REVIEW

published: 30 July 2019

doi: 10.3389/fendo.2019.00509

Insulin Resistance in Patients With

Acromegaly
Greisa Vila 1 , Jens Otto L. Jørgensen 2 , Anton Luger 1 and Günter K. Stalla 3*
1
Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,
2
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark, 3 Max Planck Institute of
Psychiatry, Munich, Germany

Acromegaly is characterized by chronic overproduction of growth hormone (GH) that

leads to insulin resistance, glucose intolerance and, ultimately, diabetes. The GH-induced
sustained stimulation of lipolysis plays a major role not only in the development of insulin
resistance and prediabetes/diabetes, but also in the reduction of lipid accumulation,
making acromegaly a unique case of severe insulin resistance in the presence of
reduced body fat. In the present review, we elucidate the effects of GH hypersecretion
on metabolic organs, describing the pathophysiology of impaired glucose tolerance
in acromegaly, as well as the impact of acromegaly-specific therapies on glucose
metabolism. In addition, we highlight the role of insulin resistance in the development
of acromegaly-associated complications such as hypertension, cardiac disease, sleep
apnea, polycystic ovaries, bone disease, and cancer. Taken together, insulin resistance
Edited by:
Marek Bolanowski, is an important metabolic hallmark of acromegaly, which is strongly related to disease
Wroclaw Medical University, Poland activity, the development of comorbidities, and might even impact the response to drugs
Reviewed by: used in the treatment of acromegaly.
Marija Pfeifer,
University of Ljubljana, Slovenia Keywords: glucose, insulin, growth hormone, IGF-I, acromegaly complications, diabetes, comorbidities,
Odelia Cooper, pathophysiology
Cedars-Sinai Medical Center,
United States

*Correspondence: INTRODUCTION
Günter K. Stalla
stalla@psych.mpg.de; The main physiological roles of growth hormone (GH) are the regulation of postnatal growth and
guenter.stalla@medicover.de lipolysis. These actions are highly dependent on the nutritional state, which partitions the metabolic
actions of GH (1). GH is released from pituitary somatotroph cells in a pulsatile fashion that is
Specialty section: tightly controlled by hormones and nutrients (2–5). GH secretion is enhanced by growth hormone-
This article was submitted to releasing hormone, fasting, stress, exercise and hypoglycemia, and suppressed by somatostatin,
Pituitary Endocrinology,
insulin, insuline-like growth factor I (IGF-I), glucose and free fatty acids (1, 3–10).
a section of the journal
GH excess in acromegaly results, with few exceptions, from a benign tumor of pituitary
Frontiers in Endocrinology
somatotroph cells and leads to chronically increased GH concentrations, which do not respond
Received: 05 May 2019
to the classical physiological feed-back inhibition (11). Therefore, acromegaly is characterized
Accepted: 12 July 2019
by a concomitant increase in both GH and IGF-I production and activity. The main metabolic
Published: 30 July 2019
consequence of acromegaly is insulin resistance, which may progress to diabetes. The underlying
Citation:
pathophysiological mechanisms are increased lipolysis, reduced peripheral glucose utilization and
Vila G, Jørgensen JOL, Luger A and
Stalla GK (2019) Insulin Resistance in
enhanced gluconeogenesis (12). Acromegaly is a unique condition of concomitant increases in
Patients With Acromegaly. GH, IGF-I, and insulin concentrations, where the increase in insulin resistance, paradoxically, is
Front. Endocrinol. 10:509. associated with reduced total body fat and even reduced fat accumulation in metabolic organs such
doi: 10.3389/fendo.2019.00509 as the liver (13, 14).

