The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis

Disclosures

Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

Renal Gluconeogenesis

Glucose, after moving into cells, is phosphorylated into glucose-6-phosphate by enzymes like glucokinase or hexokinase. In this form, cells can trap glucose because cell membranes are impermeable to glucose-6-phosphate.[2] Only cells containing the enzyme glucose-6-phosphatase, which hydrolyzes glucose-6-phosphate to glucose, are able to release glucose into the circulation. Glucose-6-phosphatase is present in the liver, the renal cortex and the intestinal epithelium giving the above tissues the ability to release glucose.[2]

The view that gluconeogenic capacity of the kidney may be restrained by conditions, like starvation or acidosis supported by net organ balance studies, is no longer existing.[3] In glucose homeostasis, the kidney may be considered as two different organs: the renal medulla and the renal cortex. This differentiation refers to the distribution of various enzymes in these parts of the kidney. Medulla holds enzymes for glucose phosphorylation, glycolysis and glycogen synthesis, but lacks glucose-6-phosphatase and gluconeogenic enzymes. Consequently, renal medulla satisfy its energy needs through glycolytic division of glucose, which produce lactate and synthesizesa small amount of glycogen for intracellular consumption. Given the lack of glucose-6-phosphatase, the renal medulla has not the capacity to release glucose into the circulation. On the other hand, the renal cortex holds gluconeogenic enzymes, synthesize glucose-6-phosphate from precursors; for instance, lactate, glutamine, glycerol, alanine and is able to release glucose into the blood stream via glucose-6-phosphatase.[4–6]

Renal glucose release in the postabsorptive (12-h fasting) state is calculated by the net glucose balance and deuterated glucose dilution methods. The renal gluconeogenesis contribution to the total glucose release is ~20%, whereas liver glucogenolysis is ~50% and liver gluconeogenesis 30%.[7] Furthermore, the renal gluconeogenesis progresses as the glycogen stores are depleting during a prolonged fasting. According to the studies by Ekberg et al., 60 h of fasting may increase the renal glucose release by 2.5-times compared to the 12-h fasting state, whereas hepatic glucose release is decreasing by 25%.[8]

At the postprandial state, the renal glucose release increases by over 50% of the total endogenous glucose release. This unexpected phenomenon in combination with suppression of the hepatic glucose release facilitates the liver glycogen stores repletion.[9] This process seems to be regulated by the sympathetic nervous system activity.[10]

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