Terguride treatment attenuated prolactin release and enhanced insulin receptor affinity and GLUT 4 content in obese spontaneously hypertensive female, but not male rats.

Glucose tolerance, serum insulin, insulin receptors in epididymal fat tissue, and GLUT 4 content in muscle, as well as serum prolactin, were studied in obese and lean spontaneously hypertensive rats (SHRs) of both sexes. Obese animals displayed insulin resistance and decreased capacity of high-affinity binding sites of insulin receptors in fat tissue plasma membranes. GLUT 4 content in musculus quadriceps was diminished only in obese females. Terguride treatment lowered prolactin serum levels, which was concomitant with ameliorated insulin sensitivity in obese animals of both sexes. Similarly, only in obese females, terguride significantly increased the affinity of high-affinity insulin-binding sites and normalized GLUT 4 content. Our results document downregulation of insulin receptors and GLUT 4 in obesity and suggest a role for prolactin in obesity-induced insulin resistance, particularly in female rats.

Terguride but not bromocriptine alleviated glucose tolerance abnormalities and hyperlipidaemia in obese and lean genetically hypertensive Koletsky rats.

Glucose tolerance, total plasma cholesterol and plasma triglycerides were studied in the genetically hypertensive obese Koletsky rats (SHR/N-cp) and in their lean siblings. The initial part of the glucose tolerance curve was substantially elevated in both obese and lean Koletsky animals compared to normotensive Wistar rats. The abnormal glucose tolerance in hypertensive rats was accompanied by increased total plasma cholesterol and plasma triglycerides. Long-term treatment with dopaminergic agonists terguride or bromocriptine (0.2 and 2.0 mg/kg/day, respectively) exerted similar effects on lipid metabolism but both drugs differed in their influence on glucose tolerance. Terguride lowered plasma lipids and normalized glucose tolerance in both obese and lean Koletsky rats. Bromocriptine reduced hyperlipidaemia but did not attenuate the abnormalities of glucose tolerance in either lean or obese Koletsky animals.

Effect of terguride on insulin binding, insulinaemia, glucose tolerance and hyperlipaemia in lean SHR Koletsky rats.

Glucose tolerance, insulin binding to erythrocytes, insulinaemia, plasma total cholesterol, plasma triglycerides, weight of fat pads, food consumption and body weight changes were studied in genetically hypertensive lean Koletsky rats. Long-term treatment with dopaminergic agonist terguride (0.2 mg/kg/day) normalized glucose tolerance and increased the percentage of bound insulin to erythrocytes in both sexes. Terguride decreased insulinaemia, cholesterolaemia, fat pads and body weight only in female rats. Food consumption was not influenced by terguride over the injection period.

Terguride attenuates prolactin levels and ameliorates insulin sensitivity and insulin binding in obese spontaneously hypertensive rats.

Glucose tolerance, serum insulin, insulin receptors in epididymal fat tissue, circulating total cholesterol and triglyceride concentrations as well as serum prolactin were studied in obese and lean spontaneously hypertensive rats (SHR) of both sexes. Obese animals displayed insulin resistance and elevated insulin and triglyceride concentrations. Moreover, in obese rats the increased mass of epididymal fat tissue was accompanied with decreased capacity of high affinity binding sites of insulin receptors in the tissue plasma membranes. Terguride treatment lowered prolactin serum levels which was accompanied by ameliorated insulin sensitivity in obese animals of both sexes. In addition, terguride treatment decreased serum insulin and triglyceride concentrations in obese females and at the same time enhanced the affinity of high affinity insulin binding sites. Our results show that obesity in SHR is associated with a decreased capacity of insulin receptors and that prolactin may play a role in obesity-induced insulin resistance, particularly in female rats.

Tumor necrosis factor alpha in various tissues of insulin-resistant obese Koletsky rats: relations to insulin receptor characteristics.

Tumor necrosis factor alpha (TNFalpha) was found to be significantly increased in skeletal muscles and retroperitoneal fat of obese insulin-resistant Koletsky rats as compared to control Wistar rats. This increase was accompanied by a depression of insulin receptor protein tyrosine kinase (PTK) activity. Neither the insulin-binding capacity nor insulin receptor affinity were related to this TNFalpha increase in these tissues. In the liver, no significant changes of TNFalpha content and only a lowering of insulin-binding capacity were found. It is concluded that an increased TNFalpha content in muscles and fat (but not in the liver) contributes to insulin resistance by lowering insulin receptor protein tyrosine kinase activity, while other insulin receptor characteristics (insulin-binding capacity and affinity of insulin receptors to the hormone) do not seem to be influenced by this factor.