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Vila et al. Insulin Resistance and Acromegaly

In the present review, we discuss the mechanisms leading IGF-I and Glucose Homeostasis
to insulin resistance in patients with acromegaly, the Prolonged administration of GH in the context of a positive
pathophysiological implications of insulin resistance in the energy balance leads to production of IGF-I by the liver. IGF-
comorbidities of acromegaly, as well as the relationship between I is a single-chain polypeptide with 50% amino acid sequence
glucose homeostasis and disease activity in acromegaly. homology with insulin, and its synthesis is stimulated not only
by GH, but also by insulin (25). Acute increases in IGF-I
concentrations exert insulin-like effects on glucose transport
WHOLE-BODY GLUCOSE HOMEOSTASIS and circulating glucose concentrations, also in the absence of
the insulin receptor (26). Nevertheless, circulating IGF-I does
IN ACROMEGALY not cause hypoglycemia, as >90% is bound to specific binding
GH and Glucose Homeostasis proteins (27). Exogenous administration of IGF-I in high doses,
The insulin-antagonistic effects of GH were initially on the other hand, mimicks administration of insulin and
described about 85 years ago following the observation that therefore acutely lowers plasma glucose levels (28). The same
hypophysectomy performed in dogs improved hyperglycemia group showed that prolonged administration of IGF-I during
and experimental diabetes (15). In the second half of the several days does not impact circulating glucose concentrations,
twentieth century, studies performed using pituitary human maybe because the increased IGF-I activity was balanced by a
GH extracts demonstrated direct effects of GH on lipolysis and feedback-induced suppression of GH as well as insulin (29).
hyperglycemia (16, 17). It was hypothesized that the GH-induced Taken together, IGF-I has insulin-agonistic actions, thereby
insulin antagonistic effect is strongly related to the lipolytic potentially counteracting the insulin-antagonistic effects of GH.
effects of GH, as free fatty acids released from fat stores inhibit Cross-sectional population studies have shown that both low
glucose disposal, resulting in insulin resistance (16, 18). This and high IGF-I are associated with increased insulin resistance,
constitutes a favorable metabolic adaptation to fasting and highlighting the complexity of the IGF-I system, which probably
exercise (where insulin levels and activity are low) by providing reflects that IGF-I is a sex- and age-dependent biomarker of
lipid utilization at the expense of glucose. By contrast, GH is not only GH activity but also nutritional status (30). Circulating
suppressed postprandially where insulin activity is maximal IGF-I per se, however, probably plays a very minor role in the
(16, 17). In addition, GH and insulin pathways have been shown regulation of glucose homeostasis in acromegaly.
to cross-talk at the postreceptor level in rodent models and in
vitro (19), but this has not been replicated in human in vivo Glucose Metabolism in Acromegaly
models (20). Since the physiological reciprocal temporal pattern The overall effect of acromegaly on glucose metabolism is mainly
of GH and insulin is abolished in active acromegaly, where determined by the insulin-antagonistic effects of chronically
the continous GH elevation chronically activates intracellular increased GH, which induces hepatic and peripheral insulin
GH signaling, it remains possible that this could impair insulin resistance as previously mentioned (12, 17, 31, 32). This is
signaling, hence causing insulin resistance. followed by a compensatory increase in beta-cell-function,
GH signaling in muscle and fat tissues is confirmed already which aims at maintaining euglycemia (33, 34) (Figure 1).
30 min after a GH surge (21). Intravenous administration of GH Over time, chronic insulin resistance and fatty acid-induced
in healthy human volunteers leads within 2 h to an increase lipotocixity deteriorate beta-cell-function eventually leading to
in free fatty acids together with reduced glucose uptake and diabetes (33, 34).
oxidation in the muscle in concomitance with increased non- An impairment of glucose metabolism is observed in over
oxidative glucose diposal and increased endogenous glucose 50% of patients with newly diagnosed acromegaly (35). Glucose
production (17, 22). The GH-induced impairment of glucose homeostasis is related to disease activity in acromegaly, as higher
uptake is causally linked to the concomitant activation of IGF-I concentrations were found associated to lower insulin
lipolysis, as the administration of the antilipolytic agent acipimox sensitivity (36). Nutrient intake and glucose physiologically
abrogates GH actions on insulin sensitivity (23). It is likely that suppress GH secretion in healthy subjects, but not in patients
also the GH-induced stimulation of gluconeogenesis is positively with acromegaly (37). Indeed, the latter is utilized in the
influenced by the increased free fatty acid levels (24). biochemical evaluation of acromegaly disease activity (38).
Taken together, GH-induced insulin resistance seems to be Surgical cure of acromegaly improves insulin sensitivity and
mainly the consequence of the increased lipolysis, impaired lowers circulating glucose and insulin concentrations (32, 34, 39).
insulin action in peripheral tissues leading to reduced glucose
uptake, and also increased gluconeogenesis in the liver [(17); Body Composition in Acromegaly
Figure 1]. GH transgenic mice are resistant to high fat diet induced
obesity, exhibiting an accumulation of lean tissue, and no
increase in adipose tissue mass (40, 41). Based on the lipolytic
Abbreviations: ERK, extracellular signal-regulated kinase; FSP27, fat-specific effects of growth hormone one would predict a remarkable
protein 27; GH, growth hormone; IGF-I, insuline-like growth factor I; IMTG, reduction of total body fat in acromegaly. Indeed, all studies
intramyocellular triglyceride; MEK, mitogen-activated protein kinase; PCOS,
polycystic ovary syndrome; PI3K, phosphoinositide 3-kinase; PPAR, peroxisome
evaluating body composition consistently describe reduced total
proliferator-activated receptor; SHBG, sex hormone binding globulin; SSA, fat content and also reduced organ-specific fat deposition in
somatostatin analog; STAT5, Signal transducer and activator of transcription 5. patients with acromegaly (13, 14, 42, 43). Nevertheless, one

