Curr Diab Rep (2017) 17: 32

DOI 10.1007/s11892-017-0860-9

OTHER FORMS OF DIABETES AND ITS COMPLICATIONS (JJ NOLAN, SECTION EDITOR)

Diabetes in Cushing Disease

G. Mazziotti 1 & A. M. Formenti 2 & S. Frara 3 & F. Maffezzoni 2 & M. Doga 3 & A. Giustina 3

Published online: 31 March 2017

# Springer Science+Business Media New York 2017

Abstract diabetes may influence the therapeutic decision making

Purpose of Review This review focuses on the pathophys- in CD, since drugs used in this setting may variably
iological and clinical aspects of diabetes mellitus occur- influence glucose homeostasis regardless of control of
ring in patients with Cushing disease (CD). hypercortisolism.
Recent Findings Insulin resistance and impairment in in-
sulin secretion are both involved in the pathogenesis of
glucocorticoid-induced diabetes. Correction of glucocor- Keywords Diabetes: . Cushing disease . Somatostatin
ticoid excess does not always resolve abnormalities of analogs . hypoglycemic drugs
glucose homeostasis, and correction of hyperglycaemia
is specifically required. In fact, insulin resistance may
persist even after correction of glucocorticoid excess
and diabetes needs to be treated for long term. On the Introduction
other hand, emerging drugs used in the treatment of
CD, such as the novel somatostatin analog pasireotide, Cushing disease (CD) is a rare disease caused by an adreno-
may have direct effects on glucose homeostasis regard- corticotropin hormone (ACTH)-secreting pituitary adenoma
less of control of cortisol excess. which results in increased production of cortisol by adrenal
Summary Diabetes mellitus is a frequent and early com- glands [1]. The prevalence of CD is estimated to be nearly 40
plication of CD with important diagnostic, prognostic cases per million, whereas the incidence of CD ranges from
and therapeutic implications. Specifically, diagnosis of 1.2 to 2.4 per million per year. CD is at least three times more
CD in patients with diabetes may be difficult due to prevalent in women than in men and mainly occurs during the
potential misinterpretation of markers of cortisol hyper- fourth to sixth decades of life [2]. Complications which char-
secretion. Moreover, diabetes mellitus is often difficult acterize CD significantly impair quality of life and survival of
to be controlled in CD requiring a careful and dedicated affected patients [3].
therapeutic approach. Finally, the coexistence of Hypercortisolism predisposes to insulin resistance and im-
pairs β-cell function [4, 5]. Consequently, in many patients
This article is part of the Topical Collection on Other Forms of Diabetes with CD diabetes mellitus can be observed when disease is
and Its Complications diagnosed [6] and several patients with previously unrecog-
nized CD may be firstly seen in diabetes outpatient clinics [7].
* A. Giustina Moreover, drugs used for treating CD may per se influence
[email protected] glucose homeostasis regardless of biochemical control of
hypercortisolism [6]. Finally, diabetes was reported in associ-
1
Endocrinology Unit, ASST Carlo Poma, Mantova, Italy ation with cardiovascular morbidity and mortality of CD [3].
2
Department of Molecular and Translational Medicine, University of This review will discuss pathophysiology and clinical
Brescia, Brescia, Italy issues in the management of diabetes mellitus in pa-
3
Vita-Salute University San Raffaele Milan, Milan, Italy tients with CD.
32 Page 2 of 9 Curr Diab Rep (2017) 17: 32

Pathophysiology of Diabetes in CD [9]. Interestingly, impairment of insulin secretion was also

shown to be associated with high-normal cortisol values in
Glucocorticoids are diabetogenic agents because they reduce subjects not affected by CD [10]. The inhibition of insulin
insulin sensitivity and impair beta-cell function [6] (Fig. 1). secretion by glucocorticoids may play a critical role in deter-
Glucocorticoids bind specific receptors in pancreatic beta- mining development of diabetes in CD, since it may prevent
cells inducing impairment of uptake and metabolism of glu- the compensatory increase of insulin secretion in response to
cose with consequent beta-cell dysfunction [6, 8]. Moreover, insulin resistance induced by glucocorticoids [4].
short-term exposure to glucocorticoids reduces the Glucocorticoids exert anti-insulin effects in the liver, skel-
insulinotropic effects of glucagon-like peptide-1 (GLP-1) etal muscle and adipose tissue (Fig. 1), by inducing a post-

