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

Area of Science:

• Nephrology
• Endocrinology
• Metabolic Physiology

Background:

• Metabolic acidosis (MA), common in chronic kidney disease, impacts glucose metabolism.
• The long-term effects of chronic MA on glucose homeostasis are not well understood.

Purpose of the Study:

• To investigate the impact of chronic metabolic acidosis on glucose homeostasis and metabolic parameters in male mice.

Main Methods:

• Chronic metabolic acidosis was induced in mice using long-term ammonium chloride (NH4Cl) administration.
• Evaluated glucose tolerance, insulin sensitivity, basal glycemia, and energy expenditure.
• Analyzed hepatic, intestinal, and renal gluconeogenesis, glucose uptake, and renal sodium/glucose co-transporter expression.
• Utilized transcriptomic analysis of kidney tissue.

Main Results:

• Chronic MA led to lower body weight, increased energy expenditure, and reduced basal glycemia.
• Improved glucose tolerance was observed without changes in insulin secretion or sensitivity.
• Decreased hepatic and intestinal gluconeogenesis, but increased renal endogenous glucose production.
• Elevated urinary glucose excretion correlated with lower renal sodium/glucose co-transporter expression.
• Kidney transcriptomics indicated enhanced anion transport, glucose/lipid metabolism, and oxidative phosphorylation.

Conclusions:

• Chronic MA improves glucose tolerance in mice, independent of insulin changes.
• This improvement is attributed to reduced hepatic gluconeogenesis, decreased renal glucose reabsorption, and increased kidney energy demands.