Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

in Journal of Endocrinology

Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

Abstract

Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

Introduction

Glucocorticoids (GCs), such as cortisol in humans and corticosterone in rodents, are produced in the adrenal cortex and play a key role in the regulation of glucose homeostasis and nutrient metabolism. Synthetic GCs, which include dexamethasone and prednisolone, are used in medical practice because of their anti-inflammatory, antiallergic and immunosuppressive effects. Although synthetic GCs are broadly prescribed in numerous pathological conditions, they have important adverse metabolic effects, including peripheral insulin resistance (IR) and glucose intolerance as well as overt hyperglycaemia and diabetes. These side effects are observed particularly in susceptible individuals such as pregnant women, obese subjects, IR individuals or first-degree relatives of diabetic patients (Van Raalte et al. 2009). The ability of GCs to produce peripheral IR is central to explain their impact on glucose homeostasis. It is well known that any reduction in peripheral insulin sensitivity, e.g., when GCs are administered, is adaptively compensated by augmented pancreatic β-cell function (Beard et al. 1984, Nicod et al. 2003, Ahrén 2008, Rafacho et al. 2008). This islet compensation meets the principle of the disposition index, the product of insulin secretion and peripheral insulin sensitivity. When β-cells fail to adjust to the insulin demand imposed by the GC treatment, fasting and/or postprandial hyperglycaemia may arise. The severity and progression of these alterations depend on several parameters including dosage, period and previous individual susceptibility among others (Novelli et al. 1999, Rafacho et al. 2008, Jensen et al. 2012). In addition to the islet's compensatory responses to IR, GCs directly affect β-cell function, which may further complicate adequate glycaemia regulation. Although less explored than insulin release, these steroids also affect the secretion of other islet hormones with important roles in glucose homeostasis, such as glucagon, somatostatin and amylin. All these alterations in islet hormonal secretion can exacerbate GCs' diabetogenic actions. In the next sections, we review the main effects of GCs on peripheral tissues and the endocrine pancreas and also consider the risks and limitations of their therapeutic use.

Cellular mechanisms of GC action

Ninety-five percent of circulating cortisol is bound to corticosteroid-binding globulins and albumin (Andrews & Walker 1999). The plasma levels of the inactive form, cortisone, are ∼50–100 nM, and the hormone is largely unbound to plasma proteins (Walker et al. 1992). Local conversion between active and inactive forms is catalysed by 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD type 1 (11β-HSD1) is a reductase that converts inactive cortisone (in humans) and 11-dehydrocorticosterone (in rodents) to active cortisol and corticosterone respectively (Low et al. 1994, Voice et al. 1996). The type 2 isoform works as a dehydrogenase that catalyses the opposite reaction (Brown et al. 1993). The actions of 11β-HSD1 and 11β-HSD2 serve as a pre-receptor control of GC action and determine local GC concentrations.

GC action at the site of cells is activated by the steroid hormone binding to its receptor. The classical GC receptor (GR), a ligand-regulated transcription factor that belongs to the superfamily of nuclear receptors, binds GCs and regulates transcription of target genes by activation or repression (Mangelsdorf et al. 1995). The GR is expressed in virtually all tissues; however, GR is able to regulate genes in a cell-specific manner, indicating that the response to GCs is regulated by factors beyond receptor expression. The GR is guided from the moment of synthesis to decay through signal transduction and by a variety of molecular chaperones such as HSP70 (Nelson et al. 2004) and HSP90 (Pratt et al. 2006), which facilitate folding, maturation and ligand binding. In addition, GR-mediated transcriptional activation is modulated both positively and negatively by phosphorylation (Ismaili & Garabedian 2004) of kinases and phosphatases. Although the activity of the GR is often thought in terms of direct gene transactivation, considerable crosstalk also occurs between the GR and a cohort of molecules to mediate their function as transcriptional factors, including octamer transcription factors, OCT1 and OCT2, cyclic adenosine monophosphate response element-binding protein and signal transducers and activators of transcription 5 (Engblom et al. 2007, Chen et al. 2012, Ratman et al. 2013). Competition for limiting transcription co-activators is an important determinant of the fate of the crosstalk between the GR and other transcription factors. In addition to these genomic GC actions, the steroid hormone can induce effects on a minute time scale, which is difficult to explain by mechanisms involving gene expression changes (Long et al. 2005). Localised cell membrane receptors with GC affinity have recently been identified (Strehl & Buttgereit 2014).

GC therapy in clinical practice

Drugs based on GCs were introduced in the 1950s and have been an important therapeutic strategy to treat rheumatic and inflammatory diseases ever since. In this regard, the relevant properties are the immunosuppressive, anti-inflammatory and antiallergic effects that GCs exert on primary and secondary immune cells, tissues and organs (Stahn & Buttgereit 2008). Estimates suggest that between 1 and 2% of the adult population in the Western world is receiving some form of long-term GC treatment, with a clear higher usage among patients of the geriatric age group (Van Staa et al. 2000). In dermatology, GCs are the most widely used therapy, for example, to treat atopic eczema. Inhaled GCs are used to treat allergic reactions in airways and to dampen bronchial hyperreactivity in asthma. Systemically, GCs are used to combat connective tissue inflammation, rheumatoid arthritis, bowel diseases and in allotransplantation (Thiele et al. 2005).

