Hyperglucagonemia following cisplatin treatment

Area of Science:

• Endocrinology
• Nephrology
• Pharmacology

Background:

• Cisplatin (cis-DDP) is a widely used chemotherapy agent.
• Nephrotoxicity is a known side effect of cisplatin treatment.
• The impact of cisplatin on glucose metabolism and glucagon regulation is not fully understood.

Purpose of the Study:

• To investigate if cisplatin-induced hyperglucagonemia relates to decreased hormone degradation.
• To determine the link between cisplatin nephrotoxicity and hyperglucagonemia.
• To assess the contribution of cisplatin-induced hyperglucagonemia to glucose metabolism disturbances in rats.

Main Methods:

• Administration of varying doses of cisplatin (cis-DDP) to male F-344 rats.
• Measurement of plasma immunoreactive glucagon (IRG) concentrations.
• Assessment of glucagon half-life and plasma disappearance rates.
• Evaluation of nephrotoxicity using mannitol pretreatment.
• Comparison with other nephrotoxic agents (glycerol, gentamicin).
• Analysis of hepatic and renal gluconeogenic enzyme activity.
• Testing response to exogenous glucagon.

Main Results:

• Cisplatin administration (5 or 7.5 mg/kg) increased fasting plasma IRG.
• Hyperglucagonemia included both pancreatic and extrapancreatic components.
• Cisplatin prolonged glucagon half-life and reduced its plasma disappearance rate.
• Reducing nephrotoxicity with mannitol decreased plasma IRG levels.
• Other nephrotoxicants also induced hyperglucagonemia, suggesting a link to kidney toxicity.
• Despite hyperglucagonemia, severe hyperglycemia and increased gluconeogenic enzyme activity were not observed.
• Cisplatin-treated rats showed normal responses to exogenous glucagon.

Conclusions:

• Cisplatin-induced hyperglucagonemia may stem from decreased glucagon degradation due to impaired renal function.
• The observed hyperglucagonemia does not significantly disrupt glucose homeostasis in rats.
• Cisplatin's effects on glucagon metabolism appear secondary to its nephrotoxic properties.