The possible role of age-related increase in the plasma glucagon/insulin ratio in the enhanced hepatic gluconeogenesis and hyperglycemia in genetically diabetic (C57BL/KsJ-db/db) mice

Jpn J Pharmacol. 1994 Nov;66(3):281-7. doi: 10.1254/jjp.66.281.


Genetically diabetic db/db mice and their normoglycemic littermates (+/+ mice) were studied to determine plasma levels of glucose, glucagon and insulin and hepatic gluconeogenic enzyme activities. Plasma glucose levels did not differ significantly between the 5-week-old db/db and +/+ mice, but increased with age in the former until the animals were 16-week-old. Similar age-associated changes were observed in the activities of the gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-1,6-diphosphatase (F-1,6-DPase). While the plasma levels of insulin and glucagon that peaked at 7 weeks of age did not parallel the hyperglycemia, the plasma glucagon/insulin (G/I) ratio roughly paralleled the hyperglycemia. Analysis of individual values for the db/db mice revealed statistically significant (P < 0.001) correlations between plasma glucose levels and hepatic G-6-Pase (r = 0.78) or F-1,6-DPase (r = 0.74) activity. There were also significant correlations between the G/I ratio and plasma glucose levels (P < 0.001, r = 0.66), hepatic G-6-Pase (P < 0.01, r = 0.48) or F-1,6-DPase (P < 0.01, r = 0.57) activity. It is thus concluded that the relative predominance of glucagon over insulin action plays an important role in the age-associated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.

MeSH terms

  • Age Factors
  • Animals
  • Blood Glucose / biosynthesis*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Models, Animal
  • Female
  • Fructose-Bisphosphatase / metabolism
  • Glucagon / blood
  • Gluconeogenesis
  • Glucose-6-Phosphatase / metabolism
  • Hyperglycemia / blood
  • Hyperglycemia / enzymology
  • Insulin / blood*
  • Liver / enzymology
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL


  • Blood Glucose
  • Insulin
  • Glucagon
  • Fructose-Bisphosphatase
  • Glucose-6-Phosphatase