Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes Abbreviations:AC -adenylyl cyclase; AC system -adenylyl cyclase signaling system; DM -diabetes mellitus; EMD-386088 -5 -c h l o r o -2 -m e t h y l -3 -( 1 , 2 , 3 , 6 -tetrahydro-4-pyridinyl)-1H-indole; GppNHp -b,g-imidoguanosine-5'-triphosphate; 5-HT receptor -5-hydroxytryptamine receptor; hCG -human chorionic gonadotropin; PACAP-38 -pituitary adenylyl cyclase-activating peptide-38. IntroductionHypertension, coronary heart diseases, atherosclerosis, nephropathy, retinopathy, neuropathy, cognitive deficit and disorders of the reproductive system are the most common complications of diabetes mellitus (DM) [1][2][3]. Chronic hyperglycemia is quite often an important contributing factor in the development of these complications. Many hormone-and growth factorregulated signaling pathways, such as the adenylyl cyclase (AC) signaling system, phospholipase C/protein kinase C signaling system and the cascade of mitogenactivated protein kinases are implicated in the regulation of the cardiovascular, nervous and reproductive systems and aberration of their functional activity in DM may contribute to complications of this disease [4][5][6][7][8]. It has been shown that in experimental types 1 and 2 DM the functional activity of hormone-sensitive AC system in the skeletal muscles, myocardium, testis, ovaries, uterus and brain of diabetic rats and the sensitivity of this system to hormones regulating AC activity are changed in tissue-and hormone-specific manner [6][7][8][9][10][11][12].The most significant changes of hormonal sensitivity of AC system were found in the myocardium, testis and Abstract:The changes in hormone-regulated adenylyl cyclase (AC) signaling system implicated in control of the nervous, cardiovascular and reproductive systems may contribute to complications of diabetes mellitus (DM). We investigated the functional state of AC system in the brain, myocardium, ovary and uterus of rats with neonatal DM and examined the influence of intranasally administered insulin on the sensitivity of this system to biogenic amines and polypeptide hormones. The regulatory effects of somatostatin and 5-HT 1B R-agonist 5-nonyloxytryptamine acting via G i protein-coupled receptors were significantly decreased in DM and partially restored in insulin-treated rats. The effects of hormones, activators of AC, are changed in tissue-and receptorspecific manner, and intranasal insulin restored the effects rather close to the level in control. In insulin-treated non-diabetic rats, AC stimulating effects of isoproterenol and relaxin in the myocardium and of human chorionic gonadotropin in the ovaries were decreased, while the effects of hormones, inhibitors of AC, were increased. These data indicate that with intranasal insulin, G i protein-mediated signaling pathways continue to gain strength. The obtained data on the influence of hormones on AC system in the brain, myocardium, ovary and uterus allow looking anew into the mechanisms of therapeutic ...

One of the causes of complications in type 1 diabetes mellitus (T1DM) is the changes in adenylyl cyclase (AC) signaling system, identi�ed on the early stages of the disease. However, the most signi�cant disturbances in this system occur on the later stages of T1DM, which ultimately leads to severe complications, but functional state of the AC system in late T1DM is poorly understood. e aim of this work was to study alterations in AC system sensitive to biogenic amines and polypeptide hormones in the heart, brain, and testes of male rats with long-term, 7-month, streptozotocin T1DM and to assess the in�uence on them of 135-day therapy with intranasal insulin. It was shown that AC effects of -adrenergic agonists in the heart, serotonin receptor agonists and PACAP-38 in the brain, chorionic gonadotropin and PACAP-38 in the testes, and somatostatin in all investigated tissues in long-term T1DM were drastically decreased. e treatment with intranasal insulin (0.48 IU/day) signi�cantly restored these effects. e results were obtained suggesting that long-term T1DM induces signi�cant alterations in hormone-sensitive AC system in the heart, brain, and testes that are much more pronounced, compared with short-term T1DM, and include a large number of hormonal regulations.

In recent years, one of the rapidly developing directions in molecular endocrinology and nanobio technology is the peptide strategy, which has become widely used for studying the molecular mechanisms of transduction of hormonal signals into the cell and for designing highly selective and highly effective reg ulators of hormonal signaling systems [1,2]. It is based on the search and development of peptides cor responding in structure to the functionally important parts of signaling proteins-receptors, heterotrimeric G proteins, and enzymes that generate second mes sengers. The most promising direction in the peptide strategy is the synthesis and study of peptides derived from serpentine type receptors, because at the level of these receptors not only the specific recognition of an external signal but also the choice of the pathway of its transduction into the cell takes place and, therefore, the intracellular targets of the hormone are deter mined. We and other authors demonstrated that pep tides corresponding to the cytoplasmic loops (CLs) of serpentine type receptors selectively interact with G proteins, trigger signaling cascades in the absence of hormone, affect the transduction of the signal gener ated by them through a homologous receptor, thus functioning as regulators of intracellular signaling [3][4][5][6][7][8][9].One of the urgent problems of modern endocrinol ogy is the search for an effective regulator of the thy roid gland and the entire hypothalamic pituitary thy roid axis, which act at the stage of activation of the thyroid stimulating hormone (TSH) receptor by the hormone. Disturbances that occur at this signal trans duction stage lead to a wide spectrum of thyroid gland diseases, including autoimmune thyroiditis and thy roid cancer. The purpose of the study was to develop selective regulators of the TSH sensitive signaling pathways on the basis of the peptides derived from the C terminal region 612-627 of the third intracellular loop (C ICL 3) of the TSH receptor. We also studied the activity of the peptides in vitro by their effects on the basal and hormone stimulated level of GTP bind ing of heterotrimeric G s and G q proteins, which are components of these cascades, and in vivo by the effect of intranasal administration of peptides on the level of thyroid hormones in the blood plasma of experimental animals. It should be noted that mutations in the C ICL 3 of the TSH receptor disturb its interaction with G s proteins and lead to loss of the ability of the mutant receptor to stimulate adenylate cyclase activity and cAMP dependent signaling pathways [10].Using solid phase peptide synthesis, we synthe sized the peptide Gln Tyr Asn Pro Arg Asp Lys Asp Thr Lys Ile Ala Lys Arg Nle Ala 612-627 Lys Ala amide (I), in which Met 626 is replaced with norleu cine having similar physicochemical properties. We also synthesized a palmitoylated analogue of this peptide (II), in which the side ε amino group of the lysine residue following Ala 627 is modified with the palmitic acid residue. The peptides were syn...

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