Role in glucose metabolism


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Glucocorticoids are so named because of early studies indicating their role in glucose metabolism, the fact that they are synthesised in the adrenal cortex and because they are steroids. Cortisol is the main glucocorticoid in humans. The name glucocorticoid is very misleading as glucocorticoids have many other functions not involving the regulation of glucose metabolism. In fact, Beck and McGarry (1962) conclude that the most important physiological actions of cortisol do not include the actions of cortisol on carbohydrate metabolism.

The effects of glucocorticoids are due to the binding of glucocorticoids to the glucocorticoid receptor. Aldosterone, a mineralocorticoid, also binds to the human glucocorticoid receptor with an affinity of the same order of magnitude as cortisol (Hellal-Levy et al., 1999). In addition, mineralocorticoid receptors and glucocorticoid receptors share 94% homology in the DNA-binding region (Molina, 2006) and both, upon ligand binding, bind to and activate a shared hormone response element (Pearce and Yamamoto, 1993). On the face of it then one can reason that mineralocorticoids such as aldosterone should be able to take over the functions of glucocorticoids and loss of glucocorticoids should have no major effect on physiology. This however is not the case.

Although aldosterone can bind to the glucocorticoid receptor with an affinity of the same order of magnitude as cortisol, this binding is unstable. This is due to aldosterone lacking C11 or C17 hydroxyl groups (present in cortisol) which form steroid-receptor contacts that stabilise the active human glucocorticoid receptor conformation required for DNA binding and transcription (Hellal-Levy et al., 1999). Also, although both the mineralocorticoid and glucocorticoid receptors bind a shared hormone response element, the receptors interact with different regulatory factors that determine their specific functions (Pearce and Yamamoto, 1993). Thus mineralocorticoids cannot take over the functions of glucocorticoids.

Furthermore, the lack of a glucocorticoid receptor has been shown to result in the death of mice shortly after birth, primarily due to the impairment of lung and adrenal development (Cole et al., 1995), the impaired lung development being primarily due to the lack of production of surfactant (Parker and Rainey, 2004). Other physiological functions of glucocorticoids are seen clearly in disorders such as Addison?s disease and Cushing?s syndrome where the levels of glucocorticoids are too low and too high respectively. The symptoms of such disorders are numerous and diverse reflecting the numerous and diverse functions of glucocorticoids.

As mentioned, the glucocorticoids exert their effects by binding to the glucocorticoid receptor. There are two known highly homogonous receptor isoforms of the human glucocorticoid receptor (hGR) known as hGRa and hGR?. The hGR? does not bind glucocorticoid and inhibits the transcriptional activity of hGRa. Whereas, the hGRa receptor functions as the ligand dependent transcription factor and it is to this receptor that glucocorticoids bind (Charmandari et al., 2004).

The hGRa resides in the cytoplasm when not bound by a ligand and remains here as an inactive multi-protein complex that includes heat shock protein 90 (hsp90) molecules. The hsp90 regulates ligand binding as well as ensuring the hGRa remains in the cytoplasm. Hsp90 is bound to the receptor in such a way that the ligand binding domain of the receptor is exposed but two nuclear localisation sequences on the DNA binding domain of the receptor are masked (Nicolaides et al., in press) thus preventing translocation into the nucleus and DNA binding. Upon ligand binding, the multi-protein complex is dissociated thus exposing the nuclear localisation sequences hence allowing translocation of the receptor into the nucleus where it can regulate the transcription of glucocorticoid responsive genes by either binding to glucocorticoid response elements in the promoter regions of target genes (trans-activation), or through protein-protein interactions with other transcription factors (Charmandari et al., 2004). The glucocorticoid receptor is expressed in virtually all cells (Rhen and Cidlowski, 2005) thus accounting for the wide ranging actions of glucocorticoids.

Glucocorticoids play crucial roles in basal and stress related homeostasis as well as helping regulate a variety of other important functions. The most obvious physiological function of glucocorticoids, because of its name, is its actions on carbohydrate metabolism. The net effect here is an increase in blood glucose levels and this is achieved through anabolic and catabolic effects (Parker and Rainey, 2004). Glucocorticoids act on liver cells to enhance the expression of enzymes required for gluconeogenesis (the production of glucose from non-carbohydrate precursors) thus increasing the blood glucose levels. In addition to this, glucocorticoids also decrease the uptake of glucose by other cells in the body (Ingle and Thorn, 1941), thus having antagonistic effects to insulin, as well as reducing the affinity of certain cells for insulin (Hadley and Levine, 2006). Highlighting this, patients with Cushing?s syndrome develop hyperglycaemia, insulin resistance and steroid induced diabetes mellitus whereas those with Addison?s disease often present with hypoglycaemia.