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Vila et al. Insulin Resistance and Acromegaly

FIGURE 1 | Effects of GH-IGF-I hypersecretion in metabolic organs.

study demonstrated higher intermuscular adipose tissue depots monolayer. An acute reduction of circulating free fatty acid
in the presence of lower visceral and subcutaneous fat in levels stimulates GH secretion (10, 49). GH, in turn, stimulates
patients with acromegaly (44). This is compatible with the lipolysis in humans leading to increased concentrations of free
observation of increased intramyocellular triglyceride (IMTG) fatty acids and glycerol (50). Endogenous GH is essential for
accumulation in healthy subjects after 8 days high dose GH the increased lipolytic rate found during prolonged fasting, with
administration (45). Whether IMTG per se contributes to insulin fasting-induced peaks in endogenous GH secretion being crucial
resistance as indicated by other studies not involving GH (46) for the increased rate of lipolysis during starvation (51, 52).
is uncertain, and it is noteworthy that IMTG also increases During the fed state, GH secretion is suppressed and insulin
following exercise in fit individuals without compromising becomes the main regulator of substrate metabolism (10, 49).
insulin sensitivity (47). This feeding-induced shift between insulin and GH in the
Ectopic lipids, however, play an important role in the control of substrate metabolism was already suggested in 1963
pathophysiology of insulin resistance accompanying obesity in by Rabinowitz and Zierler, with GH being responsible for the
the general population (48). The presence of insulin resistance utilization of endogenous lipids during fasting and stress, thereby
in the absence of hepatic lipid accumulation in patients with sparing glucose and proteins (16).
acromegaly is unique, and it is likely that the small increase in Acromegaly is associated with increased circulating levels
intramuscular fat in active acromegaly mainly reflects increased of lipid intermediates, as well as with increased lipid uptake
lipid oxidation in muscle. In all instances, biochemical control by the muscle, suggesting that fatty acids are a major fuel
of acromegaly reverses this picture, increasing total fat mass and substrate in these patients (32). This sustained stimulation of
reducing lean body mass, while improving insulin sensitivity lipolysis has three main consequences: (1) further deterioration
(13, 42, 43). of insulin sensitivity, (2) impairment of beta-cell function, and
(3) reduction of whole-body fat. Surgical cure of acromegaly
is followed by a normalization of lipolysis and glucose
PATHOPHYSIOLOGY OF INSULIN metabolism (32).
RESISTANCE IN ACROMEGALY
Fat Metabolism Beta-Cells
Lipids constitute the main energy reserves in human physiology, GH stimulation exerts insulinotrophic effects on β-cells in vitro
being primarily stored in the adipose tissue as lipid droplets (53) and in vivo, augmenting glucose-induced insulin secretion
containing triacylglycerides surrounded by a phospholipid without playing a major role in basal insulin secretion (54).

