Feature Review

Current and Emerging

Aspects of Diabetes Mellitus
in Acromegaly
Stefano Frara,1 Filippo Maffezzoni,1 Gherardo Mazziotti,2 and
Andrea Giustina1,*
Diabetes mellitus is a frequent complication of acromegaly, a disease character-
Trends
ized by chronic hypersecretion of growth hormone (GH) by a pituitary adenoma.
Diabetes mellitus is a frequent compli-
Diabetes occurs commonly but not only as a consequence of an insulin-resistant cation of acromegaly due to the effects
state induced by GH excess. The development of diabetes in patients with of growth hormone hypersecretion on
insulin sensitivity and secretion.
acromegaly is clinically relevant, since such a complication is thought to increase
the already elevated cardiovascular morbidity and mortality risk of the disease. The occurrence of diabetes mellitus in
Emerging data suggest that a specific cardiomyopathy can be identified in acromegaly is associated with high
cardiovascular morbidity and mortality.
acromegaly patients with diabetes. Moreover, the presence of diabetes may also
influence therapeutic decision making in acromegaly, since traditional and newly Diagnosis of acromegaly in patients
with coexistent diabetes mellitus is
developed drugs used in this clinical setting may impact glucose metabolism
challenging since the OGTT may be
regardless of control of GH hypersecretion. contraindicated and serum insulin-like
growth factor-1 values are influenced
Introduction by altered glucose levels and insulin
Acromegaly is a chronic disease generally caused by a GH-secreting pituitary adenoma that results sensitivity.
in increased levels of GH and insulin-like growth factor (IGF)-I [1]. Despite its relatively low incidence
Drugs used to control growth hormone
and prevalence, acromegaly is clinically relevant because GH hypersecretion may cause systemic
hypersecretion may affect glucose
complications with significant impact on the patient's quality of life and survival [2]. metabolism.

GH and IGF-I regulate intermediary metabolism by either inhibiting or promoting insulin action [3].
GH excess causes insulin resistance and impairment of pancreatic b cell function [4], predis-
posing a large number of patients with acromegaly to develop diabetes mellitus [2]. Diabetes
mellitus may be an early complication of acromegaly, often being present at diagnosis of the
disease [5], potentially interfering with the feasibility and interpretation of diagnostic tests for
acromegaly, and sometimes causing uncertainty in choosing the proper therapeutic approach
for the disease. Moreover, drugs used to treat acromegaly may per se influence glucose
homeostasis regardless of biochemical control of GH and IGF-I excess [6–9]. Finally, it is also
relevant that diabetes mellitus was shown to be associated with increased cardiovascular
morbidity and mortality in patients affected by acromegaly [10,11].

This review discusses current and emerging pathophysiological, clinical, prognostic, and thera- 1
Endocrinology and Metabolic
peutic aspects of diabetes mellitus occurring in patients with acromegaly. Diseases Unit, Department of
Molecular and Translational Medicine,
University of Brescia, 25123 Brescia,
GH–IGF-I Axis and Glucose Metabolism Italy
Pathophysiology of Diabetes Mellitus in Acromegaly 2
Endocrine Unit, ASST Carlo Poma,
Insulin resistance is the main determinant of hyperglycemia in patients with acromegaly, in the 46100 Mantova, Italy

form of type 2 diabetes (T2D). However, the mechanisms leading to impairment in insulin
sensitivity differ between the two clinical conditions. In T2D, insulin resistance is mainly associ- *Correspondence: a.giustina@libero.it
ated with overweight and increased visceral fat, which in turn causes an increase of (A. Giustina).

470 Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7 http://dx.doi.org/10.1016/j.tem.2016.04.014
© 2016 Elsevier Ltd. All rights reserved.
 Box 1. Physiology of the GH–IGF-I Axis
GH secretion by the pituitary gland is mainly under hypothalamic control, being stimulated by GHRH and inhibited by
somatostatin [12]. Moreover, GH secretion is modulated by many other neuropeptides (such as galanin), neurotrans-
mitters (for example, acetylcholine), metabolic signals (such as fasting, hypoglycemia, amino acids, and FFAs), and
peripheral hormones (IGF-I, thyroid and sex hormones, and glucocorticoids) [13–17]. GH acts by inducing the synthesis
of IGF-I in the liver [12]. IGF-I is a peptide hormone that shares nearly 50% amino acid sequence homology with proinsulin
and, like insulin, comprises / and b chains connected by disulfide bonds [4]. Interestingly, liver synthesis of IGF-I is
stimulated by insulin with effects additive to those of GH [4]. Moreover, insulin also influences IGF-I bioactivity by
downregulating IGF-binding protein-1, 2, and 3 release from the liver [4].

