Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release

Biological activities of highly potent octapeptide analogs of somatostatin (SS), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), were investigated in male rats. When analog RC-160 was administered to rats in which serum growth hormone (GH) levels were elevated by pentobarbital anesthesia, a dose-related inhibition of GH was obtained at dose range of 0.1 to 2.5 micrograms/kg. The time course of GH inhibition by RC-160, RC-121 and SS-14 was studied in rats treated with phenobarbital, morphine and chlorpromazine. Analogs RC-160 and RC-121 induced a prolonged inhibition of GH levels, in contrast to SS-14, whose effect was short-lived. The analogs suppressed the GH level for more than 2 hr, the peak inhibition being seen 30 to 60 min after the injection. The effects of analogs RC-160 and RC-121 on insulin secretion were observed in rats, in which insulin levels had been elevated by intravenous administration of glucose (500 mg/rat). Administration of RC-160 suppressed insulin secretion, dose-dependently, maximum but not complete inhibition being achieved at a dose of 100 micrograms/kg. In this model, RC-160 and RC-121, in doses of 30 micrograms/kg, induced a similar inhibition of insulin release as 200 micrograms/kg of SS-14, whose action of SS-14 was transient. The effect of analog RC-160 on glucagon release was studied in rats with glucagon levels elevated by hypoglycemia. RC-160 suppressed the secretion of glucagon, the inhibition being dose-dependent in the range of 0.1 to 2 micrograms/kg. Doses of 2 and 10 micrograms/kg of this analog completely suppressed the hypoglycemia-induced glucagon release. These results indicate that analogs RC-160 and RC-121 possess prolonged and enhanced biological activities, the former analog showing a high selectivity in inhibiting GH and glucagon release in vivo as compared with that of insulin secretion.     

Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats

Oxytocin has been suggested to have glucoregulatory functions in rats, man and other mammals. The hyperglycemic actions of oxytocin are believed to be mediated indirectly through changes in pancreatic function. The present study examined the interaction between glucose and oxytocin in normal and streptozotocin (STZ)-induced diabetic rats, under basal conditions and after injections of oxytocin. Plasma glucose and endogenous oxytocin levels were significantly correlated in cannulated lactating rats (r = 0.44, P less than 0.01). To test the hypothesis that oxytocin was acting to elevate plasma glucose, adult male rats were injected with 10 micrograms/kg oxytocin and killed 60 min later. Oxytocin increased plasma glucose from 6.1 +/- 0.1 to 6.8 +/- 0.2 mM (P less than 0.05), and glucagon from 179 +/- 12 to 259 +/- 32 pg/ml (P less than 0.01, n = 18). There was no significant effect of oxytocin on plasma insulin, although the levels were increased by 30%. A lower dose (1 microgram/kg) of oxytocin had no significant effect on plasma glucose or glucagon. To eliminate putative local inhibitory effects of insulin on glucagon secretion, male rats were made diabetic by i.p. injection of 100 mg/kg STZ, which increased glucose to greater than 18 mM and glucagon to 249 +/- 25 pg/ml (P less than 0.05). In these rats, 10 micrograms/kg oxytocin failed to further increase plasma glucose, but caused a much greater increase in glucagon (to 828 +/- 248 pg/ml) and also increased plasma ACTH. A specific oxytocin analog, Thr4,Gly7-oxytocin, mimicked the effect of oxytocin on glucagon secretion in diabetic rats. The lower dose of oxytocin also increased glucagon levels (to 1300 +/- 250 pg/ml), but the effect was not significant. A 3 h i.v. infusion of 1 nmol/kg per h oxytocin in conscious male rats significantly increased glucagon levels by 30 min in normal and STZ-rats; levels returned to baseline by 30 min after stopping the infusion. Plasma glucose increased in the normal, but not STZ-rats. The relative magnitude of the increase in glucagon was identical for normal and diabetic rats, but the absolute levels of glucagon during the infusion were twice as high in the diabetics. To test whether hypoglycemia could elevate plasma levels of oxytocin, male rats were injected i.p. with insulin and killed from 15-180 min later. Plasma glucose levels dropped to less than 2.5 mM by 15 min. Oxytocin levels increased by 150-200% at 30 min; however, the effect was not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Failure of chronic hyperinsulinemia to suppress pancreatic glucagon in vivo in the rat.

