Pirchio, Rosa (2025) Glucose metabolism in acromegaly: a translational study on the impact of surgical and medical treatments on pancreatic and adipose tissue endocrine function. [Tesi di dottorato]

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Abstract

Acromegaly and its treatments have an impact on gluco-insulinemic and lipid metabolism. As currently no study has specifically addressed the mechanisms responsible for these changes, the present two-phase translational study, including an in vitro and an in vivo study, aimed at investigating metabolic changes in acromegaly patients during acromegaly treatments. IN VITRO STUDY The aims of the in vitro study were: 1. To study the expression on models of pancreatic ß-cells (INS-1E) and adipocytes (3T3-L1) of the insulin receptor, somatostatin receptors 1-5, dopamine receptors, GH and IGF-I receptors; 2. To study on INS-1E the effects of exposure to octreotide (OCT) and pasireotide (PAS) on insulin secretion and on the expression of cellular miR-375, known to be involved in the process of insulin secretion; 3. To study on 3T3-L1 the effects of exposure to OCT and PAS on lipid accumulation. INS-1E cell proliferation was significantly inhibited by OCT and PAS after 72 hrs of treatment as compared to the control. Conversely, insulin secretion, normalized on cell proliferation, was not significantly reduced by OCT and PAS as compared to the control. In INS-1E cells stimulated with low glucose concentration, with consequent high levels of miR-375, the addition of PAS led to an increase in insulin synthesis, with a diffuse localization of insulin in the β-cell. When the same cells were administered with OCT, despite a significant increase in insulin synthesis, the intense punctuate fluorescence suggested a main storage in secretory granules, suggesting a different action of PAS and OCT in insulin storage. In 3T3-L1 cells, all tested drugs reduced lipid accumulation after 3 days of treatment, with the highest reduction obtained with OCT (-22.48%). Beyond quantitative inhibition, smaller lipid droplets, characteristic of brown/beige adipose tissue, were observed after PAS. IN VIVO STUDY Retrospective study on 110 acromegaly patients. The aims were: 1. To study the impact of treatments for acromegaly (neurosurgery and medical treatments) on glucose and lipid metabolism evaluated after short (3-6 months) and long-term (12 months, 3, and 5 years) treatment duration; 2. To study the impact of treatments for acromegaly on glucose and lipid metabolism when used as first, second or third line of treatment. Besides a comparable control of acromegaly, a significant different metabolic impact was found among treatments. Concerning first-line treatments, patients undergone neurosurgery experienced a greater improvement in glucose profile, whereas patients treated with medical therapy exhibited a better lipid profile. Among second-line treatments, a significant difference among groups was reported in fasting glucose, fasting insulin, HOMA-β, ISI0, and HbA1c, resulting the greater impairment in patients administered with PAS as compared to those undergone neurosurgery after medical therapy. No significant difference in metabolic impact of third-line treatments was observed. In conclusion, this study reported a different metabolic impact of the same treatment according to the timing of use. The difference in metabolic impact was evident for first-line treatment also after a long time, whereas only in the short-term (up to 12 months) in patients administered with a second-line treatment, resulting in a completely neutral effect for third-line treatments.

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