The effects of the GH–IGF-I axis on intermediary metabolism are complex. GH stimulates b cell proliferation, insulin gene
expression, and insulin biosynthesis and secretion [4]. During conditions of energy surplus, GH, along with insulin and
IGF-I, promotes nitrogen retention, while during famine GH modifies fuel consumption from proteins and carbohydrates
(the sole fuel for brain and heart) to lipids, allowing preservation of vital protein stores [3]. Specifically, GH stimulates
lipolysis by increasing the responsiveness of adipose tissue to b-adrenoceptor signaling [18], along with inhibition of
lipogenesis [19]. These effects lead to increased release of FFAs from adipose tissue. IGF-I promotes glucose and FFA
uptake in skeletal muscle through either IGF-I or insulin–IGF-I hybrid receptors [4].

hypothalamic somatostatin tone with consequent impairment of GH secretion [12–20]. How-

ever, in acromegaly patients visceral obesity is relatively uncommon [21] and insulin resistance is
strictly associated with GH excess. The effects of GH on intermediary metabolism can be direct
and indirect (Box 1). The direct actions of GH are mainly diabetogenic by antagonizing insulin
action and increasing lipolysis, whereas the indirect actions of GH via increased IGF-I may in turn
facilitate insulin action. Chronic GH excess leads to insulin resistance either in the liver or in the
periphery and these effects largely overcome the possible beneficial effects of IGF-I on insulin
sensitivity. Patients with acromegaly display hyperinsulinemia and increased glucose turnover in
the basal and post-absorptive states [3]. During infusion of insulin, glucose infusion rates
required to maintain euglycemia were significantly lower in acromegaly patients compared with
control subjects [22], consistent with the insulin resistance state. In acromegaly, insulin resis-
tance is induced by increased free fatty acid (FFA) production and consequent impairment of
insulin-stimulated glucose uptake in peripheral tissues, as well as increased gluconeogenesis
and suppression of adipose expression of glucose transporter (GLUT)-1 and -4 [23]. Moreover,
GH was shown to directly block insulin signaling mediators, such as insulin-receptor substrate-1
and PI-3-kinase, involved in stimulation of glucose transport in muscle and fat and in inhibition of
hepatic glucose production (HGP) [24]. Recently, there has been convincing evidence that
inflammatory signals from adipose tissue, as well as some adipokines (i.e., visfatin and vaspin),
may be involved in determining insulin resistance in acromegaly, as already demonstrated in
non-acromegaly subjects [25].

Impairment of pancreatic b cell function was also described as a necessary step towards
glycemic abnormalities in insulin-resistant patients with acromegaly [26]; the final glycometabolic
status of insulin-resistant acromegaly patients was shown to be strictly correlated with the
compensatory capacity of pancreatic b cells to counterbalance the impairment of peripheral
insulin sensitivity. Indeed, b cell dysfunction measured by homeostasis model assessment
(HOMA) was more severe in acromegaly patients with diabetes than in those with prediabetic
disorders [27]. Interestingly, b cell dysfunction was shown to correlate with the age of the
patients [27] and to predict the outcome of glucose homeostasis after cure of acromegaly [28].
Abnormal glucose metabolism was shown to persist after cure of acromegaly in patients in
whom b cell function was irreversibly impaired [28].

Epidemiological Aspects
The reported frequencies of diabetes mellitus in acromegaly differ greatly among studies,
ranging from 16% to 56% [27,29–32], a variability that is likely to reflect heterogeneity of the
study populations and differences in the criteria used for the diagnosis and classification of
glucose metabolism disorders (Box 2) [33–36]. Interestingly, some patients were also reported

Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7 471
 Box 2. Classification and Diagnosis of Glucose Metabolism Disorders
American Diabetes Association guidelines have defined diabetes mellitus as a complex, chronic illness characterized by
hyperglycemia and requiring continuous medical care with multifactorial risk-reduction strategies beyond glycemic
control [33]. Although it has several features in common with T2D, acromegaly-related diabetes is classified as a
secondary diabetes [34], like other forms of diabetes induced by pituitary diseases [35].

The diagnostic criteria for diabetes mellitus in patients with acromegaly do not differ from those applied to the general
population. The diagnosis of diabetes is based on fasting plasma glucose  126 mg/dl (7.0 mmol/l) and/or HbA1c 
6.5% and/or 2-h plasma glucose  200 mg/dl (11.1 mmol/l) during a 75-g OGTT [33]. As with most diagnostic tests, the
result should be reproduced when feasible to exclude any laboratory error, unless there is a clear-cut clinical diagnosis
[33]. Although it is preferable that the same test is repeated for confirmation, since there will be a greater likelihood of
concurrence, the presence of two tests with results above the diagnostic threshold confirms the diagnosis [33].

