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THE IMPACT OF SHORT AND MEDIUM-TERM
GLUCOCORTICOID TREATMENT ON GLUCOSE
HOMEOSTASIS
RUCSANDRA DĂNCIULESCU MIULESCU1, MĂDĂLINA MUŞAT1*,
CORINA NEAMŢU2
1
Carol Davila University of Medicine and Pharmacy, Bucharest
C.I. Parhon, Instit. Of Endocrinology, Bucharest
*corresponding author: mdmusat@yahoo.com
2
Abstract
Glucocorticoids, like GH, are the main insulin-antagonistic hormones. They have
various metabolic effects in the liver, adipose tissue, and muscle. In the liver, glucocorticoids
serve as the key promoters of gluconeogenesis by activation of pyruvate carboxylase and
phosphoenolpyruvate carboxykinase and stimulate hepatic uptake of amino acids and
glycerol. At the level of adipose tissue and muscle, glucocorticoids antagonize the insulinmediated uptake and the use of glucose. Glucocorticoids also exert a permissive effect on
lipolysis by promoting the activation of cAMP-dependent hormone-sensitive lipase, a key
enzyme inhibited by insulin. The net clinical effect of glucocorticoid excess in humans is a
relocation of fat depots, which results in the typical central obesity of Cushing syndrome.
In healthy humans, short-term increments in plasma cortisol levels result in a
slight increase in the levels of glucose, which is mediated by both hepatic and extrahepatic
effects. However, the effects of chronic administration of moderate doses of glucocorticoids
to healthy humans are usually compensated for by increased insulin release, which results
in minimal changes in glucose levels. Thus, the spectrum of glucose intolerance in patients
with Cushing syndrome or exogenous steroid use depends in large part on endogenous βcell reserve, a situation similar to that in acromegaly.
Rezumat
Glucocorticoizii şi hormonul de creştere (GH) sunt cei mai importanţi hormoni
cu acţiune antagonică insulinei. Efectele biologice diferă în funcţie de ţesut: ţesutul hepatic,
adipos şi muscular. În ficat, glucocorticoizii sunt biomolecule-cheie în gluconeogeneză prin
activarea unor enzime (piruvat carboxilaza şi fosfoenol piruvat carboxikinaza) şi prin
stimularea captării aminoacizilor şi glicerolului în celule. La nivelul ţesutului adipos şi
muscular, glucocorticoizii antagonizează captarea mediată de insulină şi utilizarea glucozei.
Glucocorticoizii exercită un efect permisiv asupra lipolizei, prin activarea unei
lipaze specifice, enzimă-cheie inhibată de insulină. Concentraţiile prea mari de
glucocorticoizi eliberaţi sistemic conduce la o redistribuire a masei ţesutului adipos, cu
apariţia obezităţii caracteristice sindromului Cushing.
În general, creşterea moderată şi de scurtă durată a glucocorticoizilor circulanţi
determină o creştere a concentraţiei sangvine a glucozei, prin mecanisme specifice, hepatice
şi extrahepatice.
Administrarea cronică a unor doze moderate de glucocorticoizi determină o creştere a
secreţiei de insulină, ceea ce conduce la menţinerea unei concentraţii normale de glucoză. Totuşi
intoleranţa la glucoză, întâlnită atât la pacienţii cu sindrom Cushing, cât şi la cei diagnosticaţi cu
acromegalie, depinde într-o mare măsură de funcţionalitatea celulelor β-pancreatice.
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Keywords: glucocorticoids; glucose levels; β-cell reserve; diabetes; 11-β-hydroxisteroid
dehydrogenase (11-β-HSD); Bcl-2-antagonist of cell death (BAD)
Introduction
Glucose homeostasis is maintained by the balance between insulin
release and action on one hand and hyperglycemic effect of glucagon,
cathecolamines, GH and cortisol, on the other hand. Disturbing the
mechanisms that regulate the glycaemic control in various illnesses or by
drug administration can result in the damage of glucose homeostasis in
susceptible persons.
Glucocorticoids are important regulators of the protein, glucose and
lipid metabolism. There are a lot of common features in metabolic
syndrome and Cushing syndrome suggesting that a common key factor
could be the excess of cortisol that could have an important role in
triggering diabetes mellitus in predisposed individuals. Despite the
similarities between the two syndromes mentioned, serum or urine cortisol
have not been found increased in obese patients with type 2 diabetes
mellitus or insulin resistance [1-3].
