Diabetes Secondary to Acromegaly: Physiopathology, Clinical Features and Effects of Treatment

The aim was to formulate clinical practice guidelines for acromegaly.

In evolutionary terms, GH and intracellular STAT 5 signaling is a very old regulatory system. Whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress and fasting. GH exerts anabolic effects directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When subjects are well nourished, the GH-induced stimulation of IGF-I and insulin is important for anabolic storage and growth of lean body mass (LBM), adipose tissue, and glycogen reserves. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of FFA, which leads to decreased glucose and protein oxidation and preservation of LBM and glycogen stores. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the basal state, the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress, the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50%, with a similar increase in muscle protein breakdown. GH is a counterregulatory hormone that antagonizes the hepatic and peripheral effects of insulin on glucose metabolism via mechanisms involving the concomitant increase in FFA flux and uptake. This ability of GH to induce insulin resistance is significant for the defense against hypoglycemia, for the development of "stress" diabetes during fasting and inflammatory illness, and perhaps for the "Dawn" phenomenon (the increase in insulin requirements in the early morning hours). Adult patients with GH deficiency are insulin resistant-probably related to increased adiposity, reduced LBM, and impaired physical performance-which temporarily worsens when GH treatment is initiated. Conversely, despite increased LBM and decreased fat mass, patients with acromegaly are consistently insulin resistant and become more sensitive after appropriate treatment.

This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are advantageously benefitted by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.