Diabetogenic actions of GCs in skeletal muscle and adipose, hepatic and bone tissues

There are a myriad of risks associated with excessive GC use; these risks have been recognised since GCs came into clinical use (Schäcke et al. 2002). Given GCs' strong capacity to counteract the action exerted by insulin and raise blood sugar levels, it is not surprising that IR and glucose intolerance is a concern in patients with Cushing's syndrome and disease (endogenous GC overproduction) and in patients prescribed GC-based therapy for immunomodulatory purposes (Raúl Ariza-Andraca et al. 1998). In addition, hypercortisolaemic conditions share many characteristics with metabolic syndrome, a cluster of abnormalities including hyperglycaemia, abdominal obesity, dyslipidaemia and hypertension (Anagnostis et al. 2009). Low-dose GC therapy is considered when the daily dose is <7.5 mg prednisolone or equivalent (van der Goes et al. 2010). When such a dose is administrated orally, plasma prednisolone levels peak 2–4 h after intake at about 400–500 nM (∼150–200 ng/ml) and return to baseline within 12 h after steroid administration (Wilson et al. 1977, Tauber et al. 1984). These values are in the same range as normal endogenous cortisol levels: reference values for samples taken between 0400 and 0800 h are 250–750 nM and for samples taken between 2000 and 2400 h are 50–300 nM. This indicates that the absolute cortisol values are not as important for developing adverse effects during low-dose GC therapy as is the diurnal variation. Current knowledge gives at hand that development of diabetes after starting low-dose GC treatment seems rare, but progression of already impaired glucose tolerance to overt diabetes is possible (van der Goes et al. 2010). Therefore, clinical recommendation states that baseline fasting glucose should be monitored before initiating therapy and during following up according to standard patient care. Certainly, the adverse effects are more pronounced during high-dose GC therapies (>30 mg prednisolone or equivalent daily). In a retrospective study of HbA1c levels in patients with rheumatic diseases subjected to prednisolone treatment, it was found that around 82% had HbA1c levels higher than 48 mmol/mol (given in IFCC standard, corresponding to 6.7% in DCCT standard). Serum HbA1c levels higher than 52 mmol/mol (7.1%) were seen in 46% of the patients and 23% of the patients had HbA1c levels as high as 57 mmol/mol (7.6%), which should be considered as a high-risk factor for diabetes. Taken together, it was found that the cumulative prednisolone dose was the only factor significantly associated with the development of steroid-induced diabetes among rheumatic patients (Origuchi et al. 2011).

Adipose tissue

GCs regulate the maturation of pre-adipose cells into differentiated adipose cells as well as metabolism in adipose tissue (Rebuffé-scrive et al. 1992). As the GR is predominantly expressed in adipose cells located in intra-abdominal fat, GCs are more highly activated in these fat deposits (Pedersen et al. 1994). A striking feature observed under conditions of GC excess is enhanced accumulation of visceral fat and loss of peripheral fat deposits in the arms and legs (Reynolds et al. 2012; Fig. 1). In the peripheral fat deposits, GCs promote the expression of the key lipolytic enzyme hormone-sensitive lipase (Slavin et al. 1994); thus, acute infusion of cortisol in healthy humans induces triglyceride hydrolysis and the release of fatty acids and glycerol to the systemic circulation (Divertie et al. 1991). On the contrary, it has been suggested that GCs promote increased fat mass and triglyceride synthesis in visceral fat. Hence, GCs and insulin work in concert to activate lipoprotein lipase (Ottosson et al. 1994), which leads to relocation of fat deposits from arms and legs to abdominal sites. Furthermore, GC treatment was shown to inhibit 5′ AMP-activated protein kinase (AMPK) activity specifically in rat visceral, but not subcutaneous adipose tissue (Christ-Crain et al. 2008), which may explain the redistribution of fat deposits that occurs during GC excess. This hypothesis remains to be proven in humans but is supported by the observation that patients with Cushing's syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue (Kola et al. 2008). In Addition, GC-induced attenuation of insulin signalling in the adipose tissue has been associated with reduced glucose uptake (Ortsäter et al. 2012). In summary, GCs exposure leads to impaired insulin signalling and a systemic elevation of fatty acids and triglycerides which contributes to IR. Furthermore, GCs induce abdominal obesity.

Figure 1
Figure 1

Effects of GCs on peripheral tissues involved in the control of glucose homeostasis. Excess or prolonged GC treatment may disrupt glucose homeostasis by interfering with several metabolic-related tissues. In visceral adipose tissue, GCs elevate LPL activity, leading to fat accumulation at this fat site. Fat in the limbs appears to respond to GCs with increased HSL activity, resulting in increased lipid (FFA and glycerol) release, supplying substrates for hepatic TG synthesis and gluconeogenesis, and also in intramuscular fat accumulation. These steroids may also affect insulin signalling in adipose tissue. GCs impair insulin-stimulated glucose uptake in skeletal muscles and induce muscle wasting, which, in turn, provides gluconeogenesis substrates. In the liver, GCs have a negative effect on rate-limiting enzymes controlled by insulin. Finally, GC in excess may also alter osteocalcin synthesis in osteoblast cells, leading to reduced osteocalcinaemia. FFA, free fatty acids; GCs, glucocorticoids; G6Pase, glucose-6-phospatase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; PEPCK, phophoenolpyruvate carboxykinase; TG, triacylglycerol.