Besides diabetes mellitus, there are recognized milder conditions, also known as prediabetes, that identify individuals
with at relatively high risk of developing overt diabetes in the future and who are affected by IFG and/or IGT [36]. IFG and
IGT should not be viewed as independent clinical entities but rather as risk factors not only for diabetes but also for
cardiovascular disease [36]. IFG is defined by fasting plasma glucose 100–125 mg/dl or 5.6–6.9 mmol/l, while in IGT 2-h
plasma glucose is 140–199 mg/dl or 7.8–11.0 mmol/l after an OGTT. Prediabetes (IFG or FPG) may also be defined as
HbA1c between 5.7% and 6.4% [33].

to have ‘prediabetes’ [i.e., impaired glucose tolerance (IGT) or impaired fasting glucose
(IFG)], with less than 30% of acromegaly patients being normoglycemic in some series
[30,32]. The prevalence of glucose metabolism disorders in acromegaly may be considered
higher than that observed in populations defined to be at high risk of diabetes [32]. As in the
general population, diabetes and prediabetes in acromegaly were associated with higher
body mass index [27,29,32], greater age [27,29–32], and family history of diabetes [27,30].
Differently from the general population, women with acromegaly appeared to have greater
visceral adiposity than men, with increased prevalence of diabetes along with higher fasting
insulin, higher insulin resistance, and lower high-density lipoprotein (HDL)-cholesterol [37].
Important determinants of diabetes in acromegaly are the activity and duration of pituitary
disease. Although both GH and IGF-I levels have been used as biomarkers of disease activity
[38] and both have been implicated as predictors of mortality in acromegaly [39], in some
studies very high serum GH values were associated with glucose intolerance [30]. However,
as for other complications of acromegaly [40], IGF-I was also shown to correlate with
abnormalities in glucose metabolism better than random or oral glucose tolerance test
(OGTT) nadir GH concentrations [27,30–32,41]. Serum IGF-I values correlated with insulin
sensitivity but not with insulin secretion, the latter being more correlated with the age of the
patients [27].

Despite its correlation with duration of GH hypersecretion, diabetes mellitus may develop early in
patients with acromegaly and more than 20% of naive acromegaly patients may have diabetes at
diagnosis of the disease [29]. Diabetes may develop before the onset of other clinical features of
GH hypersecretion and acromegaly may be incidentally discovered in 0.5–3% of patients with
diabetes [5,42], a prevalence much higher than that expected from epidemiological studies
performed in the general population [43].

Clinical Aspects
Diagnosis of Acromegaly in Patients with Diabetes Mellitus
Diagnosis of acromegaly is based on measurement of both GH and IGF-I [38]. From the
pathophysiological point of view, GH and IGF-I could give different but complementary infor-
mation, with one parameter (GH) more linked to the presence and activity of adenomatous tissue
and the other (IGF-I) to the peripheral activity of the hormone secreted by a pituitary adenoma.
From the clinical point of view, both GH and IGF-I were shown to predict the mortality risk in
acromegaly [39]. Biochemical diagnosis of acromegaly is based on GH measurement on
random blood samples or on repeated samples but preferably during OGTTs [38]. Following

472 Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7
an OGTT, GH concentrations decline rapidly and markedly, most likely because of inhibition of
GH-releasing hormone (GHRH) and/or stimulation of somatostatin release [12]. The suppression
of GH secretion is independent of plasma glucose concentrations during an OGTT, whereas it
was shown to be closely correlated with the whole-body insulin sensitivity [44]. The suppressive
action of circulating glucose on central GH release was shown to be 50% lower in insulin-
resistant subjects compared with those with normal insulin sensitivity [44]. IGF-I (assayed in a
single blood sample) is a surrogate marker of GH hypersecretion but represents a quite accurate
estimation of the biological impact of circulating GH levels [38,45]. Diagnostic algorithms have
been defined and specific biochemical cut-off values have been proposed to facilitate and
standardize the management of acromegaly [38,46,47]. Universal biochemical criteria for the
diagnosis and cure of acromegaly were defined for the first time in the Cortina consensus [38]
and revised 10 years later based on recent methodological advances in the assays for both
GH and IGF-I [48]. According to the current consensus guidelines, acromegaly is diagnosed if
IGF-I levels (determined by a reliable standardized assay) are above the age-adjusted normal
range and GH levels during an OGTT are higher than 0.4 mg/l, as measured by ultrasensitive
assays [48].

