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

• Published in: eLife 2024-07, Vol.12
• Main Authors: Faniyan, Tumininu S, Zhang, Xinyi, Morgan, Donald A, Robles, Jorge, Bathina, Siresha, Brookes, Paul S, Rahmouni, Kamal, Perry, Rachel J, Chhabra, Kavaljit H
• Format: Article
• Language: English
• Subjects: Acute phase proteins; Analysis; Animals; Blood sugar; Denervation; Diabetes; Drug development; Energy conservation; Females; Glucose; Glucose - metabolism; Glucose transporter; Glucose Transporter Type 2 - genetics; Glucose Transporter Type 2 - metabolism; GLUT2; glycosuria; Glycosuria - metabolism; Heart rate; Homeostasis; Hyperglycemia; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - metabolism; Hypothalamo-Hypophyseal System - physiology; Hypothalamus; Hypothalamus - metabolism; Insulin; Kidney - metabolism; Kidneys; Male; Medicine; Mice; Mice, Knockout; Nerves; Phenotypes; Pituitary; Pituitary-Adrenal System - metabolism; Pituitary-Adrenal System - physiology; Plasma; Proteins; Proteomics; Reabsorption; Sensory neurons; Short Report; Urine
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.91540

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all 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 (also known as ) 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 the body's defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal 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 the 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.