Fig. 1 Mechanisms and target tissues of the diabetogenic effect of substrate-1; PI3K, phosphatidylinositol-3 kinase; PKB, protein kinase
hypercortisolism in Cushing disease. ACTH, adrenocorticotropin B; PEPCK, phosphoenolpyruvate carboxykinase; GLP-1, glucagon-like
hormone; GHD, growth hormone deficiency; IRS-1, insulin receptor peptide-1
Curr Diab Rep (2017) 17: 32 Page 3 of 9 32

receptor defect of insulin receptor substrate-1 (IRS-1), pituitary gland, with final effects depending on hormone con-
phosphatidylinositol-3 kinase (PI3K) and protein kinase B centrations and time of exposure [22]. In patients exposed to
(PKB) [6]. These actions cause a reduction of glucose uptake glucocorticoid excess, GH deficiency (GHD) may develop as
as an effect of impaired glucose transporter migration to the an effect on increased hypothalamic somatostatin tone (Fig. 1)
cell surface. Moreover, in skeletal muscle, glucocorticoids re- [23]. The functional GHD may contribute to the development
duce the phosphorylation of insulin-stimulated glycogen syn- of metabolic complications of hypercortisolism, mainly medi-
thase kinase-3, consequently impairing glycogen synthesis ated by alteration of body composition and consequent im-
[11]. Insulin resistance is also indirectly favoured in CD by pairment of insulin action [24]. However, the real impact of
increased proteolysis and lipolysis resulting in elevation of GHD on diabetes in patients with CD is not yet fully
amino acids and fatty acids which in turn may cause impair- elucidated.
ment in different steps of insulin signalling [12]. In CD, the
distribution of body fat with increased visceral adiposity and
consequent occurrence of metabolic syndrome predisposes to Clinical Aspects
the development of insulin resistance [13]. Moreover, gluco-
corticoids may influence the secretion of adipokines, such as Patients with glucocorticoid-induced diabetes have generally
adiponectin and leptin, which may have a relevant impact on a poorly controlled glucose homeostasis [25] and may harbour
insulin sensitivity [14]. typical features of hypercortisolism, such as hypokalemia, fa-
Glucocorticoids influence glucose metabolism also in the cial plethora, easy bruising, reddish purple striae, proximal
fasting state when an increase of glucose production from the myopathy, dorso-cervical fat pad, sexual dysfunction in men
liver (Fig. 1) may occur as an effect of induction of key en- and menstrual disorders, acne and hirsutism in women.
zymes involved in gluconeogenesis, such as phosphoenolpyr- Moreover, patients with glucocorticoid-induced diabetes
uvate carboxykinase (PEPCK) [15]. may suffer from coexistent complications of hypercortisolism
Over the last few years, there has been experimental evi- such as hypertension, recurrent infections, ischaemic cardiac
dence for the existence of crosstalk between bone remodelling disease, fragility fractures and neuropsychiatric disorders
and glucose metabolism with uncarboxylated osteocalcin pos- which may have a synergistic relevant impact in influencing
tulated to play a central role in the control of fuel metabolism quality of life and survival of patients with CD [26].