In several patients diabetes mellitus may be the first clinical presentation of acromegaly triggering
the diagnostic work-up of GH hypersecretion [49]. However, the diagnostic approach to
acromegaly in patients with coexistent diabetes mellitus could be difficult. Pulsatile spontaneous
GH secretion is maintained in T2D [50] and enhanced in insulin-treated diabetes [51]. Therefore,
elevated random GH levels in hyperglycemic subjects are not necessarily diagnostic for acro-
megaly. Indeed, evaluation of GH levels after OGTT may theoretically also be necessary in
acromegaly patients with diabetes, since the effects of rapid glucose increase during an OGTT
may not be reproduced by chronic hyperglycemia. The rapid increase in glucose levels or even
other mechanisms associated with oral glucose overload (e.g., the release of intestinal hor-
mones) seems to play a role in GH suppression [50]. However, in patients already diagnosed
with diabetes mellitus, particularly those on antidiabetic therapies or with significant hypergly-
cemia, an OGTT may not be indicated for safety reasons. In these patients, besides random GH,
diagnosis relies on serum IGF-I. However, interpretation of IGF-I levels may also be difficult in this
clinical setting [52]. Serum IGF-I values and bioactivity are variably influenced by different
degrees of insulin resistance and b cell dysfunction occurring in patients with diabetes mellitus
[4]. Low insulin production as well as insulin resistance may cause inappropriately normal IGF-I
levels in diabetic patients with acromegaly [4]. To overcome these potential diagnostic pitfalls,
dynamic tests with galanin and thyrotropin-releasing hormone have been proposed. Galanin
was found to paradoxically decrease circulating GH levels in patients with active acromegaly [53]
and the results were not influenced by coexistent disorders of glucose metabolism [54].
Therefore, when the biochemical diagnosis of a patient with suspected acromegaly and diabetes
is not clear cut, a confirmatory galanin test may be recommended. A possible limitation of this
approach is that galanin is not routinely used in clinical practice and may not be readily available
in some institutions.

Clinical Outcomes of Patients with Acromegaly and Diabetes

The main challenge in the treatment of diabetes is represented by the prevention of microvas-
cular and macrovascular complications to reduce morbidity, mortality, disability, and costs [55].

Although there have been no clinical studies specifically evaluating the outcomes of chronic
complications of diabetes in acromegaly, some pathophysiological aspects merit a mention.
There is evidence suggesting a role for GH in the pathogenesis of microangiopathic compli-
cations of diabetes, such as diabetic nephropathy, with effects occurring early during progres-
sion of the disease [56]. Patients with acromegaly seem to have higher albuminuria than the
normal population [57]. GH and IGF-I excess may also play a role in the pathogenesis of diabetic

Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7 473
retinopathy, as suggested by the seminal demonstration that hypophysectomy led to a
decrease in the severity of retinopathy in non-acromegaly patients with diabetes [58].

The role of GH and IGF-I excess in the development and outcome of atherosclerosis and
diabetic macroangiopathy remains controversial [59–62]. Some studies have suggested that
acromegaly may even be protective against atherosclerosis [59,61], although acromegaly
patients with coexistent diabetes were shown to more frequently have hypertension and
proatherogenic lipid profiles characterized by hypertriglyceridemia and decreased HDL-choles-
terol [2]. This apparent inconsistency may be explained by experimental evidence showing that
IGF-I may be protective by stimulating nitric oxide production from endothelial cells, inducing
vasodilatation, and counteracting oxidized low-density lipoprotein (LDL)-induced cytotoxicity
and vascular smooth muscle cell apoptosis with protection against plaque instability and
ruptures [63]. In this context, it is worth mentioning that the mortality rate among patients with
elevated GH and IGF-I is 2.6–3.5 times greater than that in the general population and some
studies have reported an association between diabetes and mortality in acromegaly [39]. The
pathophysiological and clinical determinants of such an association remain largely unknown (see
Outstanding Questions). In the general population, T2D predisposes to atherosclerotic coronary
artery disease (CAD), which is one of the main factors determining the high risk of mortality in this
clinical setting. In patients with acromegaly, diabetes was shown to be responsible for an
increase in mortality risk [39] but CAD might not be the main determinant of this risk [59,61]. It
may be hypothesized that diabetes may cause worsening of hypertrophic cardiomyopathy in
acromegaly leading to more severe diastolic dysfunction [64], possibly with more frequent
arrhythmic complications [65]. Consistent with this pathophysiological hypothesis, T2D and
associated hyperinsulinemia were shown to promote the development of a specific form of
cardiomyopathy that is independent of CAD and hypertension and is characterized by impaired
myocardial insulin signaling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired
calcium homeostasis, abnormal coronary microcirculation, and neuroendocrine and immune
derangements leading to fibrosis, hypertrophy, cardiac diastolic dysfunction, and, eventually,
systolic heart failure [66]. These morphological and functional abnormalities are similar to those
caused by GH excess in acromegaly [2], supporting the hypothesis that diabetes may predis-
pose acromegaly patients to develop more severe cardiac disease (Figure 1). Another possible
determinant of increased mortality in acromegaly patients with diabetes may be the obstructive
sleep apnea that is a frequent complication of GH hypersecretion [67] and is often associated
with diabetes mellitus in the general population [68].