The catabolic effects of glucocorticoids involve mainly the breakdown of protein in skeletal muscle and skin and connective tissue and their conversion into glucose and glycogen (Long and Lukens, 1936; Parker and Rainey, 2004). In addition, cortisol reduces extra-hepatic utilisation of amino acids and encourages their mobilisation. Extra-hepatic protein stores are also broken down and reduced and protein synthesis is reduced. All this has the effect of increasing plasma amino acid levels (Parker and Rainey, 2004; Ingle et al., 1948). Furthermore, glucocorticoids induce ?trapping? of amino acids by the liver, where they are utilised for gluconeogenesis, glycogen formation, and protein synthesis within the liver (Parker and Rainey, 2004; Noall et al., 1957). Because of these effects of glucocorticoids, patients with Cushing?s also present with progressive loss of protein, growth retardation, muscle wasting, skin thinning, reduction in lymphoid tissue and osteoporosis. Patients with a deficiency in cortisol do not seem to show a measurable increase in protein synthesis as might be expected (Beck and McGarry, 1962; Parker and Rainey, 2004).

Glucocorticoids also induce the mobilisation of fatty acids and glycerol from adipose tissue for gluconeogenesis. Formation of adipose tissue is also inhibited. Also, glucocorticoids stimulate appetite and the deposition of fat in the central and truncal areas resulting in loss of fat and muscle in the extremities and fat build up in the face and trunk of the body in conditions of cortisol excess. The mechanism for this redistribution is as of yet unknown (Parker and Rainey, 2004).

Glucocorticoids also play roles in electrolyte and water balance. Adrenal insufficiency leads to abnormalities including excessive loss of sodium, decreased serum and intracellular sodium, potassium retention and increased serum and intracellular potassium thus leading to metabolic acidosis as well as impairing glomerular filtration and water excretion (Beck and McGarry, 1962; Parker and Rainey, 2004). Cortisol has been shown to increase sodium retention and potassium excretion (Beck and McGarry, 1962; Hepps et al., 1959; Parker and Rainey, 2004) and the impaired glomerular filtration and water excretion due to adrenal insufficiency can also be corrected using glucocorticoids (Oleesky and Stanbury, 1951).

In the absence of cortisol, patients may also present with reduced vascular volume and hypotension even without any external fluid loss, this is the result of abnormal vasodilation which itself can be said to be the result of inadequate heart muscle function, poor vascular tone of the arterials and an alteration in the permeability of the capillaries (Beck and McGarry, 1962; Parker and Rainey, 2004). Reduced vascular volume and hypotension is normally corrected by nor-adrenaline but in the absence of glucocorticoids vascular responsiveness to nor-adrenaline is reduced as a result of ?cationic shifts in the arteriolar smooth-muscle cells? (Beck and McGarry, 1962; Ramey et al., 1951). It must be noted that aldosterone probably has some role to play in producing inadequate heart muscle function (Beck and MacGarry, 1962).

Being steroids, glucocorticoids are able to easily cross the blood-brain barrier and so they also have neurological actions. The important brain areas containing glucocorticoid receptors include the hippocampus, amygdala and frontal lobes, which are known to be involved in learning and memory (Lupien et al., 2007). Glucocorticoids have been shown to enhance the formation and recall of flash-bulb memories, memories of events associated with a heightened sense of emotion, both negative and positive. The formation of such memories involves the amygdala and the hippocampus (Lupien et al., 2007). Increased levels of cortisol were shown to produce better consolidation of fear associated memories and this effect was seen to be more important in men (Zorawski et al., 2006).

Glucocorticoids have also been shown to induce hypo-vigilance, i.e. reduced neural response to sensory stimuli. Patients with Addison?s disease have been shown to have elevated sensory perception and treatment with glucocorticoids returned the sensory perception to normal suggesting that glucocorticoids act by inhibiting the central nervous system (Henkin et al., 1967). However, Born et al. (1989) later found that glucocorticoids enhanced the response to auditory stimuli after initially confirming the hypo-vigilance hypothesis (Born et al., 1987). This shows that a more complex relationship between glucocorticoids and cognitive processing exists. Yerkes and Dodson?s (1908) inverted U-shape curve can help describe the relationship between glucocorticoids and cognitive processing. Such a curve would predict that efficient cognitive processing is increased as the levels of glucocorticoids is increased but only up to a point at which further increases in glucocorticoid levels result in a fall in cognitive efficiency.

