It has been reported that impaired glucose metabolism observed in patients with CD or acromegaly is uniquely associated with disease pathophysiology. Chronic exposure to elevated GH and IGF-1 levels is associated with insulin resistance, which may be counteracted by the compensatory hyperfunction of pancreatic beta cells in patients with acromegaly with normal glucose tolerance [
18]. Similarly, in CD, chronic hypercortisolism blocks the binding of insulin to peripheral tissues, resulting in insulin resistance, and inhibits the release of insulin by pancreatic beta cells [
17]. Excess cortisol can also affect glucose metabolism in hepatic tissue by stimulating gluconeogenesis or indirectly inhibiting insulin sensitivity by depleting storage of hepatic glycogen.
Recently, there has been a greater understanding of the mechanisms that underlie the development of hyperglycemia in patients with acromegaly or CD treated with pasireotide. The hyperglycemic effects of pasireotide are primarily due to its tendency to reduce insulin and incretin secretion [
19]. Insulin secretion is mediated in large part by sst
2 and sst
5 [
20,
21], and glucagon secretion is mediated primarily by sst
2 [
21,
22]. Pasireotide binds to sst
2 and sst
5 and binds with highest affinity to sst
5, which is expressed not only by pituitary cells but also by other cell types. For example, pasireotide binds to sst
5 in pancreatic islet cells, which leads to reduced insulin secretion that is not observed with SRLs that bind to sst
2 with greater affinity [
19,
23]. Reduced insulin levels associated with pasireotide are unable to counterbalance the reduced insulin sensitivity caused by uncontrolled acromegaly or CD [
18]. However, two mechanisms could explain why the hyperglycemic effect is transient. First, pasireotide has minimal effects on glucagon secretion and no effects on insulin sensitivity in healthy volunteers [
19]. In contrast, octreotide and lanreotide suppress glucagon secretion, which could be due to increased binding of sst
2 [
21,
22], a key mediator of glucagon secretion to which octreotide and lanreotide bind with greater affinities than pasireotide [
8]. By improving biochemical control, it is likely that insulin sensitivity will increase, which should improve glucose tolerance, even if insulin secretion remains reduced. Second, it was reported that levels of IGF-binding protein 2 increased after 24 weeks of pasireotide LAR [
24], which could attenuate the long-term hyperglycemic effects of pasireotide LAR.