To determine the effects of chronic hyperinsulinemia on glucagon release, rats were made hyperinsulinemic for 14 days by supplementation of drinking water with sucrose (10%; sucrose-fed) to increase endogenous release or by implantation of osmotic minipumps (subcutaneous, s.c.; or intraperitoneal, i.p.) to deliver exogenous insulin (6 U/day). Both s.c. and i.p. rats also had sucrose in the drinking water to prevent hypoglycemia. Plasma insulin levels were significantly elevated in sucrose-fed, s.c., and i.p. rats. However, glucose levels were significantly elevated in sucrose-fed rats only. Surprisingly, plasma glucagon concentrations were elevated in i.p. and s.c. rats and were not suppressed in sucrose-fed rats. Inverse relationships were found between the plasma levels of insulin and glucose (n = 65; r = -0.42, p less than 0.0001) and between glucose and glucagon (n = 73; r = -0.46, p less than 0.0001). However, unexpectedly, a positive correlation between insulin and glucagon (n = 65; r = 0.47, p less than 0.0001) was established. As suppression of plasma glucagon levels below basal was not observed in any of the hyperinsulinemic or hyperglycemic rats, we wished to establish further whether pancreatic glucagon release could be suppressed below basal levels in the rat by another means. Thus, high doses of somatostatin (50-100 micrograms.kg-1.min-1) were infused for 45 min into normal rats without or with a concomitant hyperinsulinemic, hyperglycemic glucose clamp. Somatostatin fully suppressed insulin, but although plasma glucagon levels were decreased by somatostatin infusion relative to saline-infused animals, there was still no suppression below basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Route of administration as a factor in the selectivity of hormone suppression of a somatostatin analog in rats

The method of administration of [D-Ala5,D-Trp8] somatostatin is of central importance in determining the degree and duration of suppression of insulin and glucagon release. The analog decreased insulin levels in rats when injected by s.c. or i.v. routes, with a nadir 15 minutes following injection. After i.v. injection, insulin levels rapidly returned to basal values while s.c. injection produced significant suppression for 60 minutes. Neither type of injection altered glucagon levels. Intravenous infusion resulted in inhibition of both insulin and glucagon release, with rebound hyperglucagonemia, but not hyperinsulinemia in the post-infusion period. Plasma glucose levels reflected these hormonal changes. Thus, dramatic alterations in the specificity of this somatostatin analog may be achieved by employing different methods of administration.     

Pharmacological doses of oxytocin affect plasma hormone levels modulating glucose homeostasis in normal man

Pharmacological doses of oxytocin administered in basal conditions evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin and adrenaline levels. The effects of oxytocin on plasma glucagon and adrenaline levels were potentiated by hypoglycemia. When the endogenous pancreas secretion was suppressed by cyclic somatostatin (150 micrograms/h) and exogenous glucagon (3.5 micrograms/h) and insulin (0.2 mU/kg.min) were both replaced, oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels suppressing the glucose infusion rate (GIR) in the first 60 min. On the contrary at higher insulin infusion rate (0.6 mU/kg.min) plasma glucose levels and GIR remained unaffected throughout the study. Oxytocin seems also to potentiate glucose-induced insulin secretion as evidenced by hyperglycemic glucose clamp. In conclusion, pharmacological doses of oxytocin seem to exert a prevalent hyperglycemic effect by a combined action at the liver site (as glycogenolytic agent) and at the endocrine pancreas (as a stimulatory agent of A cell secretion).     

