Differential effects of metformin on reductive activity and energy production in pituitary tumor cells compared to myogenic precursors

Tulipano, Giovanni; Paghera, Simone; Missale, Cristina; Giustina, Andrea

doi:10.1007/s12020-020-02373-7

Cited by 3 publications

(12 citation statements)

References 27 publications

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“…AMPK pathway is suggested to be a key mediator of glucocorticoid-metformin interaction (5,(34)(35)(36). In addition, metformin could show positive and protective effects during endogenous GC excess via an increase of serum insulin-like growth factor-I (37) and fibroblast growth factor 21 (38)(39)(40), and/or via a suppression of neuroendocrine tumor growth (9,41,42). However, the underlying mechanism behind a potential protection against glucocorticoid-associated adverse side-effects remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

et al. 2021

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ContextGlucocorticoid excess exhibits multiple detrimental effects by its catabolic properties. Metformin was recently suggested to protect from adverse metabolic side-effects of glucocorticoid treatment. Whether metformin is beneficial in patients with endogenous glucocorticoid excess has not been clarified.ObjectiveTo evaluate the phenotype in patients with endogenous Cushing’s syndrome (CS) treated with metformin at the time of diagnosis.Patients and MethodsAs part of the German Cushing’s Registry we selected from our prospective cohort of 96 patients all 10 patients who had been on pre-existing metformin treatment at time of diagnosis (CS-MET). These 10 patients were matched for age, sex and BMI with 16 patients without metformin treatment (CS-NOMET). All patients had florid CS at time of diagnosis. We analyzed body composition, metabolic parameters, bone mineral density and bone remodeling markers, muscle function and quality of life.ResultsAs expected, diabetes was more prevalent in the CS-MET group, and HbA1c was higher. In terms of comorbidities and the degree of hypercortisolism, the two groups were comparable. We did not observe differences in terms of muscle function or body composition. In contrast, bone mineral density in metformin-treated patients was superior to the CS-NOMET group at time of diagnosis (median T-Score -0.8 versus -1.4, p = 0.030). CS-MET patients showed decreased β-CTX levels at baseline (p = 0.041), suggesting reduced bone resorption under metformin treatment during glucocorticoid excess.ConclusionThis retrospective cohort study supports potential protective effects of metformin in patients with endogenous glucocorticoid excess, in particular on bone metabolism.

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Section: Discussionmentioning

confidence: 99%

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

et al. 2021

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“…More precisely, we compared rat pituitary tumor cell lines responsive to metformin to rat myogenic precursors as a model of rapidly proliferating, undifferentiated, normal cells whose growth was not negatively affected by metformin. In the attempt to evidence any difference in the compensatory metabolic response to metformin between pituitary tumor cells and normal cells, we ruled out the chance to compare the pituitary tumor cells to normal pituitary cells because the proliferation rate is related to the ATP requirement by cells, with rapidly proliferating cells requiring more ATP than differentiated, non-proliferating cells [ 12 , 20 ].…”

Section: Metabolic Rearrangements That Occur Upon Metformin Treatment In Normal and Tumor Cellsmentioning

confidence: 99%

“…Our study [ 20 ] provided evidence that metformin can exert differential effects on redox activity and energy formation in pituitary tumor cells compared to normal proliferating cells, with consequences on their growth in vitro. Moreover, it also suggested that the pyruvate metabolic branch point is most likely to play a main role in the variability of the cell response to metformin.…”

Section: Metabolic Rearrangements That Occur Upon Metformin Treatment In Normal and Tumor Cellsmentioning

confidence: 99%

“…The increased reductive activity also ruled out a prompt conversion of pyruvate to lactate in these cells. This reaction would have consumed NADH with a negative impact on the cell reductive activity [ 20 ]. Alternatively, the selective impact of pyruvate on the reductive activity in rat pituitary tumor cells, may also be explained by the use of pyruvate in the anaplerotic reaction catalyzed by pyruvate carboxylase, which generates TCA cycle intermediates and mitochondrial reducing equivalents [ 148 , 175 ].…”

Section: Metabolic Rearrangements That Occur Upon Metformin Treatment In Normal and Tumor Cellsmentioning

confidence: 99%

“…Epidemiological studies and preclinical evidence have suggested the efficacy of metformin as a therapeutic agent for the treatment of two types of endocrine tumors, in detail differentiated thyroid cancer and pancreatic neuroendocrine tumors [ 13 , 16 , 17 ]. Furthermore, in vitro studies using cell lines and few studies in animal models have suggested to extend the efficacy of metformin to other endocrine tumors and contributed to characterize the differential effects of metformin in distinct cell types [ 18 , 19 , 20 ]. These laboratory-based data have not been confirmed by clinical evidence yet.…”

Section: Introductionmentioning

confidence: 99%

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Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Tulipano

2021

IJMS

Self Cite

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Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.

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Advances in the mechanism of action of metformin in pituitary tumors

Zhang¹,

Yin²,

Wang³

2023

World J Meta-Anal

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Differential effects of metformin on reductive activity and energy production in pituitary tumor cells compared to myogenic precursors

Cited by 3 publications

References 27 publications

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Advances in the mechanism of action of metformin in pituitary tumors

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