Acromegaly may cause a metabolic bone disease (‘acromegalic osteopathy’) [69] characterized
by increased bone turnover [70], impaired bone microstructure, and high risk of vertebral
fractures [71], largely independent of bone mineral density values [72]. Diabetes is an emerging
cause of secondary osteoporosis in the general population [73] and there is evidence that it may
also cause impairment in bone strength in patients with acromegaly [74,75]. Bone micro-
architecture was shown to be more severely impaired in acromegaly patients with diabetes
[74] and vertebral fractures occurred more frequently in acromegalic males with diabetes than in
those without diabetes [75].

GH and IGF-I are potent stimulators of either normal or transformed cell proliferation so they can
act as permissive factors for the proliferative action of other growth factors [76]. Neoplasms are a
common complication of acromegaly [2], at a higher incidence than that observed in the general
population. Interestingly, the risk of malignant tumors was found to be about three times higher in
acromegaly patients with diabetes compared with those without diabetes [77], similar to that
observed in the general population [78–80] and consistent with the hypothesis that high insulin
and IGF-I may have additive mitogenic effects, interacting with hybrid IGF-I/insulin receptors
highly expressed in diabetes [4].

474 Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7
 Diabetes
Acromegaly
Mellitus

Insulin resistance, hyperglycemia,

GH hypersecreon
funconal neuroendocrine
systemic and locally elevated IGF-I
derangements

Increased oxidave stress, endothelial dysfuncon, mitochondrial

dysfuncon, impaired calcium handling, remodelling of extracellular matrix

Myocardial fibrosis
and LV hypertrophy

Early diastolic
dysfuncon

Late diastolic Arrhythmia

dysfuncon

Systolic dysfuncon

Heart failure

Figure 1. Proposed Model of Synergistic Cardiomyopathic Disease in Patients with Acromegaly and Diabetes
Mellitus. The figure shows the pathophysiological determinants and clinical features of cardiomyopathy that might be seen
in patients with acromegaly complicated by diabetes mellitus. White arrows indicate the common pathways to myocardial
damage. Intensity of arrow color represents the severity of the complication. Green boxes identify reversible stages of the
complication whereas the yellow box identifies partially reversible stage of cardiomyopathy and red boxes identify
irreversible stages of cardiomyopathy.

Outcome of Diabetes Mellitus during Treatment of Acromegaly

Multimodal treatment is often required to control acromegaly by suppressing GH hypersecre-
tion, reducing IGF-I levels, controlling tumor growth, and improving symptoms and comorbid-
ities. Available therapeutic approaches to acromegaly are neurosurgery, medical management,
and radiotherapy.

Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7 475
Effects of Neurosurgery
Trans-sphenoidal surgery is the treatment of choice for intrasellar microadenomas and nonin-
vasive macroadenomas (i.e., those without cavernous sinus or bone invasion) and when the
tumor is causing compressive symptoms [46]. Surgical removal of GH-secreting pituitary tumors
improves both glucose tolerance and diabetes [81]. Insulin secretion and sensitivity were both
shown to improve in the short term (1–2 months) after neurosurgery and normalization of
glucose homeostasis occurred in 23–58% of patients with preexisting diabetes [28,82]. How-
ever, no data on long-term response are available, particularly in subjects in whom cure of
acromegaly and/or improved b cell function was not achieved [28,82].

Another important factor determining the outcome of glucose metabolism disorders after
neurosurgery is the occurrence of post-surgical hypopituitarism. Hypopituitarism may be
present at diagnosis of acromegaly and successful surgery could immediately restore pituitary
function to normal together with resolution of GH hypersecretion [83]. However, in some patients
hypopituitarism may persist in the long term or may occur as a complication of surgery. GH
deficiency (GHD) may develop after neurosurgery, in some series with a prevalence exceeding
50% of acromegaly patients who were defined as surgically cured from the disease, mainly when
radiation therapy is performed after neurosurgery [84]. Although clinical data on this issue are
scarce and controversial, it is conceivable that the transition from active acromegaly to complete
loss of GH secretion may favor the persistence of or even further impair glucose metabolism.
GHD was shown to be associated with increased visceral adiposity and insulin resistance [85]
and such abnormalities were also demonstrated in patients becoming GH deficient as an effect
of acromegaly overtreatment [86].

Effects of Somatostatin Analogs

First Generation
First-generation long-acting somatostatin analogs (i.e., octreotide LAR and lanreotide Autogel)
are the primary treatment option if surgery is not appropriate and the primary first-line therapy
after surgery in patients with persistently active acromegaly [87]. These drugs signal via
somatostatin receptor subtype 2 and, to a much lesser extent, targeting receptor subtype
5, leading to a decrease in GH secretion and tumor shrinkage [88]. About 50% of
patients treated with these drugs achieve full biochemical control of acromegaly, although this
percentage was shown to decline when data from registries of unselected patients were
considered [89].

