Adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate: levels and cyclase activities in liver and adipose tissue from diabetic mice (db/db).

Abstract

The adenylate and guanylate cyclase activities and the adenosine and guanosine 3′:5′‐monophosphate (cyclic AMP and cyclic GMP) contents have been investigated in the liver and adipose tissue of control homozygote (+m/+m), heterozygote (db+/+m) and diabetic homozygote (db+/db+) mice (C57BL/Ks‐J‐db m strain).The response to (−)‐isoproterenol of the adenylate cyclase system in isolated fat cells, as well as in adipocyte plasma membranes, from diabetic mice (db+/db+), is impaired as compared to their thin littermates (+m/+m) and also to heterozygote (db+/+m) mice. The increase in cyclic AMP formation elicited by (−)‐isoproterenol was 10‐fold and 4‐fold higher in isolated adipocytes and in adipocyte plasma membranes respectively from lean control as compared to diabetic mice. The cyclic AMP content of adipose tissue from diabetic mice (44.0 ± 7.6 fmol per mg of wet weight) was markedly lower than that from control and heterozygote mice (128.3 ± 41.5 and 128.4 ± 34.5 fmol per mg of wet weight, respectively). In contrast the basal adenylate cyclase activities of liver homogenates and the activties stimulated by glucagon, epinephrine and fluoride were similar in the three groups of animals. Similarly, the hepatic cyclic AMP content did not differ in the three genotypes of mice. These findings indicate that disturbances in cyclic AMP metabolism in adipose tissue from diabetic mice might result from a phenomenon secondary to the diabetic syndrome.The specific activity of guanylate cyclase in liver and adipocytes progressively decreased from lean control (+m/+m) to heterozygote (db+/+m) to homozygote diabetic (db+/db+) mice; e.g. the guanylate cyclase activity in adipocyte plasma membranes was markedly diminished in diabetic mice (18.9 ± 1.9, 12.7 ± 0.9 and 4.7 ± 1.4 pmol cyclic GMP · min−1· (mg protein)−1 for homozygote control, heterozygote and diabetic mice, respectively). A similar situation was noted in respect of the cyclic GMP levels in the liver and adipose tissue of these animals. Thus, the cyclic GMP content in tissues from diabetic mice represented only 13% and 43% of that in the liver and adipose tissue respectively of control mice. These data are consistent with the existence of a dosage effect of the db gene on cyclic GMP metabolism. On the other hand identical maximal guanylate cyclase activities were obtained after preincubation with Triton X‐100 of adipocyte plasma membranes from the three kinds of mice. At least, there was a 19‐fold and 2.5‐fold stimulation of guanylate cyclase activity by sodium azide in liver homogenates from homozygote diabetic mice and homozygote control, respectively; the hypersensitivity to NaN3 of guanylate cyclase activity in liver and adipose tissue could be related to a disturbance in peroxide metabolism in the tissues of the mutant.