Gluconeogenesis in the kidney: in health and in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a global health issue with increasing prevalence. Despite large improvements in current therapies, slowing CKD progression remains a challenge. A better understanding of renal pathophysiology is needed to offer new therapeutic targets. The role of metabolism alterations and mitochondrial dysfunction in tubular cells is increasingly recognized in CKD progression. In proximal tubular cells, CKD progression is associated with a switch from fatty acid oxidation to glycolysis. Glucose synthesis through gluconeogenesis is one of the principal physiological functions of the kidney. Loss of tubular gluconeogenesis in a stage-dependent manner is a key feature of CKD and contributes to systemic and possibly local metabolic complications. The local consequences observed may be related to an accumulation of precursors, such as glycogen, but also to the various physiological functions of the gluconeogenesis enzymes. The basic features of metabolism in proximal tubular cells, and their modifications during chronic kidney disease will be reviewed. The metabolic modifications and their influence on kidney disease will be described, as well as the local and systemic consequences. Therapeutic interventions will finally be discussed.

Is Environmental Cadmium Exposure Causally Related to Diabetes and Obesity?

“…The kidney is the only organ other than the liver that produces and releases glucose into the circulation [ 20 , 21 , 22 , 23 ]. The liver and kidney are directly involved in blood glucose control.…”

“…The kidney is also responsible for filtration, and reabsorption of glucose. In normal health, an approximate of 160 to 180 g of glucose is retrieved each day [ 20 , 21 , 22 , 23 ]. The sodium glucose co-transporter 2 (SGLT2) and SGLT1 mediate 90% and 10% of the tubular reabsorption of glucose, respectively [ 23 ].…”

“…In normal health, an approximate of 160 to 180 g of glucose is retrieved each day [ 20 , 21 , 22 , 23 ]. The sodium glucose co-transporter 2 (SGLT2) and SGLT1 mediate 90% and 10% of the tubular reabsorption of glucose, respectively [ 23 ]. Increased renal expression of these glucose transporters has been implicated in an elevation of renal threshold for glucose excretion in diabetes type 2 patients [ 21 ].…”

“…Loss of tubular gluconeogenesis and a switch to glycolysis are known pathologic features of CKD [ 23 ]. In clinical trials, SGLT2 inhibitors were effective to attenuate the deterioration of kidney function in CKD patients [ 24 ].…”

“…The rapid and massive HO-1 expression in response to Cd, leads to a transient increase in the intracellular heme concentration. This results in the stimulation of gluconeogenesis, and a shift to dominant glycolysis, a known pathologic feature of CKD [ 23 ].…”