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Vila et al. Insulin Resistance and Acromegaly

The pathophysiology underlying beta-cell-failure in acromegaly Adipose Tissue

seems similar to that observed during the development of type In general, circulating GH concentrations are inversely correlated
2 diabetes where insulin resistance leads to a compensatory to adipose tissue mass in both mice and humans (68). GH
hyperfunction of beta-cells (33, 34). Insulin resistance and directly impairs glucose utilization in 3T3 adipocytes and
lipotoxicity eventually lead to beta-cell dysfunction with failure also impairs insulin signaling in adipose tissue by influencing
to fully counterbalance the increased needs for insulin secretion p85α expression that suppresses PI3K activity (69–72). GH
(33, 34). Several studies have shown an improvement in beta-cell receptor signaling phosphorylates the tyrosine residues on
function after normalization of GH concentrations in patients STAT5, leading to STAT5 activation (73). STAT5 mediates
with acromegaly (39, 55). Despite direct effects of GH on the GH-effects on lipolysis by increasing the transcription of
glucose metabolism, other hormonal alterations accompanying several metabolic genes such as peroxisome proliferator-activated
acromegaly may influence beta-cell function: 1) Acromegaly receptor (PPAR)-gamma and fatty acid synthase (73, 74). In
is associated with increased postprandial glucose-dependent addition, both STAT5- and mitogen-activated protein kinase
insulinotropic polypeptide (GIP) concentrations, which in turn (MEK)/extracellular signal-regulated kinase (ERK)-dependent
stimulate insulin secretion and influence postprandial (but not intracellular signaling mediate the effects on GH in suppressing
fasting) hyperinsulinemia (56); 2) A cross-sectional study found mRNA and protein levels of fat-specific protein 27 (FSP27), a
that beta-cell function strongly and directly correlates with the negative regulator of lipolysis (75). The importance of FSP27
bone marker osteocalcin, revealing that the bone-beta-cell cross- supression for GH signaling in adipocytes is highlighted by the
talk initially described in other populations is also present in fact that FSP27 overexpression fully abrogates the effects of GH
patients with acromegaly (57). on lipolysis and insulin resistance in adipose tissue, mainly by
inhibiting PPAR-gamma phosphorylation (75, 76).
Liver Acromegaly is also associated with decreased expression of
GH signaling in the liver is essential for the production of IGF-I the insulin-sensitizing adipokine adiponectin, but also with
and for the maintenance of a normal hepatic lipid metabolism increased circulating concentrations of the proinflammatory
(58). GH-induced hepatic IGF-I production depends on the adipokine visfatin, which is linked to enhanced inflammation and
local availability of insulin, with increased hepatic sensitivity to insulin resistance in many tissues (77–79). In addition, GH excess
GH in the presence of high portal insulin levels (59). Higher in acromegaly increases the expression of proinflammatory
portal insulin concentrations are associated with increased cytokines within the adipose tissue, which in turn might
IGF-I concentrations, partially also due to the insulin-induced also contribute to the increased insulin resistance (80). This
inhibition of hepatic IGFBP1 production (60). Patients with finding confirms that adipose tissue inflammation can be
acromegaly have an increased glucose turnover, as GH increases found also in the absence of increased adipose tissue mass.
hepatic glucose production by increasing glycogenolysis (17). The functionality rather than the size of adipose tissue mass
Chronic GH administration impairs insulin sensitivity in the seems to determine the phenotype, as successful treatment of
liver, thereby reducing the ability of insulin to suppress acromegaly resulted in a reduction of lean body mass and
gluconeogenesis and glucose output (12, 32, 61). increase of total body fat mass together with improvement
of insulin sensitivity and a reduction in proinflammatory
Muscle cytokines (80).
Local GH perfusion in the brachial artery leads to a rapid
decrease in muscle glucose uptake and oxidation (17, 62, 63).
These rapid GH effects in muscle cells could be either direct or
secondary to the increased lipid utilization (17). GH signaling in ROLE OF INSULIN-RESISTANCE IN THE
muscle induces signal transducer and activator of transcription 5 DEVELOPMENT OF
(STAT5) phosphorylation and increased expression of canonical ACROMEGALY-ASSOCIATED
GH-dependent genes including IGF-I and cytokine-inducible COMORBIDITIES
SH2-containing protein (17, 21). The molecular mechanisms
subserving GH-induced insulin resistance in human subjects Diabetes
remain uncertain. Studies in rodent models show impairment of Diabetes is a late consequence of impaired glucose metabolism
insulin signaling at the level of phosphoinositide 3-kinase (PI3K) in acromegaly, and occurs when the increased beta-cell function
activity (64), but this is not observed in human studies in vivo fails to compensate for the chronically increased insulin
(20, 21, 65, 66). resistance (33, 34) (Figure 2). The prevalence of diabetes in
On the other hand, it has been shown that GH infusion patients with acromegaly is 20–35% at initial disease diagnosis
increases lipolysis and suppresses pyruvate dehydrogenase (81, 82). The frequency of diabetes is related to disease
activity, which indicates substrate competition between glucose control in acromegaly, and IGF-I concentrations are higher
and lipid intermediates (67) in accordance with the Randle in patients with diabetes, when compared to patients with
hypothesis (18). However, it is noteworthy that human in vivo impaired glucose tolerance or normal glucose metabolism (81,
studies rely mainly on mRNA and protein expression in crude 83). Age and positive family history for diabetes were found
biopsies at specific time points, which may not be able to detect to be independently associated with impairment of glucose
real time changes in complex signaling pathways. metabolism in acromegaly (35).