Somatostatin and its analogs are able to inhibit insulin secretion and this effect may potentially
impair glucose homeostasis in acromegaly, especially in patients with preexisting glucose
intolerance or T2D. An increase in serum glycated hemoglobin (HbA1c) and post-OGTT glucose
levels during octreotide and lanreotide treatment was reported in few studies [90,91]. However,
a meta-analysis of 31 studies involving 619 patients with acromegaly showed that plasma insulin
values decreased during treatment with octreotide or lanreotide but the overall impact of this
effect on glucose homeostasis was shown to be marginal, particularly when acromegaly was
biochemically controlled by treatment [6]. In the studies that reported an increase in HbA1c,
changes did not exceed 0.5% [6]. Moreover, preexisting diabetes or glucose intolerance tended
to remain unchanged or improve during octreotide or lanreotide treatment, whereas worsening
of glucose control was observed in only 25% of these patients [6]. Such a result was confirmed
even when ‘partial-responder’ acromegaly patients were treated with higher doses of octreotide
LAR than those used in conventional regimens [92].

Second Generation
Long-acting pasireotide is a second-generation somatostatin analog that targets multiple
receptor subtypes and was recently approved for the treatment of acromegaly patients with

476 Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7
inadequate response to surgery and first-generation somatostatin analogs. Pasireotide shows
higher affinity than octreotide and lanreotide to somatostatin receptor subtype 5, which is highly
expressed not only in pituitary adenomas but also in b cells and modulates insulin secretion [88].
Moreover, somatostatin receptor subtype 5 was shown to inhibit secretion of glucagon-like
peptide-1 (GLP-1) [93]. Studies performed in healthy volunteers showed that pasireotide
inhibited insulin secretion and incretin response with minimal inhibition of glucagon secretion
and no impact on insulin sensitivity [9,94]. These effects may predispose acromegaly patients to
develop glucose homeostasis disorders during pasireotide treatment. In a Phase III clinical trial
[95] comparing pasireotide LAR with octreotide LAR in medically naive patients with acromegaly,
hyperglycemic events occurred in 28.7% of patients on pasireotide versus 8.3% of patients on
octreotide. Moreover, new-onset diabetes mellitus was diagnosed in 19.1% versus 3.9% of
cases. Six of the 14 adverse events resulting in patient discontinuation in the pasireotide group
were due to elevations in blood glucose. Similarly, hyperglycemia and diabetes were quite
frequent complications of pasireotide LAR treatment in the Phase III PAOLA trial designed to test
the superiority of pasireotide LAR in treating patients who were inadequately controlled on the
maximum approved dose of octreotide LAR or lanreotide Autogel [96]. In this study, diabetes
occurred in 21% and 26% of patients treated with pasireotide LAR 40 and 60 mg, respectively,
compared with 8% of patients treated with first-generation somatostatin analogs [96]. Interest-
ingly, a recent exploratory analysis of the PAOLA trial showed that about half of patients
undergoing treatment with pasireotide did not need to be treated with antidiabetic drugs,
suggesting that effective control of disease may obviate the need to treat hyperglycemia
[97]. Therefore, an accurate metabolic assessment should be performed before starting treat-
ment with pasireotide LAR, and in patients with poorly controlled diabetes mellitus antidiabetic
treatment should be optimized before treatment is started. Blood glucose levels should be
monitored weekly for the first 3 months after initiating pasireotide LAR and the first 4–6 weeks
after dose increasesi. Patients who develop significant hyperglycemia as an effect of pasireotide
treatment may require initiation of antidiabetic therapy. The optimal treatment for pasireotide-
induced diabetes in acromegaly remains unknown, although mechanistic studies performed in
healthy volunteers suggest that dipeptidyl peptidase (DPP)-4 inhibitors and GLP-1 receptor
agonists may be effective agents for counteracting and reducing pasireotide-associated hyper-
glycemia [98]. If hyperglycemia cannot be optimally controlled despite medical management, the
dose of pasireotide LAR should be reduced or the drug should be discontinued. Interestingly,
hyperglycemia resolved within 3 months to near-normal levels in patients who crossed over from
pasireotide to octreotide LAR [95], suggesting that this effect was reversible.

It is noteworthy that all data so far available on pasireotide-induced diabetes are derived from
clinical trials that provided information for selected populations and thus do not yet allow us to
define the effectiveness and safety of this drug in real life. Similarities exist with the beginning of
the first-generation somatostatin analog era, when early clinical trials raised concerns about
potential negative effects of these drugs on glucose homeostasis that were then minimized by
investigating the effects of somatostatin analogs in unselected patients in subsequent clinical
studies [99]. From this point of view, post-marketing surveillance studies will allow us to clarify the
relevance and real clinical impact of pasireotide LAR-induced hyperglycemia in the management
of acromegaly (see Outstanding Questions).

