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

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.