Central adrenergic suppression augments the insulin and glucagon secretory, and the glycogenolytic responses in streptozotocin-diabetic rats.

It has been suggested that the increased activity of the sympathetic nervous system and the resultant increase in the tissue catecholamine levels contribute to the pathogenesis of diabetes. In this study we evaluated the effect of clonidine, a central adrenergic agonist that decreases sympathetic tone, on the serum levels of glucose, insulin, glucagon and norepinephrine and on the hepatic glycogen content in normal and streptozotocin-diabetic rats. The animals were treated with clonidine 25 micrograms/kg/day interperitoneally for 3 weeks to suppress the central adrenergic impulses. Clonidine treatment significantly increased the weight gain, but did not affect plasma glucose, insulin, glucagon and norepinephrine in the diabetic animals. Pancreatic insulin and liver glycogen contents were significantly higher in the clonidine-treated than in the untreated diabetic rats. However, clonidine did not affect pancreatic insulin and liver glycogen content of nondiabetic animals. The intravenous administration of glucagon increased plasma glucose in the clonidine-treated, but not in the saline-treated diabetic rats. Insulin-induced hypoglycemia significantly enhanced glucagon release in clonidine-treated but not in saline-treated diabetic rats. We conclude that the suppression of central adrenergic activity may ameliorate the effects of insulin insufficiency on pancreatic hormone secretion and hepatic glycogen content.     

Hepatic glucagon clearance during insulin induced hypoglycemia

Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7 +/- 5.9 ng/min in the baseline to 322.6 +/- 6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6 +/- 7.2 ng/min to 103.1 +/- 28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8 +/- 13.8% vs 32.9 +/- 11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5 +/- 4.9% and 21.3 +/- 6.4%) was not affected by a fall in the plasma glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute sodium salicylate on the abnormal counterregulatory glucagon and epinephrine responses to insulin hypoglycemia in diabetic rats

Effects of acute sodium salicylate infusion on glucagon and epinephrine responses to insulin hypoglycemia were studied in streptozotocin diabetic and age-matched control rats. Sodium salicylate (50 mg/kg/h) was infused intravenously alone for 90 minutes and then with insulin in short-term (10-15 days post-streptozotocin) and long-term (80-100 days post-streptozotocin) diabetic as well as age-matched control rats to produce hypoglycemia. Sodium salicylate decreased basal plasma glucose in control and diabetic rats but increased basal plasma glucagon levels only in control rats. The infusion of sodium salicylate during insulin-hypoglycemia in control and short-term diabetic rats caused a significant increase in glucagon secretion. Long-term diabetic rats have impaired glucagon and epinephrine secretory responses to insulin-hypoglycemia. This defect was normalized by acute sodium salicylate infusion during insulin-hypoglycemia. However, indomethacin (5 mg/kg i.p.; twice at 18 hr intervals) improved, but failed to completely normalize the abnormal glucagon and epinephrine secretory responses to insulin-hypoglycemia in long-term diabetic rats. These results suggest that endogenous prostaglandins may play a partial role in the impairment of glucagon and epinephrine secretion in response to insulin-hypoglycemia in long-term diabetic rats.     

Effects of recurrent hyperinsulinemia with and without hypoglycemia on counterregulation in diabetic rats