Effects of Pegvisomant
Pegvisomant is a pegylated human GH receptor antagonist generally used as second-line
medical treatment of acromegaly in patients resistant to or intolerant of first-generation somato-
statin analogs [87,100]. In clinical trials, pegvisomant was shown to normalize serum IGF-I in
more than 90% of acromegaly patients, whereas this percentage decreased in surveillance
studies to about 60% [101,102]. Pegvisomant was reported to have more favorable effects on
glucose homeostasis than somatostatin analogs, in terms of lowering fasting plasma glucose

Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7 477
levels and improving glucose tolerance [101–104]. Pegvisomant improved insulin sensitivity and
the endogenous glucose production rate (which predominantly reflects HGP) and decreased
overnight FFA levels [23]. These effects were also observed in patients with diabetes mellitus and
IGT [104,105]. It remains unclear whether the favorable outcome on glucose homeostasis during
pegvisomant treatment is dependent on specific drug effects or may derive from improved
biochemical control and/or removal of inhibitory effects of somatostatin analogs on insulin
secretion [100]. When pegvisomant was added to somatostatin analogs in partial-responder
acromegaly patients, no substantial changes in glucose metabolism were reported [106].

Effects of Cabergoline
Cabergoline was shown to be effective in controlling acromegaly in patients with slightly
increased serum IGF-I [107–109]. Although dopamine agonists were shown to have direct
favorable effects on glucose metabolism by enhancing insulin-mediated suppression of HGP
and stimulating splanchnic glucose uptake [110], the outcome of diabetes and prediabetes in
acromegaly during cabergoline therapy remains largely unknown.

Treatment of Diabetes in Patients with Acromegaly

There are no specific recommendations for treatment of acromegaly-related diabetes [2] and all
antidiabetic therapies available for T2D can be potentially used in acromegaly patients [111].
However, there are some pathophysiological and clinical peculiarities that may influence the
therapeutic approach to diabetes in acromegaly patients (Figure 2).

According to current guidelines, weight loss (i.e., at least 7% of body weight) and increased
physical activity (i.e., at least 150 min/week of moderate aerobic activity such as walking or
cycling) are recommended as the first step for appropriate therapeutic management of T2D
before starting medical therapies [112]. However, it is noteworthy that acromegaly patients do
not usually have excess fat mass [21], and the effects of weight loss on insulin resistance and
glucose homeostasis in this specific clinical context remains unknown. Moreover, acromegaly
patients often suffer osteoarthropathy [2], which may greatly limit their physical activity.

When lifestyle modifications are insufficient in controlling hyperglycemia, oral antidiabetic drugs
should be considered. No studies have specifically investigated the effects of antidiabetic
therapies in acromegaly. As in the general population of patients with T2D [113], metformin
was reported to be the drug most frequently used in patients with acromegaly-related diabetes
[114]. This choice has a strong rationale, since decreased insulin sensitivity and increased HGP
(i.e., the targets of metformin) are the most important pathophysiological factors underlying
hyperglycemia in acromegaly. Metformin is usually well tolerated, although it might have
gastrointestinal side effects such as gut discomfort, flatulence, or diarrhea. These effects
may be clinically important in acromegaly patients undergoing treatment with somatostatin
analogs that are known to cause similar gastrointestinal adverse events [99]. Metformin may also
cause lactic acidosis, especially in patients with advanced renal or hepatic insufficiency [115].
This life-threatening side effect of metformin, although rare, should be taken into account in
acromegaly patients undergoing treatment with pegvisomant (alone or in combination with first-
generation somatostatin analogs) or pasireotide, since these were shown to cause liver damage
[95,96,100] potentially predisposing to lactic acidosis.

In cases of non-optimal glycemic control or drug intolerance, a second-line drug could be added
or administered in substitution for metformin [113]. Pioglitazone primarily targets insulin resis-
tance (i.e., the main pathophysiological mechanism of acromegaly-related diabetes) thereby
improving insulin sensitivity in the liver and skeletal muscle and is able to significantly reduce HGP
[116]. However, this peroxisome proliferator-activated receptor gamma (PPAR-g) activator is not
usually recommended because of its relevant side effects, including weight gain, fluid retention

478 Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7
 GH Excess
Impaired insulin secreon and Increased lipolysis and
increased glucagon secreon: decreased glucose
uptake:
- Sulfonylurea/glinides
- Increns - Thiazolidinediones

Adipose ssue:
- Lipolysis
Pancreas:
- Adipocyte differenaon
- β-cell exhauson
- Glucose uptake