via improvement of insulin secretion and sensitivity (Fig. 1) Noteworthy, in CD, risk of mortality is double than in the
[16]. In fact, osteocalcin knockout mice were shown to be general population; diabetes, hypertension and uncontrolled
glucose intolerant and insulin resistant, whereas injections of hypercortisolism have been reported to predict risk of death
osteocalcin in these mice resulted in decreased weight gain, in this setting [1].
decreased insulin resistance, reduced hepatic steatosis and in- Diagnosis of glucocorticoid-induced diabetes is based, as
creased energy expenditure [17•]. Interestingly, patients with in the general population, on measurement of fasting plasma
CD have generally low circulating osteocalcin levels [18], glucose, glycated haemoglobin (HbA1C) and plasma glucose
reflecting the inhibitory effects of hypercortisolism on osteo- values under oral glucose tolerance test [27]. However, in
blast proliferation and function [19]. Indeed, glucocorticoid- patients exposed to glucocorticoid excess, the measurement
induced osteoporosis is a unique clinical model to study such of fasting glucose may underestimate the real prevalence of
an interplay between bone remodelling and fuel metabolism glucose disorders, as suggested by the observation that more
since exposure to glucocorticoid excess is associated with than one half of patients with hypercortisolism and diabetes
both suppression of osteoblast function and impairment of had normal fasting glucose [6]. Since the most important met-
insulin secretion and sensitivity. There are experimental data abolic effects of glucocorticoid excess occur during the post-
in animal models suggesting that suppression of osteoblast prandial period, the diagnostic gold standard for identifying
function induced by exposure to glucocorticoid excess may the impairment of glucose metabolism in CD is the oral glu-
play a role in the pathogenesis of glucocorticoid-induced dia- cose tolerance test [6].
betes [20•]. In fact, targeted disruption of glucocorticoid sig- Diagnosis of CD in patients with diabetes, even more than
nalling in osteoblasts partially prevented the impaired meta- in the general population, may be a clinical challenge. Indeed,
bolic responses in experimental animals treated with gluco- diabetes mellitus may induce per se a functional
corticoids [20•]. Moreover, heterotopic expression of hypercortisolism and may influence the response to pharma-
osteocalcin improved glucocorticoid-induced glucose intoler- cological tests used for diagnosis of CD, making difficult the
ance [20•]. Whether this experimental evidence may be trans- interpretation of biochemical data in diabetic patients with
lated to humans exposed to glucocorticoid excess is still a suspected CD [28–30]. On the other hand, there is no single
matter of uncertainty [21•]. test that may be reliable alone to identify with certainty pa-
Glucocorticoids modulate growth hormone (GH) secretion tients with hypercortisolism [31]. According to the current
by various and competing effects on the hypothalamus and guidelines [32], screening for Cushing syndrome is
32 Page 4 of 9 Curr Diab Rep (2017) 17: 32

