Insulin Regulation of Renal Glucose Metabolism

Insulin plays a central role in coordinating renal glucose handling by modulating both reabsorptive and synthetic processes in the nephron. In the proximal tubule, insulin binding to its receptor activates intracellular cascades—principally the PI3K/Akt pathway—that suppress the transcription of gluconeogenic enzymes and promote sodium‐coupled glucose reuptake via SGLT2. Concurrently, insulin influences glucose permeability in downstream segments through regulation of GLUT transporters. Under normal physiology, these actions restrain renal glucose output and complement hepatic glucose homeostasis. In insulin‐resistant states, however, selective impairment of signalling nodes leads to a paradoxical increase in renal gluconeogenesis even as sodium reabsorption persists, contributing to systemic hyperglycaemia, hypertension and salt retention. Understanding these dual roles of insulin in the kidney has global significance for the treatment of diabetes and its cardiovascular and renal complications, and has spurred the development of targeted therapies such as SGLT2 inhibitors and anti‐inflammatory strategies to rebalance renal metabolism.

Research from Nature Portfolio

Recent studies have uncovered a novel regulatory axis in which high‐fat diet-induced upregulation of the (Pro)renin receptor in the proximal tubule drives gluconeogenesis via PGC-1α and suppressed AKT signalling. Genetic ablation of this receptor in nephron segments abolished diet-stimulated expression of key gluconeogenic enzymes, revealing a hitherto unrecognised mechanism by which hyperinsulinaemia and obesity provoke renal glucose output.

Insulin Regulation of Renal Glucose Metabolism publication trend

The graph below shows the total number of articles in insulin regulation of renal glucose metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Gluconeogenesis: Metabolic pathway generating glucose from non-carbohydrate precursors, notably in the proximal tubule of the kidney.

Insulin receptor substrate (IRS): Adaptor proteins (IRS1, IRS2) transmitting signals from the insulin receptor to downstream pathways such as PI3K/Akt.

PI3K/Akt pathway: A key intracellular signalling cascade mediating metabolic effects of insulin, including suppression of gluconeogenesis.

Sodium–glucose cotransporters (SGLT): Membrane proteins (SGLT1, SGLT2) responsible for reabsorption of filtered glucose in the proximal tubule.

NF-κB: A transcription factor complex regulating inflammatory gene expression that can interfere with insulin signalling.

References

1. Selective Insulin Resistance in the Kidney. BioMed Research International (2016).
2. Inhibition of NF-κB Reduces Renal Inflammation and Expression of PEPCK in Type 2 Diabetic Mice. Inflammation (2018).
3. Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway. Scientific Reports (2021).
4. Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice. International Journal of Molecular Sciences (2023).