Insulin resistance and

increased hepac Decreased glucose uptake:
glucose producon: - Meormin
- Insulin
- Meormin
- Insulin
Liver : Muscles: - Thiazolidinediones
- Gluconeogenesis - FFA oxidaon
- Thiazolidinediones - VLDL-Col - Protein synthesis
- IGF-I - Protein breakdown
- Glucose uptake

Circulaon :
- Glucose
- Triglycerides
- HDL-Col

Figure 2. Therapeutic Targets of Antidiabetic Drugs in Acromegaly. The figure shows that sulfonylurea, glinides, and incretins increase insulin secretion whereas
metformin and thiazolidinediones improve insulin sensitivity in liver, muscle, and adipose tissue. Blue boxes, metabolic impact of growth hormone (GH) excess on each
target organ; yellow boxes, mechanism of action of specific antidiabetic drugs on target organs.

leading to edema and heart failure, increased risk of bone fractures, and a possible risk of
bladder cancer [117,118], which may be of particular concern in patients with acromegaly.

Sulfonylureas and glinides, two similar insulin secretagogues, work through the closure of ATP-
sensitive potassium channels on b cells, boosting serum insulin levels [119]. This may be useful
especially when these signals are inhibited by somatostatin analogs [88]. However, while
effective in controlling glucose levels, their use is associated with modest weight gain, high
risk of hypoglycemia, and a relevant secondary failure rate ascribed to an exacerbation of islet
dysfunction.

Trends in Endocrinology & Metabolism, July 2016, Vol. 27, No. 7 479
Incretins (oral DPP-4 inhibitors and subcutaneous GLP-1 receptor agonists) mimic the effects of Outstanding Questions
endogenous GLPs, stimulating insulin secretion in a glucose-dependent way without increasing What are the determinants of increased
hypoglycemic risk [120]. Their metabolic effects are mediated by suppression of glucagon mortality in patients with coexistent
acromegaly and diabetes mellitus?
output, slower gastric emptying, and decreased appetite [120]. A potential advantage of using
these drugs in acromegaly may be the favorable effects on skeletal health, as demonstrated in To what extent is the use of pasireotide
the general population [121] (see Outstanding Questions). Moreover, as stated above, incretins LAR for glucose homeostasis safe in
acromegaly patients treated in real-life
may have a specific role in the treatment of pasireotide-related hyperglycemia [9,94].
clinical practice?

Finally, in patients with persistently abnormal glucose homeostasis, insulin therapy should be Is the management of acromegaly-
considered, especially when b cell function is impaired by long-standing GH hypersecretion and/or related diabetes different from that of
general type 2 diabetes?
treatment with somatostatin analogs (Figure 2). It is noteworthy that the insulin analogs used in
clinical practice, such as insulin glargine, may have higher affinity for the IGF-I receptor and hybrid Do incretins have beneficial effects
receptors than native insulin, with potential promitogenic effects of these drugs [122]. Under on skeletal health in patients with
experimental conditions, insulin glargine was shown to increase resistance to apoptosis in several acromegaly?

tumor cell lines, including colorectal, breast, and prostate cancers [123]. The clinical relevance of
Can insulin treatment influence neo-
these in vitro data is limited, since studies performed in patients with diabetes did not support the plastic risk in acromegaly patients with
hypothesis that insulin glargine at physiological doses increases the risk of tumors in clinical coexistent diabetes mellitus?
practice [4]. However, the potential mitogenic effects of insulin may be of concern for acromegaly
patients who are per se at high risk of cancer (see Outstanding Questions).

In summary, the stepwise therapeutic management of diabetes in acromegaly is similar to that

applied to T2D in clinical practice, with metformin being the first-line therapy to correct
hyperglycemia related to GH hypersecretion. When hyperglycemia is induced or worsened
by pasireotide, incretins (alone or in association with metformin) should be used as the first
pharmacological choice.

Concluding Remarks
GH and IGF-I are major players in the regulation of glucose metabolism. Excess and/or
uncontrolled levels of these hormones are frequently related to significant alterations in glucose
and lipid metabolism. Diabetes in acromegaly may contribute to the increased morbidity and
mortality as well as affecting the choice of GH-lowering treatments. Various treatments for
acromegaly may impact glucose metabolism. Management of diabetes in acromegaly, although
not different in general from that of T2D, may have peculiar aspects, particularly drug related (see
Outstanding Questions).

Acknowledgments
This study was partially supported by the Glucocorticoid Induced Osteoporosis Skeletal Endocrinology Group (GIOSEG),
University of Brescia, Italy and the Italian Ministry for University and Research (MIUR).

Resource
i
www.pharma.us.novartis.com/product/pi/pdf/signifor_lar.pdf

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