Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma

Abstract

Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.

Main mechanisms and clinical implications of alterations in energy expenditure state among patients with pheochromocytoma and paraganglioma: A review

“…[23] Patients with PPGL often show impaired glucose tolerance. The incidence of diabetes among patients with PPGL ranges from 21% to 37%, [36] with a higher prevalence of impaired glucose tolerance (approximately 49.5%). [37] Diabetic ketoacidosis and hyperosmolar hyperglycemic coma can also occur.…”

Secondary diabetes mellitus in pheochromocytomas and paragangliomas

“…Being consistent with its pathogenesis, secondary DM in PPGLs is more strongly associated with parameters of impaired insulin secretion than of increased insulin resistance [ 10 ]. Furthermore, according to retrospective data, its presentation is also affected by other factors, either patient-specific, such as older age [ 7 , 11 , 82 ], or disease-specific such as longer duration of the disease [ 11 ], higher number of anti-hypertensive medications [ 82 ], higher levels of metanephrine and normetanephrine [ 7 ], larger size of the tumor [ 8 , 9 ], and presence of PPGL-associated symptoms [ 9 , 11 ]. In most cases, DM is revealed during routine blood investigations in patients with PPGLs, and sometimes, DM diagnosis precedes that of PPGLs.…”

“…Intriguingly, the latter are also shown to effectively inhibit SGLT activity and I K(M) electrical current in pheochromocytoma cell lines; the subsequent perturbance of membrane excitability in these cells might have functional implications [ 88 ]. However, SGLT2is should be used with caution in insulin-deficient patients due to risk of euglycemic DKA [ 82 ]. Similar disease-modifying or pleiotropic effects of anti-diabetic medications have been also demonstrated in other endocrinopathies, as in acromegaly [ 89 ] and primary aldosteronism [ 90 ].…”

“…Post-operatively, DM is shown to markedly improve, with complete resolution being observed at 57–79% of cases in cohort studies [ 7 – 11 ] and up to 100% in case reports [ 16 , 40 , 84 ]. Shorter duration of DM [ 10 ] or PPGL [ 82 ], preoperative DM management with diet and metformin monotherapy [ 7 , 82 ], and, notably, higher preoperative catecholamine level as well as larger tumor size appear to predict remission of DM [ 7 ]. The impact of body weight in post-operative DM prognosis appears to be controversial among studies.…”

“…While elevated BMI appears to predict DM persistence post-operatively in four retrospective studies [ 7 – 9 , 11 ], a third study fails to reveal any correlation between post-operative weight gain and glycated hemoglobulin (HbA1c) [ 91 ]. The high rates of DM remission, in conjunction with the risk of post-operative hypoglycemia principally due to excessive rebound hyperinsulinemia require vigorous glucose monitoring post-operatively and appropriate down-titration of anti-diabetic regimens, especially in insulin-treated patients [ 82 , 92 ].…”