Citation: Journal of Endocrinology 223, 3; 10.1530/JOE-14-0373

Skeletal muscle

Skeletal muscle accounts for ∼80% of insulin-mediated glucose uptake (IMGU) and is the largest glycogen store. GCs interfere directly with insulin signalling in skeletal muscle cells. Studies have shown that administration of dexamethasone reduces the expression and activity of insulin substrate 1 (IRS1) and phosphatidylinositol-4,5-bisphosphate 3-kinase in rodent skeletal muscle cells (Saad et al. 1993, Morgan et al. 2009), which would presumably lead to a reduction in IMGU and abrogation of glycogen synthesis (Fig. 1). Indeed, in a study with healthy human volunteers, prednisolone treatment for 6 days (0.8 mg/kg per day) reduced insulin-induced leg glucose uptake by 65% compared with placebo treatment (Short et al. 2009). In a study supporting this, rats treated with GCs were shown to have reduced insulin-stimulated glucose uptake, caused by attenuated insulin-induced glucose transporter type 4 translocation to the cell membrane in myotubes (Dimitriadis et al. 1997). The condition is worsened by the accumulation of ectopic fat deposition in skeletal muscle (Fransson et al. 2013; Fig. 1), which originates from the systemic GC-induced fatty acid elevation as discussed earlier. Taken together, these data show that GCs directly interfere with insulin signalling in skeletal muscle cells leading to reduced IMGU.

Hepatic tissue

Hepatic tissue plays a key role in the control of glucose and lipid homeostasis. Although insulin does not directly stimulate glucose uptake in liver cells, the hormone is responsible for hepatic glycogen synthesis and gluconeogenesis suppression. These insulin actions are mediated via insulin receptor signalling. As in skeletal muscle, GC excess also interferes with the insulin signalling cascade in hepatic tissue. In one study, dexamethasone-treated rats (1.5 mg/kg body weight for 6 consecutive days) exhibited an ∼50–70% reduction in insulin receptor binding in hepatocytes (Olefsky et al. 1975). A significant reduction in insulin receptor density was also observed in hepatocytes from rats chronically treated with dexamethasone (Caro & Amatruda 1982). Diminished tyrosine phosphorylation in either insulin receptor or IRS1 was observed in liver from rats treated with dexamethasone for 5 consecutive days (Saad et al. 1993). In addition, GCs were shown to augment endogenous glucose production in several (Rizza et al. 1982, Pagano et al. 1983, Rooney et al. 1993) but not all (Wajngot et al. 1990) studies conducted in healthy humans. GC-driven glucose production may be caused by enhanced gluconeogenesis, as GCs induce rate-limiting enzymes for gluconeogenesis, e.g., phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (Lange et al. 1994, Cassuto et al. 2005; Fig. 1). GC-mediated expression of gluconeogenic enzymes appears to be dependent on liver X receptor (LXR) expression (Patel et al. 2011). Indeed, mice lacking LXRβ (but not LXRα) were demonstrated to be resistant to dexamethasone-induced hyperglycaemia, hyperinsulinaemia and hepatic steatosis, but remained sensitive to dexamethasone-dependent immune system repression (Patel et al. 2011). Moreover, as GCs promote muscle wasting and lipolysis, they also increase the bioavailability of substrates for gluconeogenesis (Divertie et al. 1991, Kim et al. 2012; Fig. 1). Finally, fat accumulation leads to hepatic steatosis (Fransson et al. 2013), which, by itself, attenuates insulin sensitivity (Kim et al. 2012). To summarise, elevated GC levels promote gluconeogenesis in hepatic tissue leading to fasting hyperglycaemia.

Bone tissue

Osteoporosis is a common side effect observed in patients on GC-based therapy (Hoes et al. 2010). GCs also suppress osteoblast function, including osteocalcin synthesis (Prummel et al. 1991; Fig. 1). Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism (Ferron et al. 2008). In a pioneering work by Lee et al. (2007), it was demonstrated, both in cell culture and in mice, that osteocalcin increased pancreatic β-cell proliferation as well as insulin expression and release, resulting in improved glucose tolerance. In addition, uncarboxylated osteocalcin increased adiponectin expression and secretion in adipose tissue, which in turn enhanced insulin sensitivity (Lee et al. 2007). Serum osteocalcin concentrations are positively correlated with improved glucose control (Bao et al. 2011) in the development type 2 diabetes in humans. In another study, osteoblast-targeted disruption of GC signalling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of IR, glucose intolerance and abnormal weight gain in corticosterone-treated mice (Brennan-Speranza et al. 2012). Nearly, identical effects were observed in GC-treated animals following hepatic expression of both carboxylated and uncarboxylated osteocalcin. These data suggest a link between effects of GC on the skeleton and the effects of steroid hormone on glucose homeostasis.

Effects of GC treatment on pancreatic β-cells and insulin secretion

Pancreatic β-cells respond to increasing plasma glucose levels by secreting insulin, which maintains glycaemia within narrow physiological ranges. This key function can be altered by GCs through direct and indirect actions and may also depend on action of GCs as acute or chronic stimuli. In the next sections, we consider the different aspects of GCs' effects on β-cells.

Acute effects of GCs

The direct in vitro effects of GCs on glucose-stimulated insulin secretion (GSIS) are generally inhibitory and occur within a few minutes, as demonstrated in isolated rat islets exposed to corticosterone (0.02–20 mg/l) (Billaudel & Sutter 1979; Fig. 2A, left). This inhibitory action involves α-adrenergic signalling due to the blockage of GCs' effect by phentolamine (a non-selective α-adrenergic antagonist; Barseghian & Levine 1980). This rapid impact of GCs is not reproduced by synthetic steroids. GSIS inhibition in mouse (Lambillotte et al. 1997) and rat islets (Zawalich et al. 2006) is manifested only after the third hour of exposure to 1 μM dexamethasone.