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Vila et al. Insulin Resistance and Acromegaly

FIGURE 2 | Insulin resistance in the pathophysiology of acromegaly comorbidities.

Hypertension of flow-mediated vasodilatation only in subjects that showed

Insulin resistance is thought to be one of the main factors significant improvements in glucose, insulin concentrations and
contributing to hypertension in the general population (84, 85). insulin resistance (97). The authors conclude that endothelial
In acromegaly, hypertension is the most prevalent cardiovascular function in patients with acromegaly strongly relates to
comorbidity, described in up to 60% of published acromegaly insulin resistance and does not always change following rapid
cohorts (86–90). The contribution of insulin resistance in the improvement in GH and IGF-I concentrations (97). Interestingly
development of hypertension was studied in GH transgenic mice, intima media thickness of common carotid arteries, but not the
in which increased systolic blood pressure appears at the age prevalence of atheroclerotic plaques, is increased in patients
of 3–6 months and the prevalence of hypertension increases with acromegaly (98). Taken together, insulin resistance is one
with age (91). In this model hyperinsulinemia develops very of the main pathophysiological mechanisms contributing to the
early, and unlike hypertension, even improves with age. The development of hypertension in acromegaly (99). In routine
authors conclude that hyperinsulinemia might play a role in the clinical practice, patients with acromegaly and impaired glucose
pathophysiology of hypertension, but is not mandatory for the tolerance/diabetes have higher blood pressure values than
maintenance of hypertension (91). patients with acromegaly and normal glucose tolerance (100).
Hyperinsulinemia may lead to increased sodium absorption In larger populations, the presence of diabetes in patients with
in the kidney by activating the renin-angiotensin-aldosterone acromegaly is associated with a significantly increased prevalence
system, thereby also increasing the circulating plasma volume of hypertension (101).
(92). In addition, both insulin and growth hormone increase
sympathetic nervous activity (93). In accordance with Cardiovascular Disease
this, patients with acromegaly lack the nocturnal fall in Insulin resistance is an independent risk factor for cardiovascular
norepinephrine and blood pressure levels (94). disease in the general population mediating the association
Insulin resistance and hyperinsulinemia impair also between hyperglycemia and cardiovascular risk (102–104).
endothelium-dependent vasodilatation and increase oxidative Impaired glucose tolerance directly correlates to the severity
stress in endothelial cells (95, 96). Indeed, flow-mediated of acromegalic cardiomyopathy (100). Patients with acromegaly
vasodilatation, a functional test used for detecting endothelial and diabetes show an increased prevalence of cardiovascular
dysfunction was lower in patients with acromegaly when diseases (101). GH and IGF-I excess lead to morphological heart
compared to age- and gender-matched controls (97). changes (86, 105). Acromegalic cardiomyopathy displays similar
Transsphenoidal surgery led to an increase/normalization features as diabetic cardiomyopathy, and the main morphological

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Vila et al. Insulin Resistance and Acromegaly

difference between the two is the lack of intracardiac lipid SHBG production in the liver, which in turn leads to increased
accumulation in acromegaly (14, 99). The coexistence of androgen bioavailability, and this along with a direct stimulatory
hypertension further aggravates cardiomyopathy in acromegalic effect of GH on hair growth seems to be one of the reasons
patients (105, 106). Although there is no evidence for a direct underlying the increased prevalence of hirsutism in women with
effect of insulin resistance on heart morphology and dysfunction acromegaly (113, 115). Therefore, the clinical phenotype of PCOS
in acromegaly, the atherogenic properties of insulin resistance are is determined not only by the severity of hyperandrogenism,
thought to contribute to the pathophysiology of cardiovascular but also by the degree of insulin resistance/hyperinsulinemia
diseases [(99); Figure 2]. (Figure 2).