recommended only in those cases with clinical and biochem- hormonal production and their monitoring is also made diffi-
ical features of cortisol excess. Screening for hypercortisolism cult by the lack of reliable biomarkers of their action [40, 41].
is performed by measurements of urinary cortisol values, late It is noteworthy that over-replacement therapy with glucocor-
night salivary cortisol and the 1-mg overnight dexamethasone ticoids may impair some persistent metabolic complications,
suppression test. When these tests are abnormal and as diabetes and osteoporosis, in patients with history of CD
hypercortisolism is diagnosed, other tests are required to de- [42, 43].
fine the cause of cortisol excess. Endogenous Medical therapy of CD has recently become more impor-
hypercortisolism is classified in ACTH-dependent and tant as compared to the past, due to the recent availability of
ACTH-independent. This latter category includes tumours of novel compounds able to control cortisol secretion or action
adrenal glands autonomously secreting cortisol regardless of [32]. Several somatostatin receptors (SSTR), such as SSTR2
ACTH stimulation. The so-called ACTH-dependent and SSTR5 which control ACTH secretion, are expressed by
hypercortisolism includes CD and ectopic Cushing syndrome ACTH-secreting adenomas [44]. Conventional long-acting
caused by an extrapituitary tumour secreting ACTH. somatostatin analogs are not effective in CD probably because
Measurement of serum ACTH, the corticotropin-releasing glucocorticoid-induced downregulation of SSTR2 attenuates
hormone (CRH) dexamethasone test, pituitary MRI and adre- the action of these drugs [45].
nal CT are required to define the cause of hypercortisolism Pasireotide (SOM230) is a new somatostatin analog which
[32]. Finally, it is noteworthy that the pituitary adenoma re- binds with high affinity to four out of the five subtypes of the
sponsible for CD is a microadenoma in more than 90% of somatostatin receptors (SSTR1–3 and SSTR5) with much
cases, which may be not visible during radiological higher affinity for SSTR5 than conventional somatostatin an-
examination. alogs [44]. This is relevant for clinical use of pasireotide since
SSTR5 is expressed on ACTH-secreting adenomas, without
being downregulated by glucocorticoid excess and pasireotide
Therapeutic Aspects was shown to effectively inhibit ACTH release both in vitro
and in vivo, suggesting the potential for effective treatment of
A correct management of diabetes in CD includes the correc- CD [46]. A multicenter, phase 2 study demonstrated that
tion of glucocorticoid excess and the control of short-term therapy with pasireotide at two daily doses of
hyperglycaemia. 0.6 mg led to a significant decrease of urinary cortisol values
Neurosurgical removal of pituitary adenoma performed by in two third of patients and normalization of hormonal values
experienced neurosurgeon is considered the first-line therapy in 17% of patients [47]. These beneficial effects were con-
of CD [33]. Hypercortisolism undergoes remission in 65–90% firmed in a phase III clinical trial in which 20.4% of patients
of patients with microadenomas; 10-year recurrence rates achieved normalization of urinary cortisol values after
range among 10 and 20% [34]. In macroadenomas, lower 6 months of treatment with 0.6–0.9 mg of pasireotide [48].
remission rates are reported and recurrences occur often earli- The safety profile of pasireotide was similar to that of conven-
er than for microadenomas. Therefore, nearly one third of tional somatostatin analogs with respect to adverse events
patients experience in the long-term a failure of surgery and such as gastrointestinal disturbances and cholelithiasis, but
require an additional second-line treatment. Traditional radio- with an increased frequency and degree of hyperglycaemia
therapy or stereotactic radiosurgery has been proposed as with pasireotide. This is due to the fact that pancreatic β-
second-line therapy, although the slow onset of potential ben- cells express the SSTR5, which in turn regulates insulin se-
eficial effects and the high risk of hypopituitarism are critical cretion. Therefore, in pasireotide-treated patients, an impaired
drawbacks of these procedures [32–34]. Noteworthy, devel- insulin secretion is observed; the clinical relevance of this
opment of hypopituitarism may lead to a further impairment effect is increased by the insulin resistance state determined
of cardiovascular risk in patients with diabetes and history of by hypercortisolism, persisting despite pasireotide treatment
CD [35–37]. Furthermore, an increased mortality risk was [48]. In fact, more than 70% of patients treated with
shown to be associated with traditional radiotherapy in pa- pasireotide experienced hyperglycaemia or diabetes which in-
tients with ACTH-secreting adenomas, such as reported in duced treatment discontinuation in 5.6% of patients [48]. The
patients with somatotropinomas and nonfunctioning pituitary mean HbA1C increased from 5.8% in both the 0.6- and 0.9-mg
adenomas [38]. groups at baseline to 7.2% and 7.4%, respectively, at month 6
Bilateral adrenalectomy is followed by a rapid and defini- [48]. Glucose and HbA1C levels increased soon after the start
tive treatment of hypercortisolism, but it induces permanent of pasireotide treatment, necessitating the administration of
adrenal insufficiency with potential negative effects on quality glucose-lowering medications in almost half (45.6%) of the
of life and survival [39]. Indeed, an overtreatment of patients [48]. Based on these findings, a close monitoring of
hypoadrenalism may occur in some patients, since replace- glucose homeostasis should be performed in CD patients un-
ment therapies do not completely mirror the endogenous dergoing pasireotide therapy at least every week for the first
Curr Diab Rep (2017) 17: 32 Page 5 of 9 32