Figure 2
Figure 2

Sites of the insulin secretory process affected by in vitro or in vivo (ex vivo) exposure to glucocorticoids (GCs). In (A), the known components involved in the acute or chronic in vitro effects of GCs on the β-cell insulin secretory process are highlighted with a positive signal (indicates GCs stimulate/increase that action/function) or a negative signal (indicates GCs inhibit/diminish that action/function). Most notably, GCs impair β-cell glucose metabolism, favour repolarising Kv + currents, decrease PKA and PKC activation, induce ER dyshomeostasis, increase 11β-HSD1 activity and ROS generation and impair calcium handling. Together, these effects inhibit insulin secretion. In (B), the known components involved in β-cell function, which are affected by acute or long-term in vivo GC treatment, are highlighted with a positive signal, which indicates increased content or activity. Most notably, augmented glucose metabolism and cholinergic pathway activity cause increased calcium influx and insulin secretion. In this context, a positive GC effect on K+ and VDCC could not be excluded. AC, adenylyl cyclase; Ach, acetylcholine; αAR, α adrenergic receptor; DAG, diacylglycerol; ER, endoplasmic reticulum; Gi, G-coupled inhibitory protein; GLUT2, glucose transporter 2; IP3, inositol triphosphate; K+, ATP- dependent K+ channel; Kv +, voltage-dependent K+ channel; M3R, muscarinic receptor type 3; PIP2, phosphatidylinositol bisphosphate; PKA, protein kinase A; PLC, phospholipase C; ROS, reactive oxygen species; VDCC, voltage-dependent Ca2 + channel; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1.

Citation: Journal of Endocrinology 223, 3; 10.1530/JOE-14-0373

GCs may also exert a negative in vivo effect during acute administration. A single oral dose of prednisolone (75 mg; van Raalte et al. 2010) or dexamethasone (1 mg; Schneiter & Tappy 1998) in healthy volunteers resulted in decreased insulin secretion and/or a reduced insulinogenic index (the ratio between Δinsulinaemia and Δglycaemia) during a meal or an oral glucose tolerance test (oGTT) respectively. In contrast, other studies did not demonstrate this acute GC effect in healthy men (Vila et al. 2010) or normal adult rats (Stojanovska et al. 1990) during an i.v. or oGTT respectively. Similar to the in vitro observations mentioned earlier, increased sympathetic drive may be involved in GCs' inhibition of in vivo insulin secretion (Longano & Fletcher 1983). This hypothesis is based on a study conducted in adult Swiss mice treated with hydrocortisone (300 mg/kg body weight) 1 h before determining fed blood glucose and plasma insulin values. The insulinogenic index was reduced 1 h after steroid administration in fed, mice but unaltered when chlorisondamine (a ganglionic blocker) or phentolamine was given 10 min before GC administration (Longano & Fletcher 1983; Fig. 2B, left). Overall, acute exposure or administration of GCs appears to cause a decline in the insulinogenic index in humans and rodents, and this effect may be mediated by sympathetic activation of α-adrenergic receptors. It is important to highlight that 24 h after interrupting GC administration, all β-cell function parameters return to normal values (van Raalte et al. 2010).

Chronic effects of GCs

As observed in acute in vitro experiments, chronic incubation (hours to days) with synthetic GCs in in vitro conditions leads to decreased GSIS in rodent isolated islets, dispersed β-cells and insulin-secreting cell lines (Lambillotte et al. 1997, Shao et al. 2004, Ullrich et al. 2005, Zawalich et al. 2006). GCs' deleterious effects on GSIS involve impaired glucose oxidative metabolism (Shao et al. 2004), activation of repolarising K+ channels (Ullrich et al. 2005), generation of reactive oxygen species (Roma et al. 2011), endoplasmic reticulum dyshomeostasis (Linssen et al. 2011), activation of 11β-HSD1 (Davani et al. 2000) and decreased efficiency of intracellular Ca2 + on the secretory response (Lambillotte et al. 1997, Shao et al. 2004, Zawalich et al. 2006; Fig. 2A, right).

However, in contrast to the above-mentioned inhibitory effects observed in both acute and long-term GC incubation, chronic in vivo administration of these steroids leads to up-regulation of β-cell function as a result of the compensatory adaptation to GC-induced IR. Administration of high doses of prednisolone (30 mg) or dexamethasone (2–15 mg) to healthy individuals for prolonged periods (up to 15 days and up to 4 days respectively) resulted in normoglycaemia or a modest increase in fasting glycaemia (Beard et al. 1984, Schneiter & Tappy 1998, Hollindgal et al. 2002, Willi et al. 2002, Nicod et al. 2003, Ahrén 2008, van Raalte et al. 2010, Petersons et al. 2013). Importantly, in most of these studies, volunteers developed hyperinsulinaemia. In fact, during glucose challenging with a hyperglycaemic-clamp (Beard et al. 1984, Nicod et al. 2003) or an oGTT (Schneiter & Tappy 1998, Hollindgal et al. 2002, Willi et al. 2002), insulin release was significantly higher in GC-treated individuals compared with control groups. The plasma C-peptide values were also elevated after treatment with prednisolone in healthy men at basal conditions (Hollindgal et al. 2002) and during a meal tolerance test (van Raalte et al. 2010). This enhanced β-cell function was also observed in adult rats treated for up to 13 consecutive days with dexamethasone (0.125–2.0 mg/kg) based on basal hyperinsulinaemia (Novelli et al. 1999, Karlsson et al. 2001, Rafacho et al. 2008) or in vivo glucose challenging (Rafacho et al. 2008, 2011). This augmented β-cell function occurred in a dose- (Rafacho et al. 2008) and time-dependent manner (Rafacho et al. 2011). In normal adult mice, administration of dexamethasone for 10 days or corticosterone from the 1st consecutive week also resulted in basal hyperinsulinaemia (Thomas et al. 1998, Fransson et al. 2013).

