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.
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.
Kodama
H
H
Basic Research Group, Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Fujita
M
M
Yamazaki
M
M
Yamaguchi
I
I
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000096:biosynthesis*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006597:Fructose-Bisphosphatase / Q000378:metabolism; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000201:enzymology; D007328:Insulin / Q000097:blood*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D006597:Fructose-Bisphosphatase; D005952:Glucose-6-Phosphatase