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 1 O-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 f 7.6 fmol per mg of wet weight) was markedly lower than that from control and heterozygote inice (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 activities 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 guaiiylate cyclase in liver and adipocytes progressively decreased from lean control ( + m / + m ) to heterozygote (db+/+m) to homozygote diabetic (db+/db+) mice;Je.g. the guanylate cyclase activity in adipocyte plasma membranes was markedly diminished in diabetic mice (18.9 f 1.9, 12.7 & 0.9 and 4.7 +_ 1.4 pmol cyclic G M P . min-' . (mg protein)-' 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-I 00 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.

Increased Sensitivity to Lipolytic Hormones of Adenylate Cyclase in Fat Cells of Diabetic Rats

“…In fat-cell membranes of genetically diabetic mice maximal responses to epinephrine and isoproterenol of adenylate cyclase have been reported to be largely reduced, whereas basal activity and the sensitivity of the enzyme to isoproterenol have been found to be unchanged [24]. However, these findings cannot be compared with ours, since dbjdb mice are not insulindeficient like our streptozotocin-diabetic rats, but display hyperinsulinemia with insulin resistance and obesity, i.e.…”

Glucagon-stimulable adenylyl cyclase in rat liver. The impact of streptozotocin-induced diabetes mellitus.

“…Glucagon-sensitive adenylyl cyclase has been found to be increased, decreased, or unchanged in liver and in other tissues ofrats made diabetic by the intravenous administration ofstrep- 112511 lodoglucagon bound (pmol/mg protein) tozotocin (2,5,6,8,13,14). In a previous study, we found a decreased responsiveness of the catecholamine-sensitive adenylyl cyclase in skeletal muscle obtained from rats with streptozotocininduced diabetes mellitus (10).…”

“…Glucagon-stimulable adenylyl cyclase activity has been assessed in liver of animals having a variety of models of diabetes mellitus and has been conflictingly reported to be increased (5)(6)(7), decreased (1,8,9), or unchanged compared with nondiabetic control animals (2). Disparate changes have also been reported for hormone-stimulable adenylyl cyclase activities in other tissues (10)(11)(12)(13)(14). Hormone-stimulable adenylyl cyclase is formed ofthree major components which include: a specific hormone receptor, a catalytic component which catalyzes the reaction forming cAMP from ATP, and a regulatory or coupling system which is comprised ofat least two proteins linking the hormone-receptor complexes to the catalytic component (15)(16)(17)(18)(19)(20).…”

The Impact of Streptozotocin-induced Diabetes Mellitus on Cyclic Nucleotide Regulation of Skeletal Muscle Amino Acid Metabolism in the Rat

“…The findings of the present study demonstrate abnormalities of adrenergic and cholinergic regulation of protein and amino acid metabolism in diabetic muscle. Increased as well as decreased cAMP levels and catecholamine-stimulated adenylyl cyclase activities have been observed in a number of tissues obtained from a variety of diabetic models (36)(37)(38)(39). The present finding of a subsensitivity of muscle amino acid release to physiologic levels of catecholamines provides a mechanism in addition to insulin deficiency that may thereby cause glucose overproduction in diabetic man, because physiologic levels of catecholamines (0.1-10 nM) would be ineffective in restraining the accelerated rates of muscle alanine delivery in vivo as a result of this desensitization process (34,40).…”