This hyperinsulinaemia is consistent with insulin hypersecretion observed in pancreatic islets isolated from GC-treated rats (Novelli et al. 1999, Karlsson et al. 2001, Rafacho et al. 2008, 2010a,b). This enhanced β-cell secretion involves an improvement in glucose responsiveness (Karlsson et al. 2001, Rafacho et al. 2008), sensitivity (Rafacho et al. 2008) and oxidative metabolism (Rafacho et al. 2010a) as well as augmented Ca2 + handling (Rafacho et al. 2010a) and an improved response to cholinergic signals (Angelini et al. 2010, Rafacho et al. 2010a, b; Fig. 2B, right). The islet compensatory response is also accompanied by structural changes. It has been demonstrated that, β-cell mass increases in a time- (Rafacho et al. 2011) and dose-dependent manner (Rafacho et al. 2009) with GC administration, according to the correspondent degree of insulin insensitivity. Taken together, these results show that when humans or animal models are exposed to prolonged steroid treatment, they develop augmented β-cell function and mass to counteract the IR resulting from GC administration.

GC treatment, β-cell dysfunction and glucose intolerance

Depending on the GC regimen, glucose homeostasis is maintained at normal or near normal physiological conditions by adaptive β-cell compensations. However, these adaptations do not always guarantee an adequate glucose homeostasis. Although insulin hypersecretion observed after prolonged steroid treatment appears to be consistent in most experiments carried out in healthy volunteers (Beard et al. 1984, Schneiter & Tappy 1998, Ahrén 2008, van Raalte et al. 2010) and normal adult rats (Karlsson et al. 2001, Rafacho et al. 2008, 2009, 2011), glucose intolerance is also present. In these studies, hyperinsulinaemia is normally associated with normoglycaemia or modest increases in blood glucose values, but the insulin (Schneiter & Tappy 1998, Rafacho et al. 2008, 2011) and C-peptide hypersecretion (van Raalte et al. 2010) during glucose or meal challenges, respectively, do not prevent elevation in postprandial blood glucose levels. Therefore, the insulinogenic index may not necessarily match the peripheral insulin demand imposed by GCs.

The negative impact of GCs on glucose homeostasis is more apparent in individuals or rodents with any degree of susceptibility to glucose intolerance, such as those with low insulin sensitivity (Larsson & Ahrén 1999), low insulin response to glucose (Wajngot et al. 1992), first-degree relatives of patients with type 2 diabetes (Jensen et al. 2012), obesity (Besse et al. 2005) and those who are older (Novelli et al. 1999). In these contexts, β-cell function does not correspond to the peripheral insulin demand, and the deregulation of glucose homeostasis becomes more pronounced, reinforcing that individual background is a critical factor. Indeed, this susceptibility to β-cell failure after treatment with dexamethasone has also been observed in animal models with an obesity background, such as fa/fa rats (Ogawa et al. 1992) and ob/ob mice (Khan et al. 1992).

In an attempt to analyse whether GCs have any direct effects on β-cells in vivo independent of peripheral GC actions, a transgenic mice model that specifically overexpresses GR in these cells was generated (Delaunay et al. 1997, Davani et al. 2004). These mice were normoglycaemic, but displayed glucose intolerance associated with reduced insulin secretion during a glucose load (Delaunay et al. 1997). When these transgenic mice aged, hyperglycaemia developed together with marked glucose intolerance and reduced in vivo and ex vivo GSIS. Remarkably, no change in β-cell apoptosis was observed in these mice (Davani et al. 2004). This deterioration in GSIS was prevented by incubating islets with benextramine (a selective α2-adrenergic receptor antagonist), suggesting the involvement of adrenergic signals. In any case, the analysis of direct GC effects on β-cells in vivo is difficult because the systemic metabolic consequences of GC treatment most likely mask the GC-mediated changes in β-cell function. Of note, almost all the morphofunctional β-cell changes elicited by GC administration are transitory and reversible after 10 days of discontinuation of steroid treatment in rats, suggesting an unacknowledged plasticity in the regulation of β-cell function and growth (Rafacho et al. 2010b).

Effects of GCs on glucagon release and other islet hormones

Glucagon secretion by pancreatic α-cells plays a key role in glucose homeostasis. Glucagon's release is enhanced at low plasma glucose levels, but decreases under hyperglycaemic conditions (Quesada et al. 2008, Marroqui et al. 2014). Glucagon is one of the most important hyperglycaemic hormones and acts as insulin's counterpart, opposing numerous anabolic insulin-mediated actions. The hyperglycaemic effect is mainly produced by activating hepatic glycogenolysis and gluconeogenesis, which results in the release of endogenous glucose into the bloodstream. This process restores normoglycaemia under hypoglycaemic conditions (Quesada et al. 2008, Marroqui et al. 2014). Hyperglucagonaemia may be present in diabetes. In addition, inhibition of glucagon release at high glucose levels may be impaired in this metabolic condition. This impaired α-cell function can lead to higher hepatic glucose output, further contributing to hyperglycaemia in diabetic patients (Quesada et al. 2008; Marroqui et al. 2014). As in the case of β-cells, in the next section we summarise the acute and chronic effects of GCs on α-cell function.

