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      Abnormalities in Glucose Metabolism

A close relationship between GH and the regulation of intermediary metabolism has been known to exist for over 80 years. The Nobel Laureate Bernardo Houssay discovered that hypophysectomized dogs have an increased insulin sensitivity and are more prone to develop hypoglycemia [2]. GH is one of the major counteregulatory hormones and is also involved in certain physiological (puberty) and pathological (Dawn phenomenon in patients with diabetes) states of insulin resistance and increased glucose production [3]. On the other hand, IGF-1 itself may result in hypoglycemia by interacting with both, its own receptor or by spilling over to the insulin receptor [4]. The 2 main metabolic consequences of any state of GH excess are a decreased peripheral glucose uptake and an increased hepatic glucose production [2]. Neither the number, nor the affinity of insulin receptors, are abnormal in peripheral blood monocytes and erythrocytes from patients with active acromegaly, so the insulin resistance in acromegaly is the result of post-receptor defects occurring in the insulin signaling cascade [5, 6]. GH excess interferes with the normal phosphorylation of the insulin receptor and its mediators [7]. Previous studies have shown that GH suppresses insulin receptor substrate-1-associated phosphatidyI-inositol-3-kinase activity, which is crucial for glucose uptake in muscle and fat [8, 9]. Being a fundamentally lipolytic hormone, GH increases free fatty acids (FFAs), which themselves suppress glucose transporters in muscle and adipose tissue [3, 7]. At least in the early stages of the disease, patients with acromegaly maintain a normal fasting glucose at the expense of a compensatory increment in insulin production by pancreatic beta cells [3, 7]. If GH excess remains untreated, particularly in subjects with other diabetogenic risk factors (family history, obesity), impaired fasting glucose, glucose intolerance, or even frank fasting hyperglycemia develop [7, 10].

The prevalence of glucose metabolism abnormalities in acromegaly varies between 15 and 50%, again, depending on the ethnic background of the studied population and the concomitant presence of other risk factors [7, 11]. Thus, one would expect a higher prevalence of diabetes in acromegaly patients of Native American or Mexican Mestizo descent, than among Caucasian or Asian population, since the background prevalence of diabetes in the former is significantly higher than in the latter [11, 12]. Regardless of the genetic background, abnormalities in glucose metabolism are perhaps the most common co-morbidities in acromegaly [11]. Furthermore, many studies have shown that less than 30% of patient suffering from the disease will actually have an absolutely normal glucose metabolism [14–19]. In fact, a significant proportion of patients with acromegaly are unaware of having abnormalities of glucose metabolism until they undergo the standard oral glucose tolerance test used to diagnose the disease (Table 1). Diabetes mellitus has been reported to be present in 20–53% of patients with acromegaly, whereas the prevalence of impaired fasting glucose and glucose intolerance varies between 8.9–19 and 15–31.6%, respectively (Table 1) [14–19]. Diabetes in acromegaly has been variably associated with advanced age, body mass index (BMI), family history of diabetes and hypertension [11]. Women with acromegaly are consistently more prone to develop diabetes than men [18, 20]. Such gender dimorphism is probably the result of a greater visceral adipose tissue dysfunction in women than in men [18–20]. The association between diabetes and biochemical indices of acromegalic activity (i.e., GH 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

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