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A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria
Preprint   Open access

A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria

Tumininu S. Faniyan, Xinyi Zhang, Donald A. Morgan, Jorge Robles, Siresha Bathina, Paul S. Brookes, Kamal Rahmouni, Rachel J. Perry and Kavaljit H. Chhabra
bioRxiv
Cold Spring Harbor Laboratory
09/05/2023
DOI: 10.1101/2023.09.01.555894
PMCID: PMC10542134
PMID: 37790458
url
https://doi.org/10.1101/2023.09.01.555894View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all of the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Glut2 knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in body’s defense mechanisms against a threat – were the top candidates which were either upregulated or downregulated in renal Glut2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria, but are met with a compensatory increase in endogenous glucose production.

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