Acute effects of GCs on α-cell function and glucagon release

One study reported that corticosterone (10−7 M) potentiated glucagon release induced by a glucose-free medium or arginine in isolated perfused rat pancreas (Barseghian & Levine 1980). In contrast, incubation of mouse pancreatic islets with dexamethasone (0.5–50 nM), corticosterone (50 nM) or 11-dehydrocorticosterone (50 nM) for 2 h reduced glucagon secretion induced by low glucose levels, effects that were reversed by a GR antagonist (Swali et al. 2008). The inhibitory action of 11-dehydrocorticosterone was partially reversed by a selective 11β-HSD1 inhibitor. This fact, along with the co-localisation of this enzyme in human and rodent islet α-cells, indicates that this islet cell type serves an important local function in pancreatic GC metabolism (Swali et al. 2008). This situation may be different in other species, for example in rats, where this enzyme is expressed in non-α-cells (Rafacho et al. 2014). In contrast with the above-mentioned results, prednisolone (10−5 M) failed to modify glucagon secretion in mouse pancreatic islets (Marco et al. 1976). Likewise, incubation of rat pancreatic islets with dexamethasone (1 μM) for 3 h did not modify glucagon secretion (Rafacho et al. 2014). Thus, in vitro experiments with acute GC exposure have reported divergent effects on glucagon secretion. These divergences may depend on different factors, including the preparation and species studied as well as the specificity and potency of the different GCs used.

Chronic effects of GCs on α-cell function and glucagon release

α-cell growth regulation by long-term GC exposure has been explored during development. α-cell mass was decreased in 21-day-old foetuses obtained from pregnant rats that received dexamethasone in drinking water (1 μg/ml) either during the last week of pregnancy or throughout gestation (Dumortier et al. 2011). In contrast, GR inactivation in the pancreatic β-cell (rat insulin promoter-Cre transgene) or in cells expressing pancreatic and duodenal homeobox 1, which is involved in pancreas development, did not modify α-cell mass in adult mice (Gesina et al. 2004). Adult rats treated with dexamethasone (1 mg/kg) for 5 consecutive days exhibited a 50% increase in α-cell mass (Rafacho et al. 2014). Similarly, administration of corticosterone to adult rats fed a high-fat diet promoted a synergistic positive effect on α-cell mass (Beaudry et al. 2013). In general, GC administration in adults appears to up-regulate α-cell mass, while the opposite effect is observed during development.

Glucagon release is also modulated by GCs. Rats treated with dexamethasone (1 mg/kg) for 5 consecutive days exhibited hyperglucagonaemia (Rafacho et al. 2014). In this model, isolated pancreatic islets exhibited impaired inhibition of glucagon release at high glucose levels. Similarly, dexamethasone (0.25 mg/kg) administered for 7 days in rhesus macaques induced fasting hyperglucagonaemia (Cummings et al. 2013), and prednisolone (0.2–0.3 mg daily) administered for 4 days increased basal and arginine-induced glucagon secretion in isolated mouse islets (Marco et al. 1976). In contrast to the above-mentioned results obtained for in vivo GC treatment, glucagon release was suppressed in isolated rat islet cells incubated for 18 h with dexamethasone at 10−9 and 10−10 M, but was without effect at higher steroid concentrations (Papachristou et al. 1994). Thus, in vivo and ex vivo chronic studies mostly point to enhanced α-cell secretion after GC administration. The resulting hyperglucagonaemia may aggravate GC-induced hyperglycaemia by stimulating hepatic glucose release and opposing insulin actions (Quesada et al. 2008; Fig. 3).

Figure 3
Figure 3

Diabetogenic effects of GC treatment: implication of islet hormones. GC treatment can induce IR in peripheral tissues. As a compensatory adaptive process, the endocrine pancreas increases insulin release, leading to hyperinsulinaemia. An adequate compensatory response to the insulin requirements imposed by IR allows for normoglycaemia. However, an insufficient β-cell response could lead to impaired glucose tolerance, which can progress to overt hyperglycaemia and type 2 diabetes. GC treatment also induces high plasma levels of glucagon and amylin, and may affect somatostatin concentrations. Although somatostatin inhibits α- and β-cells, the potential changes in this hormone induced by GCs do not appear to produce a significant negative effect in these conditions. Hyperglucagonaemia increases hepatic glucose output, which exacerbates hyperglycaemia and glucose intolerance and further opposes insulin action, decreasing the insulin effect. High amylin levels have been related with increased predisposition to amyloid formation in decreased insulin sensitivity conditions, such as those generated by GCs. Amyloid aggregation is related with increased β-cell death and malfunction. The molecular mechanisms underlying the high plasma levels of glucagon and amylin induced by GC treatment are still unknown.

Citation: Journal of Endocrinology 223, 3; 10.1530/JOE-14-0373

Clinical studies have also evaluated GCs' effects on human α-cell function. Administration of prednisolone (40–100 mg daily) for up to 4 days induced fasting hyperglucagonaemia and glucagon hypersecretion in response to arginine (Marco et al. 1973). Similarly, daily dexamethasone treatment (2 mg) for 3 days led to increased basal plasma glucagon levels and enhanced alanine-induced glucagon release in non-obese subjects (Wise et al. 1973). Both responses were even more pronounced in obese individuals and patients with Cushing's syndrome. Moreover, administration of dexamethasone (3 mg twice daily for 2 days) and prednisolone (30 mg for 2 consecutive weeks) led to increased fasting and postprandial glucagon levels (Beard et al. 1984, van raalte et al. 2013). In contrast, in a few studies, fasting glucagon concentrations were found to be unchanged by dexamethasone (3 mg twice daily for 2 and ½ days; Larsson & Ahrén 1999). Thus, the majority of clinical studies show that GC treatment may up-regulate α-cell function, which may enhance GCs' diabetogenic actions (Fig. 3).