Cortisol major source is the adrenal cortex, but the hormone is also
produced in the omental fat [4, 5]. Released in the portal blood stream,
cortisol seems to alter metabolic pathways in the liver. In obese people the
levels of cortisol in adipose tissue are increased by reducing cortisone
(inactive hormone) into cortisol (active) by the 11-β-hydroxisteroid
dehydrogenase type 1 (11-β-HSD1) which is present in humans in adipose
tissue [6] and in the liver [7]. 11-β-HSD1 is sometimes over-expressed in
visceral adipose tissue as compared to subcutaneous fat and it could act as a
paracrin factor, increasing cortisol in abdominal fat, but not in the systemic
circulation [1].
The studies on transgenic mice overexpressing the gene coding for
11-β-HSD1 in adipocytes showed increased glucocorticoids levels in the
adipose tissue and portal vein and induced visceral obesity, insulin
resistance, hypertension and dyslipidemia. In contrast, 11-β-HSD1 knockout mice showed reduced gluconeogenesis, improved glucose tolerance,
lower plasma triglycerides and increased plasma HDL levels. Stewart et al.
suggested that increased activity of 11-β-HSD1 in mouse omental fat could
be responsible for the diabetogenic effect of this tissue (”omental Cushing
disease”) [8]. However, data from mouse studies cannot be extended in
humans. Moreover in humans 11-β-HSD1 activity was increased in
subcutaneous adipose tissue with no correlation to abdominal adiposity [9].
Recently, several catheterism studies performed during abdominal surgery
for obesity have not proved any difference between cortisol level in portal
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vein compared to peripheric blood [1, 10]. Their conclusion is that omental
11-β-HSD1 does not have a role in increased cortisol at the hepatic level in
obese people. Plasmatic cortisol levels are also normal in diabetic patients
with type 2 diabetes [2, 3].
However preclinical data suggest that specific inhibitors of 11-βHSD1 could lower intracellular cortisol levels and thus may play a role in
the treatment of metabolic syndrome [11, 12]. Epidemiological data sustain
a beneficial effect of coffee in prevention of type 2 diabetes mellitus.
Atanasov et. al. consider that these could in part be due to blocking of 11-βHSD1 activity and subsequently to low intracelular cortisol and prevention
of transcription for phosphoenolpyruvate carboxykynase [13].
Though the pathogenic action of cortisol in abdominal adipocytes
remain to be proved, the link between cortisol excess and obesity as in
Cushing’s syndrome is beyond doubt. Acute administration of cortisol is
followed by rapid installed insulin resistance and hype [14, 15]. Cortisolinduced diabetes is also proved [14].
Glucocorticoids are widely used therapeutic tools, particularly for
anti-inflamatory and immunomodulatory purposes. Glucocorticoids excess
induces hyperglycemia by the following mechanisms:
- in the liver, glucocorticoids serve as the key promoters of
gluconeogenesis by activation of pyruvate carboxylase and
phosphoenolpyruvate carboxykinase and stimulate hepatic uptake
of amino acids and glycerol;
- insulin resistance of peripheral tissues;
- glucocorticoids inhibit insulin secretion by blocking adrenoreceptor
signaling or by inhibition of Kv channels;
- glucocorticoids induce apoptosis of β-cells;
- glucocorticoids can modulate GAD (glutamate decarboxilase)
expression and may influence the development of autoimmune
diabetes.
Glucocorticoids induces pancreatic β-cells death
Previous studies have shown a relative deficit of insulin in
Cushing’s syndrome as opposed to metabolic syndrome or type 2 diabetes,
which raised the suspicion of a toxic effect of cortisol on the pancreatic beta
cells, as these patients had a blunted insulin release secondary to induced
hyperglycaemia [16].