To understand the mechanisms whereby recurrent hypoglycemia increases the risk of subsequent hypoglycemia, it was necessary to differentiate the effects of recurrent hyperinsulinemia from those of hyperinsulinemic hypoglycemia. We examined basal and hypoglycemic endocrine function in normal rats, streptozotocin-diabetic controls, and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (DH) or hyperinsulinemic hyperglycemia (DI). DH and DI rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. In diabetic controls, basal plasma ACTH tended to be increased, and plasma corticosterone, plasma somatostatin, and pancreatic prosomatostatin and proglucagon mRNA were increased (P < 0.05) vs. normal rats. These parameters were normalized in DH and DI rats. In diabetic controls, glucagon, epinephrine, norepinephrine, corticosterone, and peak glucose production responses to hypoglycemia were reduced (P < 0.05) vs. normal rats. In DI rats, epinephrine responses were normalized. Conversely, DH rats displayed marked further impairment of epinephrine and glucose production responses and increased peripheral insulin sensitivity (P < 0.05 vs. diabetic controls). Both insulin regimens partially normalized glucagon and fully normalized norepinephrine and corticosterone responses. In summary, recurrent hyperinsulinemia in diabetic rats normalized most pituitary-adrenal, sympathoadrenal, and pancreatic parameters. However, concurrent hypoglycemia further impaired epinephrine and glucose production responses and increased insulin sensitivity. We conclude that 1) recurrent hypoglycemia may increase the risk of subsequent hypoglycemia by increasing insulin sensitivity, and 2) epinephrine counterregulation is particularly sensitive to impairment by recurrent hypoglycemia.     

Biological activity and receptor binding characteristics to various human tumors of acetylated somatostatin analogs.

Several somatostatin analogs with recently synthesized acetylated N terminus were assayed in vivo for their effects on sodium pentobarbital-stimulated growth hormone (GH) levels in fed male rats and gastrin-releasing peptide (14-27)-stimulated gastrin levels in fasted male rats. The binding characteristics of these analogs to somatostatin receptors were also examined in various human tumors and normal tissues. The analog RC-101-I, injected at a dose of 0.1 micrograms/100 g body wt, significantly suppressed GH release (P less than 0.01) for at least 2 hr. Analog RC-160-II caused the longest inhibition of GH release, greater than that induced by nonacetylated parent analog RC-160, with GH levels showing significant suppression (P less than 0.01) for more than 3 hr. Analogs RC-160-II and RC-101-I and RC-160, injected at a dose of 1.0 micrograms/100 g body wt, significantly (P less than 0.01) suppressed gastrin-releasing peptide (14-27)-stimulated serum gastrin. Analog RC-101-I was active in this test at a dose of 0.1 micrograms/100 g body wt. RC-160-II showed significant binding to somatostatin-14 receptors in all investigated tissues (human colon, human colon cancer, breast cancer, human pancreas and pancreatic cancer, human prostate and prostate cancer, and rat cerebral cortex), but there were marked variations in binding affinities among various normal and cancerous tissues. The highest affinity was found in membranes of colon cancer (Ka = 18.4 nM-1) and breast cancer (Ka = 12.46 nM-1). The binding affinity of RC-160-II to somatostatin receptors in membranes of the breast cancer was similar to that of RC-160. RC-101-I showed higher binding affinity to somatostatin-14 receptors than RC-160 in human breast, pancreatic, and prostate cancer. With the exception of breast cancer tissue, the binding affinity of RC-101-I was significantly lower than that of RC-160-II in membranes of all investigated tissues. It can be concluded that acetylated somatostatin analogs RC-101-I and RC-160-II possess prolonged and enhanced biological activities in suppressing serum GH and gastrin in rats. Significant variations in binding affinities for these analogs in different tissues and various tumors suggest that differences may exist between somatostatin receptors in normal versus malignant tissues. This raises the possibility that some of these analogs could be used more selectively in the treatment of various neoplasms.     

Multiple subcutaneous injections of somatostatin induce tachyphylaxis of the suppression of plasma insulin, but not glucagon, in the rat