Effects of GCs on somatostatin, amylin and ghrelin release

Pancreatic δ-cells secrete somatostatin, which indirectly affects glucose homeostasis, suppressing both insulin and glucagon release (Quesada et al. 2008). In vivo experiments showed that dexamethasone administration (0.5 mg/kg) for 3 or 8 days in rats increased somatostatin gene expression and protein content in the pancreas (Papachristou et al. 1994). However, plasma somatostatin levels were not measured in these conditions. In in vitro experiments, incubation of isolated islet-cells with dexamethasone for 18 h produced a biphasic effect: while low doses (10−10 M) stimulated the somatostatin gene and protein expression, high doses (10−8–10−5 M) produced the opposite effect (Papachristou et al. 1994). At this chronic exposure, the high doses reduced somatostatin release into the medium. When foetal pancreatic islets were cultured for 8 days with corticosterone (0.1 μg/ml), both the somatostatin concentration in the medium and the islet somatostatin content were increased (McEvoy et al. 1981). Thus, few experiments indicate that GC may regulate directly or indirectly δ-cell function (Fig. 3). Elevation in plasma somatostatin concentrations should inhibit α and β-cell functions under normal physiological conditions. However, this appears not to be the case during GC administration, given that GC treatment results in hyperglucagonaemia and hyperinsulinaemia.

The islet amyloid polypeptide (IAPP), also called amylin, is co-secreted with insulin by pancreatic β-cells in response to food intake, most likely via the same mechanisms that allow for insulin release. This hormone decreases postprandial glycaemia by inhibiting gastric emptying and suppressing glucagon secretion (Westermark et al. 2011). However, type 2 diabetes has also been related with the formation of toxic amyloid aggregates that can induce β-cell apoptosis (Westermark et al. 2011). This aggregation might be associated with IR and insulin (and amylin) hypersecretion (Westermark et al. 2011), which also result from GC treatment. With this enhanced hormonal release, impaired intracellular IAPP processing may initiate the process of amylin aggregation. For instance, dexamethasone treatment for up to 12 days led to increased levels of both proinsulin and Iapp mRNA in rat islets (Bretherton-Watt et al. 1989, Koranyi et al. 1992). Similarly, both enhanced plasma amylin levels and amylin secretion from isolated pancreata were found in dexamethasone-induced IR rats (Pieber et al. 1993, Mulder et al. 1995). Similar findings in amylin changes have been reported in humans after dexamethasone treatment (Ludvik et al. 1993), indicating that GC administration may enhance IAPP release (Fig. 3).

Ghrelin is released not only by P/D1 cells from the stomach but also by ϵ-cells from the pancreas (Wierup et al. 2013). Only few ϵ-cells are present in each islet. Ghrelin inhibits insulin and somatostatin secretion, but increases glucagon release (Chuang et al. 2011, Wierup et al. 2013). In addition, this hormone potently stimulates growth hormone release from the anterior pituitary gland and stimulates appetite (Malik et al. 2008). In hypercortisolemic patients with Cushing's disease, plasma ghrelin concentrations increased after successful surgery, while prednisolone administration (30 mg/day) for 5 days decreased plasma ghrelin levels in healthy individuals (Otto et al. 2004). However, no changes were observed in response to a unique bolus of hydrocortisone (0.6 mg/kg) in healthy men (Vila et al. 2010). In a neonatal rat model, dexamethasone (0.5–0.05 mg/kg) administrated for 4 consecutive days led to augmented plasma ghrelin levels in newborns (Bruder et al. 2005). However, any of the above-mentioned studies discriminated the ghrelin source, either the stomach or the pancreas. Thus, much research is necessary to address whether GCs can affect the function of ϵ islet-cells.

Conclusions and future perspectives

The diabetogenic effects of GCs are a limiting factor to their clinical use, particularly in individuals with diabetes risk factors. These side effects include unfavourable actions on peripheral tissues, such as skeletal muscle, liver, bone and adipose tissue, which mainly result, among other effects, in decreased insulin sensitivity, augmenting insulin needs. In response to this GC-induced IR, the endocrine pancreas undergoes compensatory β-cell changes in function and mass, which lead to hyperinsulinaemia and enhanced stimulated insulin release, to maintain normoglycaemia. Despite the fact that most of these adaptations are observed in healthy subjects and animal models under GC treatment, the adaptations do not necessarily guarantee an adequate insulinogenic index to prevent glucose intolerance. These β-cell adaptations are less efficient in susceptible individuals, increasing the risk of impaired glucose homeostasis during GC treatment. Up-regulated β-cell function resulting from steroid treatment contrasts with the direct inhibitory actions observed in both acute and long-term in vitro GC exposures. Thus, the effects derived from in vivo GC treatment may prevail over the potential direct GC actions on β-cells. In any case, further research is necessary to unravel the molecular mechanisms of both direct and indirect GC actions on the endocrine pancreas.

Several studies have also documented acute and chronic GC effects on non-β pancreatic cells. The mechanisms implicated are not clear, but may involve multiple factors, including direct actions on islet cells as well as effects derived from adaptations to IR, hyperglycaemia, hyperinsulinaemia or other conditions. Remarkably, the majority of in vivo animal studies and clinical reports show that, in addition to hyperinsulinaemia, GC treatment induces higher plasma levels of glucagon and amylin and may probably affect somatostatin. The increased plasma amylin levels might also be considered diabetogenic because enhanced IAPP concentrations may lead to increased rates of toxic amylin aggregation (Couce et al. 1996). In addition, the hyperglucagonaemia observed with GC treatment opposes insulin actions and may aggravate steroid-induced hyperglycaemia by increasing hepatic glucose output, as indicated in diabetes (Quesada et al. 2008). Thus, the impaired release of the different islet hormones may increase the diabetogenic effects of GCs.

