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The type 1 diabetes mellitus (DM1) and dysfunction of thyroid are the most common endocrine diseases, which are interrelated. However, the molecular mechanisms of thyroid dysfunction in DM1 and the role of adenylyl cyclase signaling system (ACSS) in this process remain poorly understood. Typically for studying etiology and pathogenesis of thyroid diseases in DM1 the models of acute DM1 induced by high doses of streptozotocin (STZ) are used. At the same time, a suitable model for this purpose is the model of mild DM1 induced by moderate doses of STZ, which more closely resembles human DM1. The aim of this work was a comparative study of the thyroid functional state in rats with 30-day acute DM1 induced by injection of STZ at a dose of 65 mg/kg, and in rats with the 30- and 210-day mild DM1 induced by three consecutive injections of STZ at medium doses (30-40 mg/kg). For this purpose in diabetic animals the levels of thyroid hormones and TSH and the functional activity of hormone-sensitive ACSS in membranes isolated from thyroid were studied. It was shown that in blood of rats with acute DM1 the levels of fT4, fT3 and tT3 were decreased by 45%, 23% and 19%, respectively, while the level of TSH did not changed significantly. In rats with 30-day mild DM1 the concentration of fT4 was decreased by 32%, while the levels of tT4, tT3 and TSH were similar to those in control. In rats with prolonged mild DM1 after 150 and 210 days after the first treatment with STZ the levels of tT4, fT4 and tT3 were significantly reduced, but the concentration of TSH in rats with 210-day mild DM1 was increased by 119%. The results obtained in the study of the thyroid status and TSH levels in rats with prolonged mild DM1 are in good agreement with the data obtained in the study of thyroid diseases in patients with DM1. It was found that the basal activity of adenylyl cyclase (AC) in the membranes isolated from thyroid of diabetic rats did not change, except for rats with prolonged mild DM1 where this activity was increased by 21%. In all groups of diabetic rats the decrease of AC stimulating effects of GppNHp (10(-5) M) and TSH (10(-8) M) was found, and in the rats with prolonged mild DM1 the AC effect of PACAP-38 (10(-6) M) was also reduced. The decrease of the AC effect of TSH varied among different groups of the diabetic animals: in the rats with acute DM1 this effect was reduced by 46% and in the rats with the 30- and 210-day mild DM1--by 18% and 34%. Thus, it was concluded that the key cause of thyroid resistance to TSH under conditions of DM1 is a weakening of the signal transduction generated by TSH via the ACSS.

One of the common complications of type 2 diabetes mellitus (DM2) are cardiovascular diseases and dysfunctions of the reproductive system, indicating the urgency of developing new approaches to their correction. Last years for the treatment of DM2 began to use bromocryptine (BC), the agonist of type 2 dopamine receptors, which not only restores the energy metabolism, but also prevents the development of cardiovascular diseases. However, the mechanisms and targets of BC action are poorly understood. The purpose of this study was to investigate the effect of BC treatment on functional activity of adenylyl cyclase signaling system (ACSS) in the myocardium and testes of male rats with DM2, which is caused by high-fat diet and treatment with streptozotocin (25 mg/kg). The treatment with BC (60 days, orally at a dose of 0.6 mg/kg once every two days) was started 90 days after the beginning of high-fat diet. Diabetic rats had an increased body weight, elevated triglycerides level, impaired glucose tolerance, and insulin resistance. The treatment with BC resulted in the restoration of glycometabolic indicators and in the improvement of insulin sensitivity. Adenylyl cyclase (AC) stimulating effects of guanylylimidodiphosphate (GppNHp), relaxin, and agonists of β-adrenergic receptors (β3-AR)--isoproterenol and norepinephrine were decreased in the miocardium of the diabetic rats. The corresponding effects of the β-agonists BRL-37344 and CL-316243 was preserved. The inhibitory effect of somatostatin on forskolin-stimulated AC activity was attenuated, while the inhibitory effect of noradrenaline mediated through α2-AR increased. The treatment with BC resulted in the normalization of the adrenergic signaling in the myocardium and partially restoration of AC effects of relaxin and somatostatin. In the testes of diabetic rats, the basal and stimulated by GppNHp, forskolin, human chorionic gonadotropin and pituitary AC-activating polypeptide AC activity were decreased, and the inhibitory effect of somatostatin was attenuated. The changes in testicular ACSS in the case of BC treatment were weakly expressed. Thus, long-term BC treatment restores the functional activity of ACSS in the myocardium and testes of diabetic rats that underlies the therapeutic effect of BC on functions of the cardiovascular and reproductive systems disturbed in DM2 and should be considered when developing strategies for treatment type 2 diabetes and its complications.

We studied the diurnal dynamics of testosterone concentration in male rats with 240-day neonatal streptozotocin-induced diabetes mellitus, which is similar to human type 2 diabetes mellitus. We also studied the effects of intranasal administration of luliberin on testosterone level and the regulation of activities of adenylate cyclase and stimulatory G-proteins in the testicles of diabetic and intact animals by human chorionic gonadotropin. In rats with neonatal diabetes, a decrease in the mean diurnal level of testosterone and its morning rise were observed. The increase in testosterone level 30 min after luliberin administration was significantly reduced in diabetic animals, but no differences in the response to luliberin were observed in intact and diabetic rats 2-6 h after the treatment. The stimulatory effects of human chorionic gonadotropin on adenylate cyclase activity and binding of guanosine triphosphate by stimulatory G-proteins were reduced in the plasma membranes from the testicles of rats with neonatal diabetes in comparison with control specimens. Therefore, rats with neonatal diabetes were characterized by androgen deficiency, which can be related to the impairment of hypothalamic-pituitary-gonadal axis and reduced sensitivity of the adenylate cyclase system in the testicles of diabetic rats to human chorionic gonadotropin.