guanosine-triphosphate and Diabetes-Mellitus--Type-1

The sensitivity of components of the adenylate cyclase signaling system (heterotrimer G proteins and adenylate cyclase enzyme) to the regulatory effects of hormones mediated through G proteins (stimulatory effect of isoproterenol and relaxin and inhibitory effects of somatostatin) was decreased in the myocardium of hyperglycemic rats under conditions of transitory hyperglycemia caused by intravenous glucose and in hyperglycemia associated with insulin insufficiency in 24-h type 1 streptozotocin-induced diabetes mellitus. Changes in hormone sensitivity of the adenylate cyclase system were tissue-specific: clearly manifest in the myocardium, minor in skeletal muscles, and virtually absent in the brain of hyperglycemic rats. The main disorders of this system in the myocardium were observed at the stage of hormone receptor coupling with G proteins, which was seen from reduced stimulatory effect of GppNHp on adenylate cyclase activity and attenuation of the regulatory effect of hormones on adenylate cyclase enzyme and G proteins functionally coupled with it.

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Animals; Brain; Cells; Cyclic AMP; Diabetes Mellitus, Type 1; GTP-Binding Proteins; Guanosine Triphosphate; Hyperglycemia; In Vitro Techniques; Isoproterenol; Male; Muscle, Skeletal; Protein Binding; Rats; Rats, Wistar; Receptors, Peptide; Relaxin; Somatostatin; Streptozocin

We examined changes in guanosine triphosphate-dependent signal transduction mechanisms in the retina from the early stages of the streptozotocin-diabetic rat, a model for Type 1 (insulin-dependent) diabetes mellitus. Guanosine triphosphate binding, guanosine triphosphatase activity, and binding of (azido) guanosine triphosphate decreased significantly in the retina as early as 2 weeks after the induction of diabetes. The ability of guanosine triphosphate to inhibit forskolin-stimulatable adenyl cyclase was also abolished. These data suggest functional deterioration of G-proteins, especially Gi, in diabetic retina. Further studies using retinal rod outer segments revealed deterioration in light-sensitive, guanosine triphosphate-dependent functions of transducin in diabetic rats. Pertussis toxin-catalysed ADP ribosylation of the alpha subunit of transducin, a heterotrimeric G-protein of rod outer segments, was also reduced in diabetes. No functional effects were seen in purified subunits of transducin subjected to non-enzymatic glycation in vitro. On the other hand, incubation of non-diabetic rod outer segments with (12-0-tetradeconyl) phorbol-13-acetate, a protein kinase C agonist, in the presence of magnesium and adenosine triphosphate resulted in the reduction of guanosine triphosphate-binding and hydrolysis, thus indicating that protein kinase C may be involved in the regulation of these activities. The significance of these observations in the early visual abnormalities associated with diabetes is discussed.

Topics: Adenosine Diphosphate Ribose; Adenylate Cyclase Toxin; Animals; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Glucose; Glycosylation; GTP Phosphohydrolases; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Kinetics; Pertussis Toxin; Rats; Rats, Inbred Strains; Retina; Rod Cell Outer Segment; Transducin; Virulence Factors, Bordetella