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BACKGROUND AND PURPOSEMetformin is commonly used to treat type 2 diabetes (T2D). While new clinical applications have been ascribed to metformin, including treatment of anovulatory infertility, its effects on male reproduction have not been investigated. The Sertoli cell (SC) is crucial for germ cell development, exerting metabolic control of spermatogenesis, therefore, we investigated the effects of metformin on SC metabolism. EXPERIMENTAL APPROACHRat SCs were cultured in the absence and presence of metformin (5, 50 and 500 μM). mRNA and protein levels of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1 (PFK 1), lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by quantitative PCR and Western blot respectively. LDH activity was assessed and metabolite production/consumption determined by 1 H-NMR. KEY RESULTSMetformin (50 μM) decreased mRNA and protein levels of GLUT1, GLUT3, MCT4 and PFK 1 but did not affect LDH mRNA or protein levels. However, although glucose consumption was maintained in metformin-treated cells, LDH activity, lactate and alanine production were increased, indicating an enhanced glycolytic flux. No metabolic cytotoxicity was detected in SCs exposed to supra-pharmacological concentration of metformin. CONCLUSIONS AND IMPLICATIONSOur results indicate that metformin: (i) decreases mRNA and protein levels of glycolysis-related transporters in SCs but increases their activity; and (ii) stimulates alanine production, which induces antioxidant activity and maintains the NADH/NAD + equilibrium. The increased lactate in metformin-treated SCs provides nutritional support and has an anti-apoptotic effect in developing germ cells. Thus, metformin can be considered as a suitable antidiabetic drug for male patients of reproductive age with T2D.

The results obtained establish androgens as modulators of glycolytic metabolism in PCa cells by stimulating glucose consumption, as well as the production and export of lactate, which may represent a crucial issue-driven prostate tumor development. These findings also highlight the importance of PCa therapies targeting AR and metabolism-related proteins.

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Regucalcin (RGN) is a calcium (Ca(2+))-binding protein widely expressed in vertebrate and invertebrate species, which is also known as senescence marker protein 30, due to its molecular weight (33 kDa) and a characteristically diminished expression with the aging process. RGN regulates intracellular Ca(2+) homeostasis and the activity of several proteins involved in intracellular signalling pathways, namely, kinases, phosphatases, phosphodiesterase, nitric oxide synthase and proteases, which highlights its importance in cell biology. In addition, RGN has cytoprotective effects reducing intracellular levels of oxidative stress, also playing a role in the control of cell survival and apoptosis. Multiple factors have been identified regulating the cell levels of RGN transcripts and protein, and an altered expression pattern of this interesting protein has been found in cases of reproductive disorders, neurodegenerative diseases and cancer. Moreover, RGN is a serum-secreted protein, and its levels have been correlated with the stage of disease, which strongly suggests the usefulness of this protein as a potential biomarker for monitoring disease onset and progression. The present review aims to discuss the available information concerning RGN expression and function in distinct cell types and tissues, integrating cellular and molecular mechanisms in the context of normal and pathological conditions. Insight into the cellular actions of RGN will be a key step towards deepening the knowledge of the biology of several human diseases.