Ambivalent effect of long lasting terguride treatment on genetically based glycide and lipid metabolism abnormalities in SHR/N-cp Koletsky rats.

Experiments were carried out in the genetically hypertensive obese rats of Koletsky type (SHR/N-cp obese), in their lean siblings (SHR/N-cp lean) and in the rats of Han-Wistar strain. The effect of long lasting terguride treatment was monitored when the animal represents a control for itself. Blood was sampled to heparinized capillaries from retrobulbar plexus in the same animal before and after the terguride treatment. Long lasting terguride treatment shows decrease in "area under the glucose tolerance curve" in all groups of animals, increase in glycaemia in normotensive males, increase in insulinemia in normotensive rats of both sexes and in SHR/N-cp lean males and decrease of insulinemia in SHR/N-cp obese males, increase of triglyceridemia in normotensive rats of both sexes and in SHR/N-cp lean males, and decrease of triglyceridemia in SHR/N-cp lean females and SHR/N-cp obese of both sexes, increase in cholesterolemia in normotensive and SHR/N-cp lean males, decrease in cholesterolemia in normotensive, SHR/N-cp lean and obese females. Thus ambivalent effect of terguride treatment is more expressive in glucose tolerance and in plasma triglycerides. Ambivalent effect of long lasting terguride treatment is profoundly expressed in correlation between pre-treatment state of individual parameters and the effect of treatment expressed in percentage changes in post-treatment state. In all cases statistically significant correlation coefficients show negative mark. Thus it is apparent that terguride increases monitored parameter when this parameter is low before treatment, and vice versa. When it is considered "area under the glucose tolerance curve", significance was attained in all groups, when judging basal glycaemia, significance was attained in normotensive and SHR/N-cp lean rats of both sexes, taking into account insulinemia, significance was attained in normotensive and SHR/N-cp obese rats of both sexes, when analysing plasma triglycerides, significance was attained in normotensive rats of both sexes and in SHR/n-cp lean females and obese males, when we consider total plasma cholesterol, significance was attained in normotensive rats of both sexes and in SHR/N-cp lean males. From the clinical point of view it must be underlined that terguride is potent to increase insulinemia. Thus there is open a possibility of the other clinical indication of the mentioned drug.

The determination of basal glycemia and glucose tolerance curve: the manners of blood sampling.

There were analyzed the conditions under which the basal glycemia and/or glucose tolerance curve is not contaminated by stress induced changes in glycide metabolism. When the basal glycemia was monitored, blood was sampled to heparinized capillaries from retrobulbar plexus under the light ether anaesthesia or by decapitation without narcosis. The animal represented the control for itself. No differences was found in basal glycemia under the two mentioned blood sampling. In the second series of experiments glycemia was monitored in the time schedule which is used in glucose tolerance test, i.e., blood sampling was performed 30, 60, 120 and 180 min after the first sampling from retrobulbar plexus either under light ether anaesthesia (in 14 h starvated rats or in rats with free access to diet) or under Nembutal anaesthesia (in 14 h starvated rats). No differences were found in glycemia when two types of narcosis is compared. No signs of augmentation were detected. In the last series when blood sampling was taken in two sec intervals, time dependent augmentation of stress glucose elevation was found. The augmentation was more expressed in the rats with free access to diet than in starvated animals.

Multiple regression analysis of parameters of lipid and glycide metabolism in obese and lean genetically hypertensive Koletsky rats under long lasting terguride treatment.

Experiments were carried out in the genetically hypertensive obese rats of Koletsky type (SHR/N-cp) and in their lean siblings. Regression analysis was performed when plasma triglycerides was used as a dependent variable and plasma insulin, insulin binding to erythrocytes, basal plasma glucose tolerance data were used as independent variables. Coefficient determination (R2) as well as the tests of hypotheses of regression coefficients being zero were used to indicate which independent variables contributed the least in the explanation of dependent variable. This way we reduced the list of variables to give a simpler regression equation. In the control animals insulinemia was found to be dominant independent variable in all groups except SHR/N-cp obese females where the dominant independent variable was represented by the basal plasma glycaemia. Under the terguride treatment only in SHR/N-cp female rats the dominant independent variable remained the same as in controls. In the other groups the dominant independent variable was different in relation to the control animals. Long lasting terguride treatment normalized hypertriglyceridemia only in SHR/N-cp obese females. Thus the data obtained by multiple regression analysis of parameters of lipide and glycide metabolism show the close relationship to alleviating effect of terguride in hypertriglyceridemia.

