical Physiology, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa.

Email: jkoeslag{at}gerga.sun.ac.za

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