and IGF-1 levels) is somewhat controversial. This controversy is partly explained by the fact that GH and IGF-1 levels directly correlate until GH concentrations of approximately 20 ng/mL are reached, at which point the generation of IGF-1 reaches a plateau [21, 22]. Some studies have found IGF-1 levels, expressed either as times the upper limit of normal or z-scores, to be related to diabetes [17–19]. In general, GH levels at diagnosis do not seem to be associated with glucose metabolism abnormalities [17–19, 23], although one study found upon multivariate analysis that a GH greater than 30 ng/mL had an OR for the development of diabetes of 2.76 (95% CI 1.19–6.4, p = 0.01) [24]. Although older studies had found that diabetes, particularly when co-existing with hypertension, was related to mortality in acromegaly [19], more recent series using multivariate analysis have failed to confirm such an association [25, 26]. A possible explanation for such a discrepancy is that acromegalic patients with diabetes nowadays have a better chance of achieving an adequate metabolic control than 20 years ago [26].
Table 1. Prevalence of glucose metabolism abnormalities among different series
Successful surgical treatment of acromegaly improves glucose metabolism and reduces the prevalence of diabetes [27]. In this setting, the normalization of the GH/IGF-1 axis significantly improves both, insulin secretion and sensitivity and results in the restoration of normal glucose homeostasis in 25–50% of patients [27–29]. The effect of the pharmacological treatment of acromegaly on glucose metabolism is more complex. First generation somatostatin analogues (SSA) like octreotide and lanreotide compromise beta cell function and decrease insulin and glucagon secretion since they are preferentially subtype-2 somatostatin receptor ligands [30]. However, these medications significantly improve insulin sensitivity by virtue of decreasing GH and IGF-1 levels so their net effect is usually an improvement in glucose metabolism [31, 32]. Pasireotide is a second-generation SA that targets not only subtype-2 somatostatin receptor, but also SSTR1, SSTR3 and SSTR5 with considerable affinity and is somewhat more effective than octreotide and lanreotide in normalizing GH and IGF-1 levels [33, 34]. This new SSA results in fasting hyperglycemia in over 50% of patients [34, 35]. Pasireotide-induced hyperglycemia results from its interaction with pancreatic SSTR5 which results in both a greater compromise of insulin secretion as well as an inhibition of incretin secretion [36], (Fig. 1).
Fig. 1. Consequences of GH excess in different tissues.
Changes in Lipid Metabolism
The abnormalities of lipid metabolism in acromegaly are closely linked to the disturbances in glucose homeostasis [11]. Some of these effects are the direct result of GH, whereas others are mediated by IGF-1. GH stimulates lipolysis in adipose tissue, which results in an increased flux of FFAs into the circulation providing the substrate for beta-oxidation and ketogenesis [3, 37]. The high levels of circulating FFA promotes the formation of triglyceride-rich, very low-density lipoproteins (VLDL) and is a major contributor to the insulin resistance state found in acromegaly [3, 11, 37]. By decreasing the activity of endothelial lipoprotein lipase, GH decreases triglyceride uptake by peripheral tissues [37]. FFA in turn, are known to inhibit both, spontaneous and GH releasing hormone-induced GH secretion [38]. IGF-1 decreases the activity of lecithin-cholesterol acyl-transferase, the enzyme responsible for the esterification of free cholesterol into high-density lipoprotein (HDL) particles [39]. Thus, the most common lipid abnormalities in patients with acromegaly are hypertriglyceridemia and a reduction in HDL-cholesterol [11]. Chronically, GH excess also results in elevated Lipoprotein-a levels and in an increment of small and dense LDL particles, while total cholesterol concentrations tend to remain normal [11]. The prevalence of hypertriglyceridemia and hypo-alphalipoproteinemia in acromegaly ranges from 20 to 40% and it is estimated to be up to 3 times higher than in the general population [40]. The hypertriglyceridemia of acromegaly does not seem to correlate with body weight or basal GH or IGF-1 concentrations but is rather associated with insulin resistance [41]. The low HDL levels however, do correlate with basal IGF-1 concentrations and are more pronounced in postmenopausal women than in men [20].
Taken together, the abnormalities in glucose and lipid metabolism in acromegaly result in adipose tissue dysfunction and may lead to a state of chronic inflammation and endothelial dysfunction that ultimately contribute to the increased cardio-metabolic risk of these patients. Successful treatment of acromegaly, be it by surgical removal of the pituitary adenoma or by treatment with SSA results in a significant, albeit incomplete, reduction in the prevalence of these metabolic disturbances, since 10–20% of cured or controlled patients remain dyslipidemic [27]. It is not known whether this simply reflects the prevalence of dyslipidemia in the general population or is the result of some irreversible derangements of the chronic GH excess [16]. Since the GH receptor antagonist pegvisomant reduces IGF-1 but not GH levels, one would expect that the direct metabolic effects of GH (i.e., increased lipolysis and FFA levels, and thus hypertriglyceridemia) should remain unchanged in patients controlled