Effect of dehydroepiandrosterone on lipemia, glucose tolerance, insulinemia, insulin binding to erythrocytes in SHR/N-cp lean rats of Koletsky type.

Experiments were performed in the genetically hypertensive lean males of Koletsky type. It was monitored the effect of dehydroepiandrosterone (DHEA) treatment on lipemia, glucose tolerance, insulinemia, insulin binding to erythrocytes, fat pads, body weight and pellet intake. DHEA was applied in two doses: 10 and 20 mg per kg b.w., i.p., for 11 days when glucose tolerance was monitored and for 21 days when the remaining parameters were analyzed. DHEA shows dose dependent decrease in changes of body weight over injection period, in plasma triglycerides and total plasma cholesterol, decrease being most expressed under the higher dose. High as well low of DHEA decreases the sum of glycaemia obtained 30, 60, 120 and 180 min after glucose loading (area under the curve) i.e., DHEA alleviates genetically based glucose intolerance. DHEA induced hypophagia under the higher dose treatment. Insulin binding to erythrocytes was not influenced by DHEA.

Glucose intolerance induced by oligemic brain hypoxia: the effect of terguride.

Two series of experiments were performed. In the first one experiments were carried out in Koletsky genetically hypertensive lean female rats and in the normotensive female rats of Wistar strain. Glucose intolerance was induced by oligemic brain hypoxia (4 hours of occlusion of both common carotid arteries followed by 44 hours reperfusion). Brain water content were used as a marker of brain edema. Changes in insulinemia and specific insulin binding were used as expression of regulative mechanisms participating in modification of glucose tolerance. The effect of terguride (trans-dihydro-lisuride) was tested. Brain hypoxia induced glucose intolerance in both strains of rat but brain edema was found only in the normotensive females. Both abnormalities were alleviated by terguride treatment. Basal glycaemia was not changed either by the brain hypoxia or by terguride treatment, except normotensive female where brain hypoxia induced hyperglycaemia. The second series of experiments were carried out in the normotensive females. The arrangement of experiments was the same as in first series except omission of the final glucose tolerance test. Brain hypoxia causes increase in brain water content. The mentioned elevation of brain water content was alleviated by terguride treatment. Insulin binding to erythrocytes was not influenced by brain hypoxia. Terguride treatment shows decrease of insulin binding to erythrocytes. Brain hypoxia elevates insulinemia which was not alleviated by terguride treatment.

Effect of long lasting terguride treatment on mutual relationship between glycide and lipid parameters in SHR/N-cp Koletsky rats.

Experiments were performed in the genetically hypertensive obese rats of Koletsky type (SHR/N-cp) and in their lean siblings. The effect of long lasting terguride treatment on glycide and lipid metabolism was monitored. Terguride decreases insulinemia in all groups of rats. In all groups of rats terguride increases tolerance glucose. Terguride increases insulin binding to erythrocytes in all groups of rats except SHR/N-cp obese females. The mentioned drug decreases plasma triglycerides in SHR/N-cp obese females. On the other hand, this drug increases plasma triglycerides in SHR/N-cp obese males. Correlation between basal glycemia and insulin binding to erythrocytes as well as between triglycerides and insulinemia which was found in control SHR/N-cp lean males is missing under the terguride treatment. Similarly, correlation between plasma triglycerides and insulinemia, glucose tolerance and insulinemia, basal glycemia and insulinemia, plasma triglycerides and basal glycemia are missing under the terguride treatment in SHR/N-cp lean females. Under the terguride treatment there appears correlation between insulin binding to erythrocytes and basal glycemia. We found in SHR/N-cp obese males opposite changes in number of correlations when we compare control and terguride animals. While in controls only one correlation was detected, i.e., correlation between glucose tolerance and insulin binding to erythrocytes, then under the terguride treatment there appear correlations when basal glycemia is computed versus insulin binding to erythrocytes or to glucose tolerance and/or to triglycerides. Moreover, there is under the terguride treatment correlation insulin binding to erythrocytes versus plasma triglycerides or versus insulinemia. While in SHR/N-cp lean of both sexes and in SHR/N-cp obese males profound changes in the number of statistically significant correlation coefficients were found when controls are compared with animals under the terguride treatment, the different picture we found in SHR/N-cp obese females, i.e., under the terguride treatment correlation basal glycemia versus insulinemia or versus insulin binding to erythrocytes as well as correlation insulin binding to erythrocytes versus insulinemia is present in controls as well as in terguride treated animals. In comparison with controls under terguride only two correlations are missing, i.e., glucose tolerance versus insulinemia or versus insulin binding to erythrocytes.

