Inhibitor of calmodulin and cAMP phosphodiesterase activity in BB rats.
Diabetes mellitus in humans is associated with increased plasma and tissue levels of cAMP and decreased cAMP phosphodiesterase (PDE) activity. Calmodulin (CM) is a low-molecular-weight protein essential for activation of cAMP PDE. The inhibitor (INH) is a low-molecular-weight substance that inhibits the activity of CM in multiple systems, including PDE. Spontaneously diabetic BB rats (SDR) and their nondiabetic littermates (NDR) were used in this study. Holtzman rats were rendered diabetic by streptozocin (STZ). STZ-induced diabetic rats (STZ-DR) and BB rats were studied with and without the benefit of insulin therapy. Calmodulin was assayed both by bioassay and by specific radioimmunoassay. The inhibitor was bioassayed by its ability to inhibit CM-activated PDE. Results showed that both spontaneous and STZ-induced diabetes are associated with a decrease in activity of the low-Michaelis constant (Km) cAMP PDE in the liver (39%, SDR; 70% STZ-DR). Calmodulin activity was also decreased in the livers of both animals (13%, SDR; 68%, STZ-DR). Similar data were obtained for NDRs. The inhibitor, on the other hand, was increased in the livers of untreated SDRs and STZ-DRs (155%, SDR; 125%, STZ-DR). No change was noted for NDRs. All these changes were restored toward normal after treatment with insulin. These data suggest that in diabetes the defect in the cAMP PDE-CM-INH system is demonstrated in both an environmental model, as illustrated by STZ-DRs, and a genetic model, as shown by SDRs and NDRs. The inhibitor activity, however, is not changed significantly in NDRs. We speculate that the inhibitor activity plays a role in dictating whether the genetic NDR will or will not become clinically diabetic.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011913:Rats, Inbred BB; D011919:Rats, Inbred Strains
D002147:Calmodulin; D007328:Insulin; D015105:3',5'-Cyclic-AMP Phosphodiesterases