Glucocorticoids induce β-cells death by activating the
mitochondrial apoptotic pathway. Glucocorticoids induce cell death by
reduction of the antiapoptotic protein Bcl-2, the stimulation of calcineurin
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and the dephosphorylation of BAD (Bcl-2-antagonist of cell death). The
Bcl-2 protein family comprises of anti- and proapoptotic proteins. Some of
these proteins (such as Bcl-2 and Bcl-XL) are antiapoptotic and located at
the outer mitochondrial membrane, while others (such as BAD or Bax) are
proapoptotic and cytosolic proteins. The proapoptotic proteins act as sensors
of cellular damage or stress. Cellular stress induced by irradiation, viral
infection or chemicals may result in an increase of cytosolic Ca2+ activity,
which in turn activates the phosphatase calcineurin. Calciuneurin
dephosphorylate BAD (BAD is bound to the cytosolic adaptor protein 14-33 in its phosphorylated form) which triggers its release from the cytosolic
protein 14-3-3. This enables BAD to bind to Bcl-2 at the surface of the
mitochondrial membrane. The interaction between BAD as pro- and Bcl2/Bcl-XL as antiapoptotic protein at the mitochondrial membrane disrupts
the normal function of the antiapoptotic proteins. Binding of BAD leads to
formation of permeability transition pores in the mitochondria and release of
cytochrome c and other proapoptotic molecules from the mitochondrial
intermembrane space. This in turn leads to the formation of the apoptosome
and the activation of the caspase cascade which accomplishes the
degradation of the nuclear DNA. The effects of glucocorticoids are
antagonized by the glucocorticoid receptor antagonist RU486 and glucagonlike peptide 1 analog (GLP-1). GLP-1 protects against glucocorticoidinduced apoptosis. GLP-1 receptor activation leads to G-protein-dependent
stimulation of adenylyl cyclase, cAMP formation and subsequent activation
of cAMP-dependent protein kinase A (PKA). PKA was found to
phosphorylate the proapoptotic protein BAD which favors the binding of
BAD of the protein 14-3-3, keeping BAD in the cytosol [17].
Glucocorticoids induce insulitis and diabetes
GAD is a pancreatic beta-cell autoantigen in humans and nonobese diabetic mice (NODmice). The tratment of MIN6N8a cells
(NODmouse β-cells) with a synthetic glucocorticoid, dexamethasone
induced the stimulation of GAD67 mRNA expression in a dose- and timedependent manner. Cells treated with 100 nmol/l dexamethasone for 6 h
showed a 10-fold increase in the expression of GAD67 mRNA and an
increase in GAD67 protein. The upregulation of GAD67 expression in betacells by dexamethasone was found to be due to the transcriptional activation
of the GAD67 promoter. Injection of dexamethasone into neonatal NOD
mice resulted in a significant increase in the expression of GAD67 mRNA
in pancreatic beta-cells and the development of insulitis and diabetes. The
glucocorticoid hormones can modulate GAD expression by the
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transcriptional activation of the GAD promoter and may influence the
development of autoimmune diabetes in NOD mice [18].
Glucocorticoids and insulin resistance
Glucocorticoids induce insulin resistance by several mechanisms.
In adipose tissue glucocorticoids activate lipolysis with release of free fatty
acids (FFA) and glycerol in the blood stream. Increased FFA contributes to
insulin resistance in the striate muscle and stimulate gluconeogenesis in the
liver. Glycerol serves as substrate for gluconeogenesis. Total cholesterol
and triglycerides also increase, while HDL is reduced.
Other biologic mediators of insulin resistance are also produced in
adipocytes: adiponectin, TNF alpha (tremor necrosis factor). These are
incriminated in the role of visceral fat on metabolic parameters.
Glucocorticoids down-regulate adiponectin gene expression and
reduce adiponectin plasma levels in humans. Adiponectin is an adipose
tissue derived cytokine with multiple biofunctions including its property to
increase fatty acid oxidation in skeletal muscle. Plasma adiponectin levels
are reduced in clinical conditions associated with insulin resistance and it
has been suggested that adiponectin may be the link between insulin
resistance and the metabolic syndrome and vascular disease.
The promoter of adiponectin gene – Apm1 – contains sequences
that bind to glucocorticoid receptor. Dexamethasone induces decrease of
adiponectin in vitro, while prednisolone administration raises the
concentration of adiponectin in the blood stream. Previous studies have
shown an inverse correlation between cortisol binding globulin (CBG), BMI
(body mass index) and insulin resistance. There are studies which confirm
that adiponectin, CBG and cortisol “á jeun” are significantly correlated in
healthy subjects.
Glucocorticoids have also a permissive effect on other
hyperglycemiant hormones: cathecolamines and glucagon. The results of the
above effects are insulin resistance and increased glycaemia.
Conclusions
In healthy humans, short-term increments in plasma cortisol levels
results in a slight increase in levels of glucose, which is mediated by both
hepatic and extrahepatic effects [19]. However, the effects of chronic
administration of moderate doses of glucocorticoids to healthy humans are
usually compensated by increased insulin release, which results in minimal
changes in glucose levels. Thus, the spectrum of glucose intolerance in
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FARMACIA, 2009, Vol.LVII, 1
patients with Cushing syndrome or exogenous steroid use depends in large
part on endogenous β-cell reserve, a situation similar to that in acromegaly.
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Manuscript received: 29.08.2008