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

Abstract

ABSTRACT-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 ac tivities. 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-l,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) activ ity. 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 conclud ed 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.Keywords: Diabetic (db/db) mouse, Glucagon/insulin ratio, Gluconeogenesis, Hyperglycemia Genetically diabetic (db/db) mouse was first described by Hummel et al. (1) as an animal model of NIDDM (non-insulin-dependent diabetes mellitus). Detailed stud ies from the same laboratory have later showed that hyperinsulinemia was the first detectable abnormality in the mice (2-4). Interestingly, the blood insulin levels which decrease with age appear to be inversely correlated with the blood glucose levels. On the other hand, we have recently demonstrated that insulin resistance occurred in db/db mice before the manifestation of hyperglycemia and remained constant during the course of developing hyperglycemia (5). We thus speculate that insulin resistance causes compensatory insulin release that causes age-associated insulin depletion and leads to development of hyperglycemia. Decreased glucose utilization due to in sufficient insulin release was considered to be an explana tion for the hyperglycemia in db/db mice.It has also been postulated that accelerated glucose production contributes to the hyperglycemia of db/db mice (6). The speculation was extended by Chan et al. (7), who showed that hepatic glycogenolytic and gluconeo genic enzyme activities increased in db/db mice. While glucagon enhances hepatic glucose production by stimulating gluconeogenesis and glycogenolysis, db/db mice are hyperglucagonemic (4, 8) presumably due to en hanced pancreatic glucagon release (9). These results sug gest that hyperglucagonemia which enhances hepatic glu cose production plays an important role in the develop ment of hyperglycemia in db/db mice.As described ...

Differential Hypoglycemic Effect of 2,5-Anhydro-D-Mannitol, a Putative Gluconeogenesis Inhibitor, in Genetically Diabetic (db/db) and Streptozotocin-Induced Diabetic Mice

“…Extending the previous finding that the rate of gluconeogenesis increased in the liver of db/db mice (3,4), we have recently demonstrated that there was a strong correlation between individual plasma glucose levels and hepatic gluconeogenic enzyme activities during the development of hyperglycemia in the mice (7). In addi tion, we have recently reported that insulin resistance oc curred in the db/db mice before the manifestation of hyperglycemia and remained constant during the develop ment of hyperglycemia (6).…”

“…This raises the possibility that the drastic hypoglycemia caused by AM rather than the direct effect of the drug on insulin release contributes to the depression of plasma insulin levels in db/db mice. We have previously reported that db/db mice reveal severe hyperinsulinemia at 5 weeks of age when their plasma glucose levels are still nearly nor mal (6,7). In db/db mice, there appears to be a compensa tory insulin release to restore the hyperglycemia in mice.…”

Improved Insulin Sensitivity Is Associated With Restricted Intake of Dietary Glycoxidation Products in the db/db Mouse

“…IR and increased hepatic gluconeogenesis are already present in young db/db C57/BL/KsJ mice at a time when they are still normoglycemic (42,43). A possible explanation for the enhanced hepatic gluconeogenesis, not influenced by AGE intake in this study, is the increased secretion of glucagon and the glucagon/insulin ratio in db/db C57/BL/KsJ mice (44,45). Further supportive evidence for increased gluconeogenesis in type 2 diabetes animal models was provided by increased liver mRNA levels of the transcription factor PGC-1 and the gluconeogenic enzyme PEPCK (46).…”

Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes

“…Plasma glucagon levels are elevated in db/db mice and glucagon plays an important role in their age-associated development of hyperglycemia (Kodama et al 1994). The ability of PEG-DAPD to delay the onset of hyperglycemia in pre-diabetic db/db mice and to lower the fasting blood glucose levels in diabetic db/db mice supports the dual-acting role of PEG-DAPD to increase insulin secretion and inhibit glucagon action.…”