The sugar daddy: the role of the renal proximal tubule in glucose homeostasis

Abstract

Renal blood flow represents >20% of total cardiac output and with this comes the great responsibility of maintaining homeostasis through the intricate regulation of solute handling. Through the processes of filtration, reabsorption, and secretion, the kidneys ensure that solutes and other small molecules are either returned to circulation, catabolized within renal epithelial cells, or excreted through the process of urination. Although this occurs throughout the renal nephron, one segment is tasked with the bulk of solute reabsorption-the proximal tubule. Among others, the renal proximal tubule is entirely responsible for the reabsorption of glucose, a critical source of energy that fuels the body. In addition, it is the only other site of gluconeogenesis outside of the liver. When these processes go awry, pathophysiological conditions such as diabetes and acidosis result. In this review, we highlight the recent advances made in understanding these processes that occur within the renal proximal tubule. We focus on the physiological mechanisms at play regarding glucose reabsorption and glucose metabolism, emphasize the conditions that occur under diseased states, and explore the emerging class of therapeutics that are responsible for restoring homeostasis.

Keywords: gluconeogenesis; glycolysis; oxidative phosphorylation; proximal tubule; sodium-glucose cotransporters.

Graphical abstract

Figure 1.

Glucose reabsorption and SGLT2 inhibition. Under healthy conditions (left side of inset), glucose is completely reabsorbed by sodium-glucose cotransporter 2 (SGLT2) and sodium-glucose cotransporter 1 (SGLT1) along the length of the proximal tubule. These transporters are known to be regulated by different signaling pathways and protein kinases depicted in each of the epithelial cells. On the right side of the inset, this process is being blocked using SGLT2 inhibitors. Consequently, this promotes glycosuria and has some beneficial consequences on inflammation and renal injury. FAO, fatty acid oxidation; mTOR, mammalian target of rapamycin.

Figure 2.

Major metabolic pathways within the proximal tubule (PT). Under healthy conditions (left), gluconeogenesis (blue arrows/enzyme names) is the prevalent metabolic pathway performed in the renal proximal tubule. Glycolysis (red arrows/enzyme names) is minimal. Under conditions of diabetes (right), the metabolic processes within the proximal tubule are altered. Green arrows indicate pathways that are increased while red arrows indicate downregulation. G6P, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; PFK1, phosphofructokinase 1; PKM1/2, pyruvate kinase muscle isoform 1/2.