[Features of endocrine function of the pancreas with aging in nonhuman primates with various types of adaptive behavior.]

An increasing number of studies are devoted to the study of the relationship of mental disorders, such as depression and anxiety, with the risk of developing type 2 diabetes mellitus. However, in the literature there are practically no publications on the study of the relationship of the features of higher nervous activity, in particular, adaptive behavior, in healthy individuals with the risk of developing age-related dysfunction of the pancreatic islet apparatus (PIA). The purpose of this study was to investigate features of the functioning of the PIA during aging in individuals with normal standard behavior (SB), as well as anxiety- and depressive-like behavior (DAB) in experiments on nonhuman primates. 76 physically healthy young mature and old female rhesus monkeys with SB and DAB were used in the experiments. Old animals were divided into subgroups with normal (NW) and excess (EW) body weight. All young animals were characterized by NW. The function of PIA was assessed using a glucose tolerance test. Intergroup differences in the functioning of the PIA in young animals were revealed, which were characterized by signs of impaired early insulin response, apparently due to a decrease in the sensitivity of ß-cells of the pancreas to glucose. With aging, the function of the PIA was damaged in all animals, but the features of its changes depended on both the affiliation to a particular behavioral group and the animal's body weight. During aging in animals with SB, the development of relative insulin resistance of peripheral tissues was observed, accompanied by impaired glucose tolerance and a compensatory increase in the secretory activity of the PIA, which were more pronounced in animals with EW. Age-related dysfunction of the PIA in animals with DAB and NW was similar with age-related changes in the PIA function in animals with SB and NW. At the same time, with aging, animals with DAB and EW showed a more significant peak concentration of glucose than that of old animals with SB and EW, accompanied by a minimum «disappearance¼ rate of glucose from the circulation and significantly lower insulin secretion than this in animals with SB and EW. Thus, age-related dysfunctions of the PIA in primates with SB and DAB are unidirectional with the development of insulin resistance, impaired glucose tolerance and a compensatory increase in insulin secretion, which, however, in old animals with DAB and EW are accompanied by exhaustion of the PIA function, increasing the risk of developing type 2 diabetes mellitus.

Age-specific and individual features of vasopressinergic regulation of the hypothalamic-pituitary-adrenal system in primates.

Experimental study was carried out on young mature (6-8 years) and old (21-27 years) rhesus macaques with anxious and depression-like behavior and with standard (control) adaptive behavior. The responce of the adenohypophysis to arginine vasopressin depended on age and the type of adaptive behavior. Young animals with standard behavior demonstrated much higher concentrations of ACTH in the peripheral plasma in response to arginine vasopressin than old animals. The secretion of ACTH was higher in young and old animals with anxious and depressive-like adaptive behavior and they exhibited no age-specific differences in reaction to arginine vasopressin, which were observed in control animals. Preinjection of vasopressin V1b receptor antagonist to a female with high anxiety sharply reduced ACTH secretion in response to insulin-induced hypoglycemia in comparison with ACTH secretion under the same conditions without antagonist injection. These results suggested that the vasopressinergic system of animals with anxious and depressive behavior plays an important role in the regulation of ACTH secretion and in activity of the hypothalamic-pituitary-adrenal system in general.

[Correction of impaired glucose tolerance using tetrapeptide (Pancragen) in old female rhesus monkeys].

The aim of the investigation was comparative study of the influence tetrapeptide Pancragen (St. Petersburg Institute of Bioregulation and Gerontology, St. Petersburg) on hormonal function of the pancreas compared to the effect of widely used hypoglycemic drug - glimepiride. The investigation involved 9 old (20-25 years) clinically healthy rhesus monkey females (Macaca mulatta). Five of them were injected with Pancragen (0,05 mg/animal per day during 10 days, intramuscularly) for 10 days; 4 animals received glimepiride (4 mg/animal per day during 10 days, per os). Blood samples were taken from all the animals with subsequent analysis of glucose, insulin and C peptide levels; the manipulation was performed before administration of the drugs, on the background of their administration and after their withdrawal in basal conditions, as well as during glucose tolerance testing. Pancragen and glimepiride administration induced the decrease of blood glucose basal levels in both groups of old monkeys. Pancragen also normalized insulin and C peptide levels suggesting its recovering effect on the disturbed tolerance to glucose in old animals. At the same time, glimepiride administration led to a more expressed and delayed hypoglycemic effect and C peptide secretion stimulation without any significant effect on insulin secretion. The data suggest that Pancragen is effective and safe for correction of age-related imbalance of endocrine pancreatic function, and can be used for elderly patient with disturbed glucose tolerance.

[Impact of tetrapeptide pancragen on endocrine function of the pancreas in old monkeys].

Significant increase of the elderly in the demographic structure of a modern society is one of the main reasons for increase in the number of patients with diabetes type 2 and impaired glucose tolerance. The purpose of this research was to study impact of Pancragen (tetrapeptide Lys-Glu-Asp-Trp) on endocrine function of the pancreas of non-human primates, female rhesus monkeys, and to elucidate the possibil- ity of its use for correction age-related dysfunction of pancreatic islet apparatus. In old animals after the glucose administration (standard dose) in control period, a reduced glucose "disappearance" rate and a higher values of insulin and C-peptide peaks (5 and 15 min after the glucose injection) were observed in comparison with young animals in similar experiments. Pancragen administration (50 µg/animal per day during 10 days, intramuscularly) to old monkeys caused markedly increased the glucose "disappear- ance" rate, normalized the plasma insulin and C-peptide dynamics in response to glucose administration. The recovering effect of Pancragen on the function of the pancreas partially remained 3 weeks after discontinuation of the drug. Thus, Pancragen is a promising factor for restoring the age-related endocrine dysfunction of primates.