2–3 months and periodically thereafter [49]. Moreover, pa- Some drugs, such as ketoconazole, metyrapone and
tients should be trained in self-monitoring of glucose levels. mitotane, act as adrenolytic agents inhibiting the biochemical
Metformin is typically first-line treatment as in usual cases of synthesis of cortisol in adrenal glands [45]. These drugs are
diabetes mellitus [50]; however, new agents may be more generally used in the short term due to important side effects
effective in the management of pasireotide-associated (hepatic injury with ketoconazole, hyperandrogenism with
hyperglycaemia. In fact, studies in healthy volunteers sug- metyrapone and gastrointestinal and neurological disturbances
gested that vildagliptin and liraglutide better perform than with mitotane). Interestingly, ketoconazole at doses ranging be-
metformin in counteracting pasireotide-associated tween 200 and 1000 mg daily was demonstrated to improve
hyperglycaemia [51]. Additionally, pasireotide may suppress glucose metabolism either in patients with hypercortisolism or
the GH/IGF-I axis, which is already under the inhibitory ef- in those with type 2 diabetes [58, 59]. Ketoconazole is an im-
fects of glucocorticoids; this may worsen GHD and contribute idazole derivative which is able to reduce cortisol levels by
to the development of abnormal glucose metabolism [52, 53]. inhibition of a variety of cytochrome P450 enzymes [60]. In
Based on the results of the phase III trial, pasireotide be- addition to its anti-steroidogenic effects, ketoconazole may also
came the first drug to gain approval for treatment of CD from have extra-adrenal actions, such as its glucocorticoid receptor
the EMA in the EU in April 2012 and from the FDA in the antagonism and inhibition of ACTH release [61].
USA in December 2012, being indicated for patients with Mifepristone is a high-affinity nonselective antagonist of
persistent disease after pituitary surgery or for whom surgery the glucocorticoid receptor type II, with an affinity for the
is not considered an option. glucocorticoid receptor more than three times higher than that
ACTH-secreting adenomas express type 2 dopamine re- of dexamethasone and more than 10 times higher than that of
ceptors [54], and dopaminergic drugs were shown to induce cortisol [62]. The largest prospective multicenter trial of mi-
in vitro acute inhibition of ACTH secretion [45]. In patients fepristone was performed in 50 patients with endogenous
with ACTH-secreting adenomas, long-term therapy with hypercortisolism, including 43 patients with CD, who re-
cabergoline at doses of 1 to 7 mg/week was shown to induce ceived mifepristone treatment for 24 weeks, with a starting
a sustained control of hypercortisolism in some cases [55, 56]. dose of 300 mg/day, a maximum dose of 1200 mg/day and a
Indeed, most of biochemical effects occurred during the first final mean dose of 732 mg/day [63]. In 60% of patients who
3 months of treatment; thereafter, an escape was observed. had diabetes or glucose intolerance, mifepristone induced an
Moreover, prevalence of diabetes and glucose intolerance improvement of insulin sensitivity as suggested by a decrease
was reduced by cabergoline by 60% and 46%, respectively, of at least 25% of area under the curve for glucose after an oral
and this did not depend on control of hypercortisolism [55]. glucose tolerance test [63]. In a post hoc analysis, insulin
Moreover, the other dopaminergic drug bromocriptine was sensitivity was shown to improve early (few weeks) after mi-
able to normalize glucose homeostasis in patients with diabe- fepristone treatment as direct effect of glucocorticoid short-
tes, likely by increasing insulin-mediated suppression of he- term blockade, whereas longer-term improvement in insulin
patic glucose production or enhancing splanchnic glucose up- sensitivity was shown to be more in relationship with the
take [57]. No significant side effects, except for hypotension favourable changes in body composition which occurred not
in few patients, were observed during treatment of CD with before 6 months of treatment [64]. Based on these results,
cabergoline [55, 56]. mifepristone received FDA approval in the USA for the