The time course of pancreatic effects of somatostatin was studied over a period of 2 h in unanesthetized unrestrained rats after administration of the peptide by intravenous infusion and by single and multiple subcutaneous injections. During infusion of 10 and 30 micrograms/kg per min, somatostatin continuously suppressed plasma insulin and plasma glucagon. Plasma glucose was significantly increased at the lower dose, but not affected at the higher dose. Single subcutaneous injections of 0.3 and 3 mg/kg decreased plasma insulin and glucagon dose-dependently for 20-60 min without affecting plasma glucose. Multiple subcutaneous injections of somatostatin (one to four doses of 3 mg/kg, administered at intervals of 30 min) caused an initial decrease of plasma insulin (at 30 min), a rebound-increase at 60 and 90 min, and a final return to control values by 120 min. Plasma glucagon remained continuously suppressed. Plasma glucose increased significantly at 60 and 90 min and tended to return towards control values thereafter. In conclusion, pancreatic B cells - but not A cells - of the rat develop tachyphylaxis to somatostatin within 2 h after multiple subcutaneous injections of the peptide. By this mode of administration, 'selective' suppression of plasma glucagon can be achieved with somatostatin in the rat.     

Pre-exposure to glucagon impairs glucose recovery after insulin-induced hypoglycemia in man

The effect of a two hour period of hypo- and hyperglucagonemia on a subsequent insulin-induced hypoglycemia was studied in nine healthy volunteers. Hypoglucagonemia was provoked by somatostatin (50 micrograms/h) and hyperglucagonemia by glucagon infusion (3.25 ng/kg/min) together with somatostatin, while saline alone was given as control. Hypoglycemia was induced by insulin infusion (2.4 U/h) for two hours. The hyperglycemic effect of glucagon was transient and similar nadir glucose levels were obtained in the three experiments. Preinfusion with glucagon impaired glucose recovery in spite of preserved secretion of epinephrine during restitution of blood glucose in this experiment. It is concluded, that a period of elevated glucagon levels deteriorates the restitution of blood glucose following hypoglycemia. Hyperglucagonemia, commonly apparent in poorly controlled diabetics, may therefore be of importance in explaining the impaired recovery of blood glucose seen in such patients after hypoglycemia.     

Effect of somatostatin in the Syrian hamster bearing a transplantable islet-cell tumor.

The influence of somatostatin (SRIF) on blood glucose, plasma insulin and plasma glucagon was studied in hamsters bearing a transplantable islet-cell tumor secreting insulin and glucagon as well as in normal controls. Fed anesthetized animals were infused intraperitoneally either at a dose of 10 microgram in 15 min or of 150 microgram in 30 min, and intravenously at a dose of 250 microgram in 30 min. Blood was withdrawn from the jugular vein before and after infusion. Before the infusions, tumor bearing animals (TB) had lower blood glucose, markedly elevated plasma glucagon and slightly lower plasma insulin by comparison with normal hamsters (N). Both doses of somatostatin infused by the intraperitoneal route produced a slight but significant hypoglycemia in TB hamsters but not in normals. Ten microgram SRIF did not affect insulin and plasma glucagon levels whereas 150 microgram SRIF significantly depressed plasma insulin in both types of hamsters (N and TB). This latter dose of SRIF decreased plasma glucagon in normal but not in tumor-bearing hamsters. Intravenous infusion of 250 microgram SRIF did not reduce the hyperglucagonemia of TB hamsters either. These results indicate that somatostatin does not reduce the hyperglucagonemia due to the transplantable islet-cell tumor but nevertheless decreases blood glucose and plasma insulin.     

Effect of a zinc phosphate suspension of a long-acting somatostatin analog on postprandial plasma glucose, triglyceride and glucagon concentrations in alloxan diabetic dogs

The effects of a zinc phosphate suspension of a long-acting, reportedly selective somatostatin analog, Des-Ala1,Gly2 [His4,5,D-Try]-somatostatin (100 micrograms/kg) on postprandial plasma glucose, glucagon, xylose and triglyceride levels were evaluated in alloxan diabetic dogs. Compared to the analog in aqueous solution, the zinc phosphate suspension had a more gradual onset of action in suppressing plasma glucose and xylose levels but a similar onset of action on suppression of plasma triglyceride and glucagon responses. On all these responses, the zinc suspension had a duration of action (greater than 6 hrs) at least three times as long as the aqueous solution. We conclude that such a somatostatin analog in zinc phosphate suspension may have a sufficient duration of action to be useful as an adjunct to insulin in the treatment of diabetes mellitus.     

