Glucose handling by the kidney

Abstract

The kidney contributes to glucose homeostasis through processes of gluconeogenesis, glucose filtration, glucose reabsorption, and glucose consumption. Each of these processes can be altered in patients with type-2 diabetes (T2DM), providing potential targets for novel therapies. Recent studies have indicated that the kidney is responsible for up to 20% of all glucose production via gluconeogenesis. In patients with T2DM, overall glucose production increases by as much as 300%, with equal contributions from hepatic and renal sources. This increased production contributes not only to increased fasting glucose in T2DM patients but also to raised postprandial glucose because, in contrast to the liver, glucose ingestion increases renal gluconeogenesis. Under normal circumstances, up to 180 g/day of glucose is filtered by the renal glomerulus and virtually all of it is subsequently reabsorbed in the proximal convoluted tubule. This reabsorption is effected by two sodium-dependent glucose cotransporter (SGLT) proteins. SGLT2, situated in the S1 segment, is a low-affinity high-capacity transporter reabsorbing up to 90% of filtered glucose. SGLT1, situated in the S3 segment, is a high-affinity low-capacity transporter reabsorbing the remaining 10%. In patients with T2DM, renal reabsorptive capacity maladaptively increases from a normal level of 19.5 to 23.3 mmol/l/min. Once glucose has been reabsorbed into the tubular epithelial cells, it diffuses into the interstitium across specific facilitative glucose transporters (GLUTs). GLUT1 and GLUT2 are associated with SGLT1 and SGLT2, respectively.

Diabetes Induces Aberrant DNA Methylation in the Proximal Tubules of the Kidney

“…Such PT-specific DMRs are considered to represent characteristic feature of the PT in the kidney. Among the PTspecific DMRs, those showing decreased methylation in the PT cells contained genes that are known to be the marker genes of PT cells, 7,13,14 such as Sglt2 (Slc5a2), Pck1, Gcnt1 (glucosaminyl [N-acetyl] transferase 1, core 2); an enzyme involved in the formation of glycolipid, G6pc; and Hnf4a, a nuclear receptor. These genes were highly demethylated in the PT cells, while markedly methylated in the non-PT fraction ( Figures 1D and 2B).…”

“…PT cells, as the only part of the kidney expressing the appropriate enzymes for gluconeogenesis, such as Pck1 and G6pc, also generate glucose by gluconeogenesis. 7 Functional changes in the metabolism and transport are observed in the PT cells from an early stage in diabetes and are considered to be critically involved in the development of diabetic kidney disease. 7,8 Epigenetic mechanisms may underlie PT-specific gene expressions and phenotype changes in diabetes, but the DNA methylation profile of PT cells has not been evaluated to date.…”

Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Glimepiride Following Co-administration in Healthy Volunteers: A Randomised, Open-label, Crossover Study

“…In healthy individuals, approximately 180 g of glucose per day is filtered by the kidney and this is almost completely reabsorbed back into the bloodstream [5]. SGLT2 is located in the proximal tubule and is estimated to facilitate about 90% of this reabsorption, whilst the remaining 10% is mediated by SGLT1 [5].…”

“…In healthy individuals, approximately 180 g of glucose per day is filtered by the kidney and this is almost completely reabsorbed back into the bloodstream [5]. SGLT2 is located in the proximal tubule and is estimated to facilitate about 90% of this reabsorption, whilst the remaining 10% is mediated by SGLT1 [5]. The inhibition of SGLT2 reduces glucose reabsorption in the kidney, leading to an increase in urinary glucose excretion and a reduction in plasma glucose levels [6].…”

Glucose and Lipid Transporters Roles in Type 2 Diabetes

“…The defects of these genes found in T2DM patients are concerning due to the increased chance of heart disease associated with low HDLs and excess cholesterol buildup and blockage. It is also necessary to understand to what extent lower expression and mutations of the genes contribute to the development of T2DM and other risk factors [31][32][33][34]. …”