Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function

Abstract

Blood testis barrier (BTB) is one of the tightest blood-barriers controlling the entry of substances into the intratubular fluid. Diabetes Mellitus (DM) is an epidemic metabolic disease concurrent with falling fertility rates, which provokes severe detrimental BTB alterations. It induces testicular alterations, disrupting the metabolic cooperation between the cellular constituents of BTB, with dramatic consequences on sperm quality and fertility. As Sertoli cells are involved in the regulation of spermatogenesis, providing nutritional support for germ cells, any metabolic alteration in these cells derived from DM may be responsible for spermatogenesis disruption, playing a crucial role in fertility/subfertility associated with this pathology. These cells have a glucose sensing machinery that reacts to hormonal fluctuations and several mechanisms to counteract hyper/hypoglycemic events. The role of DM on Sertoli/BTB glucose metabolism dynamics and the metabolic molecular mechanisms through which DM and insulin deregulation alter its functioning, affecting male reproductive potential will be discussed.

Keywords: Sertoli cells; blood-testis barrier; diabetes mellitus; glucose metabolism; male fertility.

Figure 1. Schematic illustration of the seminiferous tubule and the Sertoli/blood testis barrier (BTB). The BTB is a physical barrier between the interstitial space and the seminiferous tubule lumen, formed by Sertoli cells (SCs) and the tight connections between these cells. Outside the BTB is the basal compartment, where spermatogonial renewal occurs, and inside the BTB is the adluminal compartment, where meiosis, spermiogenesis and spermiation take place. Blood vessels and the Leydig cells, which produce testosterone, are located in the interstitial space. Adjacent to the basement membrane are several layers of modified myofibroblastic cells, termed peritubular cells. As a result of such particular organization, the establishment of a functional BTB is essential to create a special environment for the normal development of a fully efficient sperm.

Figure 2. Schematic illustration of Sertoli cells (SCs) main metabolic pathways. The SCs are capable of consuming a variety fuels including glucose, lactate, fatty acids and aminoacids. Nevertheless, SCs actively metabolize glucose being the majority of it converted in lactate and not oxidized in the TCA cycle. The extracellular lactate and pyruvate are transported via the members of the family of proton-linked plasma membrane transporters that carry molecules having one carboxylate group, the monocarboxylate transporters (MCT4), while glucose is imported via specific members of the family of membrane proteins called glucose transporters (GLUT1 and GLUT3). Once glucose enters the glycolytic pathway, it is decomposed to pyruvate which can (a) be converted into lactate via lactate dehydrogenase, (b) be converted into alanine via alanine transaminase or (c) be transported to the mitochondrial matrix, oxidized and decarboxylated by the pyruvate dehydrogenase forming the two carbon intermediate Acetyl-CoA which can enter the TCA cycle. The oxidation of these substrates is coupled with ADP phosphorylation via the electron transport chain to form ATP. Abbreviations: TCA, tricarboxylic acid; GLUT, glucose transporter; MCT, monocarboxylate transporter; ALT, alanine transaminase; LDH, lactate dehydrogenase; PFK, phosphofructokinase; TFP, trifunctional protein.