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Metabolic Complications of Acromegaly
Moisés Mercado · Claudia Ramírez-Rentería
Experimental Endocrinology Unit and Endocrinology Service, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
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Abstract
Diabetes is recognized as one of the most common acromegaly co-morbidities with a prevalence ranging 20–53%, while over one-third of these patients have an altered lipid profile. In fact, as in the non-acromegalic population, carbohydrate and lipid metabolism abnormalities are closely linked. Long term exposure to an excess of growth hormone (GH) and Insulin-like growth factor-1 concentrations results in insulin resistance and an increased hepatic glucose production. The lipolytic effect of GH results in the mobilization of free fatty acids that further contributes to the decreased insulin sensitivity found in these patients. Some studies suggest that the presence of diabetes contributes to the increased mortality of acromegaly, although this remains controversial. Successful treatment of acromegaly usually results in significant, albeit incomplete improvements of the abnormal metabolic profile.
© 2018 S. Karger AG, Basel
Introduction
The chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) that occurs in acromegaly affects virtually all aspects of metabolism, including protein, lipid, and carbohydrate synthesis and degradation as well as the handling of sodium, calcium, and phosphorus by the kidney. The clinical expression of these metabolic abnormalities varies among patients and is strongly influenced by ethnogentic and environmental factors. The resulting co-morbidities, including diabetes, dyslipidemia, and hypertension, contribute to the increased cardiovascular mortality risk found in these patients. In this brief review, we analyze the pathophysiology, epidemiology, and clinical characteristics of the carbohydrate and lipid metabolism abnormalities that occur in acromegaly. For an in-depth analysis of the effects of chronic GH and IGF-1 excess on the renal handling of sodium, calcium and phosphorus we refer the reader to an excellent review by Kamenicky et al. [1].
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