Obstructive Sleep Apnea Cancer

Obstructive sleep apnea is the most common sleep disorder in High IGF-I levels are associated with an increased rate of
patients with acromegaly, and also specifically associated with malignancies in the general population (116, 117). Elevated GH
increased mortality (89, 90, 92, 99). The prevalence of sleep apnea and IGF-I concentrations might promote the development and
in acromegaly ranges from 45 to 80% and does not reliably relate progression of malignancies in patients with acromegaly but
to disease activity, with conflicting studies on its reversibility this remains a controversial topic (90). A recent meta-analysis
following successful treatment of acromegaly (92, 107). revealed a moderate increased cancer risk, but this is mainly
The pathophysiology of sleep apnea in acromegaly is mainly observed in single center studies (118). While older retrospective
based on soft tissue thickening of bronchial, pharyngeal, and studies showed increased mortality due to cancer in acromegaly,
laryngeal mucosa, as well as craniofacial morphological changes the more recently published reports on acromegaly cohorts with
(92). Nevertheless, several studies support a bidirectional link normalized GH and IGF-I levels seem to indicate that the cancer
between sleep apnea and insulin resistance/metabolic syndrome mortality is comparable to the one observed in the general
in the general population (108, 109). population (117, 119).
Insulin resistance and metabolic syndrome are also associated
Polycystic Ovary Syndrome (PCOS) with an increased incidence of cancer (120). Indeed, the PI3K
Both GH and IGF-I are known to affect ovarian function and pathway, a common target of GH and insulin signaling, remains
morphology (110). Hypogonadism and menstrual irregularities an important treatment target in malignancies (121). Other
are often reported in women with acromegaly, as volume mitogenic pathways induced by both GH and insulin are
effects of the pituitary adenoma and GH excess may lead MAPK/ERK and Ras-like GTPases (117). To date, there is no
to hypogonadotropic hypogonadism (111). Insulin directly direct evidence on an additive effect of insulin resistance in the
modulates steroidogenesis in ovarian cells, and insulin resistance development of cancer in patients with acromegaly.
plays an important role in the pathogenesis of PCOS (112).
GH modulates ovarian function both directly and via IGF-I Bone Disease
(110). Hence, not only GH/IGF-I, but also hyperinsulinemia Patients with acromegaly display a significant impairment
and insulin resistance accompanying acromegaly seem to be of bone microarchitecture, increased bone formation and
involved in the pathogenesis of a PCOS-like ovarian morphology, resorption, as well as an increased incidence of fractures (122–
which was described in 50% of women with acromegaly (113). 124). The frequency of fractures in patients with acromegaly
Although androgen levels are not generally increased in women relates to disease activity, male gender and concomitant
with acromegaly, the circulating levels of sex hormone binding hypogonadotropic hypogonadism (123). Importantly, the
globulin (SHBG) were found to be low in a retrospective prevalence of diabetes is higher in acromegalic patients
analysis (114). Insulin resistance is associated with decreased experiencing fractures (125). Diabetes is associated with

TABLE 1 | Glucose homeostasis in relation to acromegaly treatment options.

Fasting glucose Glucose 2 h after Beta-cell Insulin HbA1c

OGTT function resistance

Surgery (32, 39, 55, 131) ↓ ↓ Improves ↓ ↓

Dopamine agonists (130, 144, 145) ↔ ↓ Improves ↓ ↓
First-generation SSAs ↔/↑ ↑ Deteriorates/improves ↔/↓ ↔/↑
(131–133, 146, 147)
Pegvisomant ↓ ↓ Improves ↓ ↓
(101, 131, 137–139, 148, 149)
Pasireotide (134–136, 150) ↑ ↑ Deteriorates ↔/↓ ↑
SSAs + Pegvisomant (143, 151) Positive effects of GH/IGF-I reduction counteract the SSA-induced impairment of beta-cell function, no change in HbA1c
Pegvisomant + Pasireotide (142) Risk of hyperglycemia is inversely related to insulin secretion at baseline

Arrows show increase (↑) or decrease (↓). OGTT, oral glucose tolerance test; SSA, First-generation somatostatin analogs.