Table 1 Newer anti-diabetic drugs, their mechanisms of action and their potential effects on clinical outcomes in Cushing disease (CD)

Drugs Main mechanisms of action Effects on CD outcomes

Peroxisome proliferator-activated Decrease in insulin resistance Rosiglitazone could have anti-proliferative

receptor-γ agonists effects in ACTH-secreting
(pioglitazone, rosiglitazone) pituitary adenomas [70]
Rosiglitazone may increase the risk of fracture [72]
Incretins Stimulation of insulin secretion, Exenatide may specifically reverse the
Dipeptidyl peptidase-4 inhibitors decrease in glucagon secretion inhibitory effects of glucocorticoids on
(vildagliptin) insulin secretion [76]
GLP-1 agonists (liraglutide, exenatide) Vildagliptin and liraglutide may specifically
antagonize the inhibitory effects of
pasireotide on insulin secretion [51]
Liraglutide may protect from skeletal fragility [81]
Sodium-glucose co-transporter Increase in urinary glucose excretion Potential increase in urinary and
2 inhibitors (canagliflozin, genital infections [75]
dapagliflozin and empagliflozin)
32 Page 6 of 9 Curr Diab Rep (2017) 17: 32

treatment of adult patients with endogenous CS who have type Interesting results have been achieved using the incretins in
2 diabetes mellitus or glucose intolerance and have failed sur- glucocorticoid-induced diabetes (Table 1). In healthy volun-
gery or are not candidates for surgery. teers treated with glucocorticoids, exenatide was shown to
control diabetes by decreasing glucagon secretion and gastric
Treatment of Diabetes emptying [76]. Studies in type 2 diabetes suggest that incretins
may be used in glucocorticoid-induced diabetes [77] due to
Although an improvement of glucose homeostasis generally their beneficial effects on appetite, body fat secretory activity
occurs with normalization of cortisol levels, insulin resistance and distribution and postprandial dyslipidemia [78–80].
and cardiovascular risk may persist in several patients even Interestingly, liraglutide and vildagliptin have been shown to
after cure of hypercortisolism [1]. Therefore, an important significantly counteract the negative effects of pasireotide on
therapeutic goal in patients with CD and diabetes is the control glucose homeostasis (Table 1) [51]. Possibly, these drugs in
of hyperglycaemia independently of correction of CD may have additional benefits on skeletal health, as report-
hypercortisolism. Treatment of diabetes in patients with CD ed in the general population [81].
is not different with respect to the general population with type
2 diabetes [65]. However, several pathophysiological and clin-
ical characteristics may change the therapeutic management of Conclusions
diabetes in patients with CD.
Physical activity can be recommended in CD patients. Diabetes mellitus is a frequent complication of CD. Diabetes
However, glucocorticoid-induced myopathy may greatly limit mellitus develops early during the natural history of CD mak-
their physical activity [66]. ing frequently difficult the diagnosis of hypercortisolism in
As in type 2 diabetes [67], metformin can be used as first- this clinical setting. Moreover, diabetes mellitus was shown
line therapy of diabetes also in patients with CD, taking how- to be an important determinant of mortality in patients with
ever into account that glucocorticoid-induced hyperglycaemia CD. Finally, coexistence of diabetes mellitus and CD may
tends to be more pronounced in the evening than the morning. reciprocally complicate the therapeutic approach to the two
Metformin may have gastrointestinal undesired side effects, diseases due to potential hyperglycemic effects of drugs used
such as gut discomfort, flatulence or diarrhoea, which can be in the management of CD and to the severity of hyperglyce-
worsened by the concomitant use of pasireotide in CD pa- mia in CD which often need multimodal and aggressive
tients. Risk of lactic acidosis particularly in the presence of treatment.
advanced renal or hepatic insufficiency [68] should be consid-
ered in patients treated with metformin. Compliance with Ethical Standards
Peroxisome proliferator-activated receptor-γ agonists, as
Conflict of Interest G. Mazziotti reports personal fees from Ipsen.
pioglitazone, may potentiate the effects of metformin on insu-
M. Doga, A.M. Formenti, S. Frara and F. Maffezzoni declare that they
lin resistance (Table 1) [69]. A potential advantage of this drug have no conflict of interest.
in CD may be the anti-proliferative effects on tumour cells A. Giustina reports personal fees from Novartis, Ipsen and Pfizer.
already demonstrated in experimental models of ACTH-
secreting pituitary adenomas (Table 1) [70]. On the other Human and Animal Rights and Informed Consent This article re-
views studies that involve human participants. The authors of cited arti-
hand, such as in other clinical settings [71], pioglitazone is
cles are responsible for approval by the appropriate institutional and/or
not usually recommended for the treatment of diabetes in national research ethics committee and performed in accordance with the
CD due to its undesired effects, such as body weight gain, ethical standards as laid down in the 1964 Declaration of Helsinki and its
fluid retention with increased risk of oedema, heart failure later amendments or comparable ethical standards.
and fractures [72, 73].
When diabetes is not controlled by insulin sensitizers, insu-
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