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.

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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-Pace (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 ageassociated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.
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