Repeated moderate stress stimulates the production of dehydroepiandrosterone sulfate (DHEAS) and reduces corticosteroid imbalance in old Macaca Mulatta.

Young (6-8 years) and old (21-30 years) Macaca mulatta females were subjected to gentle immobilization (2 h daily at 15.00) for 10 days. Blood specimens were collected before the exposure and 15, 30, 60, 120, 240 min and 24 h after the beginning of exposure on days 1, 3, and 10. The adrenocortical reaction to stress was maximum on day 1 in all animals. The increase of cortisol (F) and dehydroepiandrosterone sulfate (DHEAS) concentrations in young monkeys decreased on days 3 and 10, DHEAS drop being less pronounced in comparison with F, as a result of which F/DHEAS molar concentration ratio changed negligibly. In old monkeys the basal DHEAS levels were lower, while the F/DHEAS ratio was higher than in young animals. Repeated immobilizations inhibited F elevation on day 3, caused no changes in DHEAS reaction, led to increase of basal DHEAS levels and to a reduction of F/DHEAS ratio on days 2, 3, 4, 10, 11. Hence, chronic moderate stress stimulated the production of DHEAS and reduced the corticosteroid imbalance in old monkeys.

[Normalizing effect of the pineal gland peptides on the daily melatonin rhythm in old monkeys and elderly people].

In the course of aging both monkeys and people reveal decreased night and average daily level of melatonin in the blood plasma and reduced hormone circadian rhythm amplitude, which evidence the disorder of the pineal gland melatonin releasing function. Peptide preparations of the pineal gland (Epithalamin--a complex of peptides isolated from the pineal gland and Epitalon--synthetic tetrapeptide) recover night release of endogenous melatonin and lead to the normalization of the hormone circadian rhythm in the blood plasma. In elderly people Epithalamin and Epitalon modulate pineal gland functional state: people with pineal gland functional insufficiency report an increase of night melatonin level. The preparations of the pineal gland, effectively increasing melatonin concentration and having no side effects, can be used in clinical geriatric practice.

Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas.

The purpose of this research was to study age-related changes in functioning of pineal and pancreatic glands of non-human primates, rhesus monkeys, and to elucidate the possibility of their corrections with the help of epitalon, a synthetic analogue of the pharmacopoeia drug epithalamin. In old (20-27 years) animals, the basal plasma levels of glucose and insulin were found to be higher, while the night melatonin level was lower in comparison with (6-8 years) young animals. After the glucose administration to old monkeys, a larger area under the curve of the plasma glucose response, a reduced glucose 'disappearance' rate, and a reduced insulin peak (5 min after the glucose administration) were observed in comparison with young animals in similar experiments. The epitalon administration to old monkeys caused the decrease in the basal levels of glucose and insulin and the increase in the basal night melatonin level. Additionally, in the case of old monkeys, epitalon decreased the area under the plasma glucose response curve, markedly increased the glucose 'disappearance' rate and normalized the plasma insulin dynamics in response to glucose administration. Yet, it has not affected the hormonal and metabolic changes in young animals. Thus, epitalon is a promising factor for restoring the age-related endocrine dysfunctions of primates.

Peptide correction of age-related hormonal dysfunction of the pancreas in monkeys.

We studied the effect of Epithalon on the function of pancreatic islets and regulation of blood glucose level in female rhesus monkeys of various ages. Epithalon corrected the age-related decrease in glucose tolerance and restored the dynamics of insulin level in response to glucose load.

Age-associated changes in hormonal function of the pancreas and regulation of blood glucose in monkeys.

Age-associated changes in the concentrations of glucose, insulin, and DHEAS in peripheral blood plasma of female rhesus macaques were studied in intact animals and in response to a standard dose of glucose and insulin. Basal levels of insulin and glucose increased, insulin sensitivity and glucose tolerance decreased, and pancreatic reaction to glucose load was impaired in old monkeys. Insulin level positively correlated with glucose concentration, body weight, and abdomen circumference and negatively correlated with DHEAS level.

[Peptide correction of age-related pineal disturbances in monkeys]. / Peptidnaia korrektsiia vozrastnykh narushenii funktsii épifiza u obez'ian.

Investigation of the age-related changes of the pineal gland function and possible ways for their overcoming on nonhuman monkey model was the purpose of this study. Hormonal function of the pineal gland was studied in 38 Macaca mulatta females of two age groups: 6-8 years old, n = 18 and 20-26 years old, n = 20. Pineal function was studied in basal conditions and after administration of pineal peptide preparations--epithalamin and epitalon, both developed in the St. Petersburg Institute of Bioregulation and Gerontology (Russia). It has been revealed that plasma melatonin concentration in monkeys has well expressed high amplitude diurnal rhythm. Minimum is manifested at 4 p.m. and maximum--at 10 p.m.-3 a.m. In aging the mean diurnal melatonin concentration decreases by 1.5-2 times as well as in different points of the day: 9 p.m., 10 p.m., 3 a.m. and 4 a.m. Administration of pineal peptides--epithalamin (at the dose 5 mg/animal/day intramuscularly during 10 consecutive days) or epitalon (at the dose 10 micrograms/animal/day intramuscularly during 7-10 consecutive days) induced significant increase in the night plasma melatonin in old monkeys, but the treatment did not change the melatonin level in young monkeys. Taking into consideration that melatonin is very important for regulation of the diurnal rhythm of functioning of some organs and systems it should be suggested that applying epithalamin and epitalon are perspective in the correction of age-related hormonal imbalance and age pathology.