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Vila et al. Insulin Resistance and Acromegaly

an increased fracture risk also after biochemical control of glucose tolerance, and this effect was abolished after adding
acromegaly (125). To date the pathophysiological evidence metformin (132). In patients with diabetes, both impairment
linking insulin resistance with bone diseases is scarce, but cohort and improvement of glucose tolerance were observed, and
studies show impaired bone turnover, increased incidence of some cases needed optimization of diabetes therapy, but all
osteoporosis and fracture risk in non-acromegalic patients with patients had HbA1c < 6.5% at the end of the study (132). A
diabetes (126, 127). GH and IGF-1 increase bone turnover recent meta-analysis including 47 studies on this topic found
and acromegaly is associated with distinct alterations in bone a high heterogeneity in fasting glucose and HbA1c outcomes,
compartments showing lower trabecular bone quantitative revealing a significant HbA1c increase over time (133). They
parameters, while cortical bone density seems better preserved describe a marginal and non-significant increase in fasting
and found decreased only in patients with vertebral fractures glucose, which became significant only in the subgroup of
(128). In contrast, diabetes is associated with increased cortical patients receiving SSA as second-line therapy, while glucose
porosity and thinning by trabecularization of the endosteal 2 h after OGTT significantly increased (133). In addition, they
part of cortical bone (129). So it appears that diabetes and observed an improvement in insulin resistance and beta-cell
acromegaly affect bone morphology differently. To date it is not function (133).
clear whether insulin resistance plays a role in the association The multireceptor-ligand pasireotide more strongly
between fracture risk and diabetes in patients with acromegaly; suppresses insulin secretion and gut hormones and therefore
or whether this is a simple marker of disease severity and thereby hyperglycemia is observed in more than half of the patients
associated with other acromegaly complications. (130, 134, 135). In healthy volunteers, pasireotide decreases
insulin secretion and the incretin effect, but does not
impact insulin sensitivity (135). In patients with acromegaly,
INSULIN RESISTANCE IN RELATIONSHIP improvement of disease control under pasireotide increases
TO DISEASE ACTIVITY AND THERAPY OF insulin sensitivity, but the concomitant impairment of
ACROMEGALY beta-cell function is the main player determining the
deterioration of glucose metabolism (130). In 13.2% of patients
Biomarkers of glucose metabolism strongly relate to disease receiving pasireotide, treatment was withdrawn due to severe
activity in patients with acromegaly, where IGF-I serves hyperglycemia (136).
as a biomarker of overall disease control in acromegaly The growth hormone antagonist pegvisomant was the first
(35, 36). The impaired glucose metabolism often improves acromegaly medication to show a significant improvement in
following successful pituitary surgery, and patients in glucose metabolism with overnight reductions in endogenous
remission have less prevalent diabetes than patients with glucose production and free fatty acid concentrations
persistent active disease necessitating medical therapy (137–139). Pegvisomant ameliorates all aspects of glucose
(32, 34, 39, 81). One of the main factors determining the metabolism and reduces the need for antidiabetic medications
normalization of glucose metabolism after surgical cure of (101, 130). Therefore, pegvisomant is an attractive option
acromegaly is the beta-cell state. Patients with preserved in acromegalic patients with poorly controlled diabetes,
beta-cell function achieve a normalization of glucose tolerance and its dose requirements also depend on the severity of
after surgery, while impaired beta-cell function leads to diabetes (140). The positive effects of pegvisomant on glucose
persistently abnormal glucose metabolism also after successful metabolism are preserved when it is combined with an
surgery (55). SSA (141–143).
The relationship between parameters of glucose homeostasis Table 1 summarizes the effects of acromegaly-specific
and drugs used for treating acromegaly has been subject to therapies on glucose metabolism. The relationship between
extensive studies, as recently reviewed (130). A recent report dopamine agonist therapy and glucose metabolism has been
compared the effect of the three main treatment modalities on subject to only a few reports, showing a reduction in basal and
glucose metabolism in patients with biochemically controlled stimulated insulin levels (130, 144). Nevertheless, the impact
acromegaly, finding out that plasma glucose decreases after of dopamine agonists on glucose metabolism was extensively
successful surgery and after pegvisomant therapy, but increases studied in patients with prolactinomas, confirming their positive
in patients using first-generation somatostatin analogs (SSA) effect in reducing insulin resistance and ameliorating beta-cell
(131). First-generation somatostatin analogs (SSA) control function (145).
GH secretion and IGF-I production, thereby lowering disease
activity and improving insulin sensitivity in acromegaly.
In parallel, however, they suppress secretion of insulin as SUMMARY
well as of gastric and gut peptides, so their overall effect
on glucose hoemostasis is not straightforward, but marked Insulin resistance is an important metabolic hallmark of
deterioration of glucose metabolism is rarely encountered acromegaly caused mainly by the insulin-antagonizing effects
(130, 132). Colao et al. described that the effects of SSAs of GH in general and the lipolytic effects of GH in particular.
on glucose metabolism depend on the status of glucose The degree of impairment of glucose metabolism is positively
impairment before starting the therapy: SSA may increase related to disease activity in acromegaly and is usually reversed
plasma glucose levels in patients with normal or impaired after acromegaly treatment. Insulin resistance plays an important

