In Patients With Controlled Acromegaly, Indices of Glucose Homeostasis Correlate With IGF-1 Levels Rather Than With Type of Treatment

Amelie Decock; Charlotte Verroken; Frederique Van de Velde; Tina Vilsbøll; Jens Juul Holst; Guy T'Sjoen; Bruno Lapauw

Disclosures

Clin Endocrinol. 2021;95(1):65-73. 

In This Article

Abstract and Introduction

Abstract

Objective: Acromegaly is accompanied by abnormalities in glucose and lipid metabolism which improve upon treatment. Few studies have investigated whether these improvements differ between treatment modalities. This study aimed to compare glucose homeostasis, lipid profiles and postprandial gut hormone response in patients with controlled acromegaly according to actual treatment.

Design: Cross-sectional study at a tertiary care centre.

Patients: Twenty-one patients with acromegaly under stable control (ie insulin growth factor 1 [IGF1] levels below sex- and age-specific thresholds and a random growth hormone level <1.0 μg/L) after surgery (n = 5), during treatment with long-acting somatostatin analogues (n = 10) or long-acting somatostatin analogues + pegvisomant (n = 6) were included.

Measurements: Glucose, insulin, total cholesterol and high-density lipoprotein-cholesterol were measured in fasting serum samples. Glucose, insulin, triglycerides, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were measured during a mixed meal test. Insulin sensitivity was evaluated by a hyperinsulinaemic-euglycaemic clamp.

Results: There were no significant differences in glucose tolerance, insulin sensitivity or postprandial gut hormone responses between the three groups. Positive correlations between IGF1 levels and HbA1c, fasting glucose and insulin levels and postprandial area under the curve (AUC) of glucose and insulin and also an inverse association between IGF1 and glucose disposal rate were found in the whole cohort (all p < .05, lowest p = .001 for postprandial AUC glucose with r s = 0.660).

Conclusion: In this cross-sectional study in patients with controlled acromegaly, there were no differences in glucose homeostasis or postprandial substrate metabolism according to treatment modality. However, a lower IGF1 level seems associated with a better metabolic profile.

Introduction

Acromegaly is a rare endocrine disorder with an estimated prevalence of 69–120 per million, characterized by growth hormone (GH) hypersecretion leading to a multisystem disease. It is associated with glucose dysregulation in 16%–54% and diabetes in 12%–38% of patients and leads to increased cardiovascular and cerebrovascular morbidity and mortality.[1–3] In the majority of cases, a GH-secreting pituitary adenoma arising from the somatotroph cells causes the disease, and transsphenoidal surgery is recommended as the primary treatment.[4,5] After surgical remission, which is achieved in 78% and 53% of the patients for micro- and macro-adenomas respectively,[6] normalization of glucose metabolism occurs in 23%–58% of patients.[7] Diabetes is more likely to persist whether the beta-cell function was impaired preoperatively.[7] In case of persistent disease after surgery, additional medical therapy by long-acting somatostatin analogues (LA-SSA), GH antagonists (pegvisomant) or in some cases dopamine agonists is recommended.[4] Depending on disease severity (and definition of disease control), medical remission is achieved in 17%–43% of patients using monotherapy[8–11] and 62%–100% of patients using combination therapy.[12–15]

These different medical treatment modalities seem to exert divergent direct effects on glucose and substrate metabolism. For instance, LA-SSA inhibit pancreatic insulin and glucagon secretion and are suspected to decrease intestinal glucose absorption, decrease insulin clearance and augment insulin-induced glucose uptake by muscle.[3] However, their net effect on glucose metabolism is difficult to predict and different studies showed heterogeneous results. A meta-analysis by Maziotti et al suggested that overall, LA-SSA treatment only has marginal clinical impact.[16] A more recent meta-analysis demonstrated LA-SSA to affect the metabolic status with a slightly increase in HbA1c, a decrease in fasting plasma insulin and an increase in glucose after oral glucose tolerance test.[17] In contrast, treatment of acromegalic patients with pegvisomant seems to have a favourable effect on glucose homeostasis by improving insulin sensitivity and reducing endogenous glucose production. The exact mechanisms behind these effects are unclear, although limited data suggest a role of decreased free fatty acid production.[18] Nonetheless, as most of the studies included patients with active acromegaly disease, it is difficult to distinguish between effects of disease control and direct effects of therapy. A recent meta-analysis suggests a drug-related rather than a disease-related effect, given the improvement of glucose metabolism on pegvisomant monotherapy was independent of duration of treatment and disease control in a subgroup analysis.[19]

An additional possible mechanism by which LA-SSA or pegvisomant may impact glucose metabolism is through modulating secretion of gut-derived hormones such as ghrelin, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Indeed, hypersecretion of GH and insulin growth factor 1 (IGF1) but also the treatment of acromegaly seems to affect gut hormone physiology and thereby indirectly glucose metabolism.[5,20–23]

The objective of this cross-sectional study was to investigate glucose homeostasis and insulin sensitivity as well as postprandial substrate metabolism and incretin response in patients with controlled acromegaly according to the current guidelines, that is patients with IGF1 levels below their age- and sex-specific threshold and a random GH <1.0 μg/L.[4] Three groups are compared as follows: patients controlled after surgery (SUR), patients with controlled disease on LA-SSA therapy and patients with controlled disease on combination of LA-SSA and pegvisomant. Correlations between IGF1 levels and outcome parameters in the whole group will also be evaluated. We hypothesized that there will be less efficient lipid and glucose handling in the LA-SSA group as compared to the patients controlled after surgery, and a better glucose and lipid metabolism in the LA-SSA + pegvisomant group versus LA-SSA monotherapy.

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