Glucocorticoids have also been suggested to reduce cerebral oedema in the sella turcica and this has been used to produce a protective effect during operative procedures in this region resulting in a reduced mortality and morbidity (Beck and McGarry, 1962). Neurologically, a deficiency in cortisol as seen in Addison?s disease results in restlessness, insomnia and the inability to concentrate as well as a slowed EEG all of which are reversible with cortisol (Thorn et al., 1949). Neurologically, a cortisol excess as in Cushing?s syndrome results in an initial elevation of mood that varies from a feeling of well-being to euphoria, increased mental and motor excitability, increased appetite and reduced sleep. This syndrome is seen in patients undergoing glucocorticoid therapy and is often seen in the first days or weeks of beginning therapy (Beck and McGarry, 1962; Lupien et al., 2007). After the initial euphoria, cortisol excess can then lead to feelings of weakness, apathy, anxiety, depression and sometimes suicide. These behavioural changes were associated with changes in brain activity and in some cases excess cortisol can also lead to epileptic seizures and status epilepticus (Lupien et al., 2007). The mental symptoms have resulted in some of the side effects of glucocorticoid therapy being termed ?steroid psychosis? (Clark et al., 1952).

Glucocorticoids also have anti-inflammatory and immunosuppressive actions. The anti-inflammatory actions are primarily due to their role in inhibiting the expression of genes involved in the synthesis of pro-inflammatory cytokines. This effect is known as trans-repression and is a result of interactions of the activated glucocorticoid receptors with pro-inflammatory transcription factors such as NF-?B and AP-1 (Rhen and Cidlowski, 2005). The anti-inflammatory actions of glucocorticoids can also be attributed to their role in increasing the transcription of genes coding for anti-inflammatory proteins such as lipocortin-1, IL-10 and neural endopeptidases (Parker and Rainey, 2004).

The immunosuppressive actions of glucocorticoids are thought to include the suppression of cell-mediated immunity through the inhibition of transcription of several cytokines including IL-2 which is required for immune cells to become activated and divide (Ito et al., 2006). Glucocorticoids also induce the apoptosis of certain immune cells, particularly immature T cells, although the exact mechanism is unclear. In addition, glucocorticoids also suppress humoural immunity and reduce antibody production, again by reducing IL-2 production (Beck and McGarry, 1962). As a result of these actions of glucocorticoids on the immune system, disorders of adrenocorticol insufficiency lead to eosinophilia, lymphocytosis and neutropenia, all disorders in which the number of white blood cells is increased, this can be corrected by cortisol. Cushing?s syndrome on the other hand can lead to eosinopenia, lymphopenia, and a neutrophilic leucocytosis, disorders in which the number of white blood cells is reduced (Beck and McGarry, 1962).

Due to their numerous and varied physiological actions the therapeutic potential of glucocorticoids is severely restricted as a result of a large number of unwanted side effects. However, because of their potent anti-inflammatory and immuno-suppressive effects glucocorticoids are widely used in asthma, rheumatoid arthritis and other inflammatory conditions and also to suppress the immune system in auto-immune disorders as well as following transplantation to help prevent rejection of the new organs (Rhen and Cidlowski, 2005). The anti-inflammatory actions of glucocorticoids are due to trans-repression and new drugs are now being tested which aim to dissociate the trans-repression actions of glucocorticoids from their trans-activation actions (Newton and Holden, 2007). This may lead to new drugs which have the anti-inflammatory properties of glucocorticoids without the unwanted metabolic effects.

It must be noted that it is not only as immuno-suppressive drugs that glucocorticoids are used, although this is their major use. They are also used in Addison?s disease to replace the missing glucocorticoids, and as mentioned above in certain surgical procedures. They have also been tested as possible treatments for mental disorders although rather unsuccessfully (Rees and King, 1952).

Almost all of the actions of glucocorticoids are considered ?permissive? (Vinson, 2009). Glucocorticoids do not directly participate in, for example, gluconeogenesis but rather they increase the transcription of key enzymes required for gluconeogenesis to take place. As such their actions permit gluconeogenesis. Similarly, they do not directly inhibit the transcription of pro-inflammatory cytokines but rather do this indirectly by preventing pro-inflammatory transcription factors such as AP-1 and NF-?B from working.

Glucocorticoids are primarily stress hormones and so are released during stress (of any form) and their actions act to increase the availability of energy substrates in different parts of the body as well as re-allocating resources to allow for necessary adaptations to be made so as to be able to cope with the stress (Lupien et al., 2007). They are not so important in protecting from the actual stressor itself but rather from protecting against the body?s natural reaction to stress from causing harm or disrupting homeostasis (Munck et al., 1984).

All of the evidence shows that glucocorticoids are mis-named in the sense that the name is misleading, however, glucocorticoids have very important roles in physiology and particularly during stress, they are far from being physiologically insignificant, and it is the very diverse and important actions of glucocorticoids that then lead to their limited therapeutic use.

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