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Vila et al. Insulin Resistance and Acromegaly

role in the development of acromegaly-specific comorbidities AUTHOR CONTRIBUTIONS

and further studies are needed for elucidating the role of drugs
that improve insulin resistance on long-term patient outcomes GV wrote the initial version of the manuscript. JJ, AL, and GS
in acromegaly. reviewed the literature and critically revised the manuscript.

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3015854 Conflict of Interest Statement: GV has received lecture fees from IPSEN,
148. Drake WM, Rowles SV, Roberts ME, Fode FK, Besser GM, Monson JP, et al. Novartis, and Pfizer and serves on advisory boards for Pfizer and Novartis. JJ
Insulin sensitivity and glucose tolerance improve in patients with acromegaly has received lecture fees and reserach grants from IPSEN, Novartis, and Pfizer
converted from depot octreotide to pegvisomant. Eur J Endocrinol. (2003) and serves on advisory boards for Pfizer and IPSEN. AL has received honoraria
149:521–7. doi: 10.1530/eje.0.1490521 for lectures from Ipsen, Novartis and Pfizer, participation in advisory boards
149. Feola T, Cozzolino A, Simonelli I, Sbardella E, Pozza C, Giannetta from Ionis, Ipsen, Novartis, Pfizer. GS has received consultancy fees and/or
E, et al. Pegvisomant improves glucose metabolism in acromegaly: reimbursements of delegate fees for conferences/educational events and/or travel
a meta-analysis of prospective interventional studies. J Clin expenses and/or funding for research projects from Pfizer, Ipsen, Lilly, Shire,
Endocrinol Metab. (2019) 104:2892–902. doi: 10.1210/jc.2018- Novartis, Sandoz, NovoNordisk, and HRA.
02281
150. Shimon I, Adnan Z, Gorshtein A, Baraf L, Saba Khazen N, Gershinsky Copyright © 2019 Vila, Jørgensen, Luger and Stalla. This is an open-access article
M, et al. Efficacy and safety of long-acting pasireotide in patients with distributed under the terms of the Creative Commons Attribution License (CC BY).
somatostatin-resistant acromegaly: a multicenter study. Endocrine. (2018) The use, distribution or reproduction in other forums is permitted, provided the
62:448–55. doi: 10.1007/s12020-018-1690-5 original author(s) and the copyright owner(s) are credited and that the original
151. De Marinis L, Bianchi A, Fusco A, Cimino V, Mormando M, Tilaro publication in this journal is cited, in accordance with accepted academic practice.
L, et al. Long-term effects of the combination of pegvisomant with No use, distribution or reproduction is permitted which does not comply with these
somatostatin analogs (SSA) on glucose homeostasis in non-diabetic patients terms.

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