# Chronic NH4Cl loading improves glucose tolerance without modifying insulin sensitivity in mice

## TL;DR

Chronic acid loading in mice improves glucose tolerance without affecting insulin sensitivity, possibly due to changes in glucose production and kidney function.

## Contribution

The study reveals novel metabolic adaptations in chronic metabolic acidosis that improve glucose tolerance without altering insulin sensitivity.

## Key findings

- Chronic MA reduces body weight and basal glycemia while improving glucose tolerance.
- Chronic MA decreases hepatic and intestinal gluconeogenesis but increases renal glucose production.
- Kidney changes include elevated energy demands and reduced glucose reabsorption.

## Abstract

Acute metabolic acidosis (MA), a feature mostly associated with chronic kidney disease, decreases glucose tolerance and insulin sensitivity. By contrast, the effects of chronic MA on glucose homeostasis remain elusive. Here, we evaluated glucose homeostasis and metabolic parameters in male mice exhibiting chronic MA via long-term NH4Cl administration. Unlike acute MA, chronic MA resulted in lower body weight, increased energy expenditure, lower basal glycemia, improved glucose tolerance without changes in insulin secretion or sensitivity. No overall glucose uptake changes were observed. However, hepatic and intestinal gluconeogenesis were decreased whereas renal endogenous glucose production was increased in mice with chronic MA. The elevated glucose urinary excretion was associated with lower expression of renal sodium/glucose co-transporters. Transcriptomic analysis revealed that chronic MA potentiates anion transport, glucose and lipid metabolism, mitochondrial and oxidative phosphorylation pathways in the kidney. Overall, chronic MA improves glucose tolerance without changes in insulin secretion or sensitivity, likely due to reduced hepatic gluconeogenesis, decreased renal glucose reabsorption and increased energy demands in the kidney.

The online version contains supplementary material available at 10.1038/s41598-026-38007-7.