Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Abstract

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 ...

The Influence of Intranasal Insulin on Hypothalamic-Pituitary-Thyroid Axis in Normal and Diabetic Rats

“…As demonstrated earlier by us, long-term treatment of rats with the prolonged model of mild DM1 or the neonatal model of DM2, using I-I at the daily doses of 0.45-0.48 IU/rat, led to a partial restoration of activity of the brain adenylyl cyclase signaling system sensitive to monoamines and peptide hormones [24]. In our opinion, there are reasons to regard I-I-induced restoration of functional activity of the integrative network of the brain neurotransmitter systems in diabetic animals as one of the key factors responsible for an increase in sensitivity of the pituitary to TRH, enhanced synthesis and secretion of TSH by thyrotrophs and the restoration of HPT axis function.…”

“…Intranasal delivery of insulin to rat's brain was performed as described earlier [24]. Crystalline insulin (Sigma, St. Louis, Mo, USA) at concentrations 15, 22.5, 30, and 75 IU/ml was dissolved in 0.1 M citrate buffer, pH 4.5, and delivered intranasally to diabetic and nondiabetic rats once a day.…”

Alterations of Hormone-Sensitive Adenylyl Cyclase System in the Tissues of Rats with Long-Term Streptozotocin Diabetes and the Influence of Intranasal Insulin

“…A signi�cant reduction of AC effect of PACAP-38 having an important role in protection of neuronal cells from damage and neurodegenerative changes [31] speaks in favor of abnormalities in PACAP-mediated neuroprotection in the case of long-term T1DM. It has been noticed that short-term T1DM and neonatal T2DM had no effect on the regulation of brain AC activity and G s protein binding by PACAP-38 [16,25]. We showed that the 135-day therapy with I-I prevents the decline of AC stimulation induced by PACAP-38 in the diabetic brain.…”

“…As we showed earlier, in the model of short-term T1DM and the neonatal model of type 2 diabetes mellitus (T2DM), although the stimulating effects of serotonin on AC activity and GTP binding of G s proteins in the diabetic brain were reduced, the corresponding effects of EMD-386088 and, as a result, 5-HT 6 R-mediated AC signaling did not change [16,25]. ere was a decrease in the number of 5-HT 6 R and a reduced AC response to selective 5-HT 6 R agonists in the brain of patients with prolonged Alzheimer's disease due to the neurodegenerative alterations in neuronal and glial cells [28].…”

“…e intranasal route of insulin delivery was chosen proceeding from the fact that I-I has no signi�cant in�uence on the level of peripheral glucose and, therefore, does not provoke hypoglycemic episodes [13,14]. I-I normalizes metabolic processes and improves cognitive functions, but the molecular mechanisms and targets of its action have not been well de�ned [15,16]. It should be noted also that the information concerning the in�uence of I-I on human and experimental T1DM is scarce [17,18].…”