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<p>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 NH<sub>4</sub>Cl 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Nawel Zaibi,
  • Jessica Montaigne,
  • Jennifer Baraka-Vidot,
  • Judith Merrheim,
  • Claire Devos,
  • Emilie Caron,
  • Florent Auger,
  • Emmanuelle Durand,
  • Bénédicte Toussaint,
  • Souhila Amanzougarene,
  • Mehdi Derhourhi,
  • Philippe Froguel,
  • Amélie Bonnefond,
  • Régine Chambrey,
  • Christophe Breton

摘要

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.