The majority of studies about GC actions involve the use of murine models, and thus, prudence is required when translating this experimental data to humans. However, it is also important to mention that the prolonged duration of several GC therapies in clinical practice may exceed the safe period proposed in experimental approaches in human studies, which generally do not surpass 2–15 days of GC treatment (van Raalte et al. 2009). Thus, experimental data from human, although of great relevance, fail to totally mimic the conditions of clinical practice (i.e. duration). Elaboration of protocols to investigate GC actions in human volunteers is not feasible, considering the risk of irreversible negative effects, ethical issues, as well as the nature of ex vivo and in vitro techniques available for the mechanistic studies (van Raalte et al. 2009). In this regard, animal models are valuable tools, because part of the above-mentioned limitations can be resolved.

Improved knowledge of GCs' intracellular signalling mechanisms and effects will help to design better GC therapies. In this regard, it has been suggested that gene transrepression accounts for the majority of therapeutic GC effects, while transactivation of metabolic target genes is mainly responsible for the side effects (Strehl & Buttgereit 2013). Using this concept, several GR agonists dissociating transrepression from transactivation were developed (Löwenberg et al. 2008). Some of these agonists have proven useful for maintaining GCs' anti-inflammatory and immunosuppressive effects, while reducing side effects such as hyperglycaemia. However, the above-mentioned concept may be over-simplistic, and side effects may not only be explained by transactivation but also by nongenomic actions (Vandevyver et al. 2013). Thus, a great deal of research is still necessary to develop GR agonists with reduced drawbacks for glucose homeostasis. Moreover, the combination of GC-based therapies with glucose-lowering drugs could also be an interesting alternative explored to minimise the disadvantages of GC treatment.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by grants from the Brazilian foundation Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 471397/2011-3), the Spanish foundations Ministerio de Ciencia e Innovación (BFU2013-42789; BFU2011-28358) and the European Foundation for the Study of Diabetes (EFSD/BI Basic Programme and the Albert Renold Fellowship). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

Author contribution statement

A R, H O, A N and I Q discussed and wrote the manuscript. All authors approved the final version of the manuscript to be published.

Acknowledgements

The authors give special thanks to the members of their laboratories.

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    Effects of GCs on peripheral tissues involved in the control of glucose homeostasis. Excess or prolonged GC treatment may disrupt glucose homeostasis by interfering with several metabolic-related tissues. In visceral adipose tissue, GCs elevate LPL activity, leading to fat accumulation at this fat site. Fat in the limbs appears to respond to GCs with increased HSL activity, resulting in increased lipid (FFA and glycerol) release, supplying substrates for hepatic TG synthesis and gluconeogenesis, and also in intramuscular fat accumulation. These steroids may also affect insulin signalling in adipose tissue. GCs impair insulin-stimulated glucose uptake in skeletal muscles and induce muscle wasting, which, in turn, provides gluconeogenesis substrates. In the liver, GCs have a negative effect on rate-limiting enzymes controlled by insulin. Finally, GC in excess may also alter osteocalcin synthesis in osteoblast cells, leading to reduced osteocalcinaemia. FFA, free fatty acids; GCs, glucocorticoids; G6Pase, glucose-6-phospatase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; PEPCK, phophoenolpyruvate carboxykinase; TG, triacylglycerol.

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    Sites of the insulin secretory process affected by in vitro or in vivo (ex vivo) exposure to glucocorticoids (GCs). In (A), the known components involved in the acute or chronic in vitro effects of GCs on the β-cell insulin secretory process are highlighted with a positive signal (indicates GCs stimulate/increase that action/function) or a negative signal (indicates GCs inhibit/diminish that action/function). Most notably, GCs impair β-cell glucose metabolism, favour repolarising Kv + currents, decrease PKA and PKC activation, induce ER dyshomeostasis, increase 11β-HSD1 activity and ROS generation and impair calcium handling. Together, these effects inhibit insulin secretion. In (B), the known components involved in β-cell function, which are affected by acute or long-term in vivo GC treatment, are highlighted with a positive signal, which indicates increased content or activity. Most notably, augmented glucose metabolism and cholinergic pathway activity cause increased calcium influx and insulin secretion. In this context, a positive GC effect on K+ and VDCC could not be excluded. AC, adenylyl cyclase; Ach, acetylcholine; αAR, α adrenergic receptor; DAG, diacylglycerol; ER, endoplasmic reticulum; Gi, G-coupled inhibitory protein; GLUT2, glucose transporter 2; IP3, inositol triphosphate; K+, ATP- dependent K+ channel; Kv +, voltage-dependent K+ channel; M3R, muscarinic receptor type 3; PIP2, phosphatidylinositol bisphosphate; PKA, protein kinase A; PLC, phospholipase C; ROS, reactive oxygen species; VDCC, voltage-dependent Ca2 + channel; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1.

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    Diabetogenic effects of GC treatment: implication of islet hormones. GC treatment can induce IR in peripheral tissues. As a compensatory adaptive process, the endocrine pancreas increases insulin release, leading to hyperinsulinaemia. An adequate compensatory response to the insulin requirements imposed by IR allows for normoglycaemia. However, an insufficient β-cell response could lead to impaired glucose tolerance, which can progress to overt hyperglycaemia and type 2 diabetes. GC treatment also induces high plasma levels of glucagon and amylin, and may affect somatostatin concentrations. Although somatostatin inhibits α- and β-cells, the potential changes in this hormone induced by GCs do not appear to produce a significant negative effect in these conditions. Hyperglucagonaemia increases hepatic glucose output, which exacerbates hyperglycaemia and glucose intolerance and further opposes insulin action, decreasing the insulin effect. High amylin levels have been related with increased predisposition to amyloid formation in decreased insulin sensitivity conditions, such as those generated by GCs. Amyloid aggregation is related with increased β-cell death and malfunction. The molecular mechanisms underlying the high plasma levels of glucagon and amylin induced by GC treatment are still unknown.

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