Secondary diabetes mellitus in acromegaly

Secondary diabetes mellitus (DM) is a common complication of acromegaly, encountered in up to 55% of cases. Vice versa, the prevalence of acromegaly is markedly higher in cohorts of patients with type 2 DM (T2DM). The presence of secondary DM depends primarily on acromegaly status and is associated with increased cardiovascular morbidity, malignancy rate and overall mortality. The principal pathophysiologic mechanism is increased insulin resistance due to excessive lipolysis and altered fat distribution, reflected at the presence of intermuscular fat and attenuated, dysfunctional adipose tissue. Insulin resistance is ascribed to the direct, diabetogenic effects of growth hormone (GH), which prevail over the insulin-sensitizing effects of insulin-like growth factor 1 (IGF-1), probably due to higher glucometabolic potency of GH, IGF-1 resistance, or both. Inversely, GH and IGF-1 act synergistically in increasing insulin secretion. Hyperinsulinemia in portal vein leads to enhanced responsiveness of liver GH receptors and IGF-1 production, pointing towards a mutually amplifying loop between GH-IGF-1 axis and insulin. Secondary DM occurs upon beta cell exhaustion, principally due to gluco-lipo-toxicity. Somatostatin analogues inhibit insulin secretion; especially pasireotide (PASI) impairs glycaemic profile in up to 75% of cases, establishing a separate pathophysiologic entity, PASI-induced DM. In contrast, pegvisomant and dopamine agonizts improve insulin sensitivity. In turn, metformin, pioglitazone and sodium-glucose transporters 2 inhibitors might be disease-modifying by counteracting hyperinsulinemia or acting pleiotropically. Large, prospective cohort studies are needed to validate the above notions and define optimal DM management in acromegaly.

Automated summary

Secondary diabetes mellitus (DM) is a common complication of acromegaly, with a prevalence of up to 55% in cases. Conversely, the prevalence of acromegaly is higher in patients with type 2 DM (T2DM). Secondary DM is primarily dependent on the status of acromegaly and is associated with increased cardiovascular morbidity, malignancy rate, and overall mortality. The main pathophysiologic mechanism is increased insulin resistance due to excessive lipolysis and altered fat distribution, accompanied by intermuscular fat and dysfunctional adipose tissue. Insulin resistance is attributed to the diabetogenic effects of growth hormone (GH), which outweigh the insulin-sensitizing effects of insulin-like growth factor 1 (IGF-1), possibly due to higher glucometabolic potency of GH, IGF-1 resistance, or both. GH and IGF-1 act synergistically in increasing insulin secretion. Hyperinsulinemia in the portal vein leads to enhanced responsiveness of liver GH receptors and IGF-1 production, indicating a mutually amplifying loop between the GH-IGF-1 axis and insulin. Secondary DM develops due to beta cell exhaustion, primarily caused by gluco-lipo-toxicity. Somatostatin analogues inhibit insulin secretion, especially pasireotide (PASI), which impairs glycemic profile in up to 75% of cases, establishing a separate pathophysiologic entity, PASI-induced DM. Conversely, pegvisomant and dopamine agonists improve insulin sensitivity. In turn, metformin, pioglitazone, and sodium-glucose transporters 2 inhibitors may modify the disease by counteracting hyperinsulinemia or exerting pleiotropic effects. Large prospective cohort studies are needed to validate these concepts and define optimal DM management in acromegaly.