Hyperprolactinemia in obese as well as in lean females of Koletsky rats: effect of long lasting terguride treatment.

Plasma prolactin was measured in genetically hypertensive obese Koletsky rats, in their lean siblings and in normotensive rats of Wistar strain. Lean as well as obese females show hyperprolactinemia. The males of Wistar strain as well as obese rats and their siblings show comparable prolactinemia except lean males which show higher level than Wistar males. Sex dependence of prolactinemia is missing in the rats of Wistar strain. Long lasting terguride treatment decreases prolactinemia in obese as well as lean rats of both sexes. The drug showed decreased prolactinemia in the males of Wistar strain. When the group of rats are considered in correlation computation positive correlation can be documented between total plasma cholesterol and plasma prolactin. In obese females positive correlation was found between plasma insulin and plasma prolactin.

Development of lipid and glycide abnormalities in genetically hypertensive obese Koletsky rats and in their lean siblings.

Experiments were performed in the genetically hypertensive Koletsky rats and in their lean siblings at the age of two and three months. In the study of development of glycide and lipid abnormalities animal represents control for itself. At the age of two months Koletsky obese rats show relative to their lean controls elevation of plasma triglycerides (males +184%, female +152%) and insulin (males +169%, females +201%). During one month plasma triglycerides elevated in lean males +9%, in lean females 0%, but in obese males +21%, in obese females +139%. Considering insulinemia similar results were obtained. Thus during one month insulin elevates in lean males +19%, in lean females +23%, but in obese males +80%, in obese females +144%. During one month glucose intolerance is elevated as well only in obese rats. Total plasma cholesterol during period of one month shows no changes in both substrains of rats. Similar picture can be found in basal glycemia. In all groups of rats no changes were registered except one, i.e., obese females show decrease. Considering the substrain differences in basal glycemia then at age of one as well as two months obese of both sexes show elevation. As to the body weight at the age of two as well as three months there is increase in obese rats. The changes of body weight during one month are expressively higher in obese rats.

Muscle GLUT-4 and insulin binding to erythrocytes and to adipose, liver and muscle tissue in genetically hypertensive obese rats and in their lean siblings: effect of long lasting terguride treatment.

Experiments were performed in the genetically hypertensive obese rats of Koletsky type (SHR/N-cp) and in their lean siblings of both sexes. Insulin binding to erythrocytes and to adipose tissue, lever tissue and muscle tissue was monitored in the control animals and in the animals under the long lasting terguride treatment. In control animals insulin binding shows substrain and tissue dependence being elevated in lean rats except insulin binding to erythrocytes where inverse is true. Terguride increases percentage of specific insulin binding to erythrocytes in all groups except obese females, terguride increases percentage of specific binding to adipose tissue except lean females, the mentioned drug remained without effect in muscle tissue in all group except lean females where drug induced elevation was detected. The effect of terguride in liver tissue was monitored only in males of both substrains, elevation was found only in lean. GLUT-4 was analyzed only in muscle tissue. The effect of terguride was found in obese females, i.e., in the group which shows reduced GLUT-4 relative to lean females.

Effects of terguride treatment on glucose abnormalities induced by ischemic brain damage in SHR/N-cp lean Koletsky strain and in rats of Wistar strain.

BACKGROUND: Severe head injury is associated with a stress response that includes hyperglycemia, which has been shown in both experimental and clinical studies to exacerbate the severity of brain injury during ischemic conditions. OBJECTIVES: This study evaluated the possible protective effect of Terguride (trans-dihydrolisuride) on glucose metabolism against hyperglycemia. METHODS: The experiments were performed in male and female rats of Wistar and Koletsky strain. Glucose intolerance was induced in both strains by 4-hour-occlusion of both common carotid arteries followed by 44-hour reperfusion. RESULTS: Brain ischemia induced glucose intolerance in both rat strains. Basal glycemia was significantly increased by the brain ischemia in male and female Wistar rats, but not in Koletsky rats. The analysis of the effect of Terguride treatment of glucose abnormalities on the "area under the glucose tolerance curve" (AUC) has shown significant decrease of AUC in both sexes of Wistar strain and in females of Koletsky strain. Basal glycemia was significantly decreased only in males of Wistar strain. CONCLUSION: Terguride (trans-dihydrolisuride) decreases hyperglycemia in rats with ischemic brain damage. (Fig. 4, Ref. 29.)