Reciprocal changes of plasma glucose and ketone bodies in fasted and acutely diabetic rats after CNS stimulation

To assess the effect of chemical stimulation of the central nervous system (CNS) on ketogenesis, we injected neostigmine (5 x 10(-8)mol) into the third cerebral ventricle in normal rats fasted for 48 h and fed rats with diabetes induced by streptozotocin (STZ, 80 mg/kg). The hepatic venous plasma levels of ketone bodies (3-hydroxybutyrate and acetoacetate), free fatty acids (FFA), and glucose were measured for 120 min after the injection of neostigmine under pentobarbital anesthesia. In the normal rats, plasma glucose levels were significantly increased but neither ketone bodies nor FFA were affected by CNS stimulation with neostigmine. In contrast the plasma levels of ketone bodies and FFA were significantly increased in STZ-diabetic rats, while glucose levels remained unchanged. The intravenous infusion of somatostatin (1.0 microgram/kg/min) suppressed the increase in plasma ketone bodies following CNS stimulation in STZ-diabetic rats. These findings suggest that CNS stimulation with neostigmine may accelerate ketogenesis by promoting the lipolysis, which may be induced by glucagon, in fed diabetic rats but not in normal fasted rats.     

Somatostatin, insulin and glucagon secretion by the perfused pancreas from the cysteamine-treated rat

In rats, administration of a single dose of cysteamine (300 mg/kg, intragastrically) induces a depletion of pancreatic somatostatin content (approximately 60%) without modifying pancreatic insulin or glucagon content. In perfused pancreases from cysteamine-treated rats, there was a lack of somatostatin response to glucose, arginine or tolbutamide. In the absence of stimulated somatostatin release, the secretory responses of insulin and glucagon to glucose, to arginine, and to tolbutamide were not significantly different from those observed in pancreases from control rats. Our data do not support the concept that pancreatic somatostatin plays a major role in the control of insulin and glucagon release.     

Relationships between glucose, insulin and glucagon during fasting in late gestation in the rat

Plasma glucose, insulin and glucagon were measured in pregnant and age-matched virgin rats in the fed state and after fasting 6, 48 or 120 hours during day 16–21 of gestation. The fed state in pregnancy was characterized by a metabolic setting favoring anabolism. The lower plasma glucose in the fed pregnant rats was associated with higher insulin, slightly lower glucagon and higher insulin/glucose and insulin/glucagon ratios than in virgin rats. During fasting, glucose fell to sustained hypoglycemic levels in the pregnant animals whereas glucose declined but did not achieve hypoglycemia at any point in the virgins. Despite the hypoglycemia, greater levels of plasma insulin persisted in the pregnant throughout the 120 hours of fasting and insulin/glucagon ratios did not differ significantly from the euglycemic virgins. Thus, “accelerated starvation” in pregnancy cannot be ascribed to relative glucagon excess. Rather, the preservation of normal insulin/glucagon ratios despite prevailing hypoglycemia, may provide a mechanism during fasting in pregnancy for restraining maternal protein catabolism in the face of the added fuel demands of the conceptus.     

Comparative and combined effect of chlorogenic acid and tetrahydrocurcumin on antioxidant disparities in chemical induced experimental diabetes

The present study evaluates the combined effect of tetrahydrocurcumin and chlorogenic acid on oxidative stress in streptozotocin–nicotinamide-induced diabetic rats. Rats were rendered diabetic by a single intraperitoneal injection (i.p) of streptozotocin (45 mg/kg BW), 15 min after an i.p injection of nicotinamide (110 mg/kg BW). The levels of fasting plasma glucose and insulin were estimated. As an index of oxidative stress, the levels of enzymic antioxidants and lipid peroxidation products were analyzed in liver and kidney. Diabetic rats showed an increase in the levels of fasting plasma glucose, lipid peroxidative products such as thiobarbituric acid reactive substances and lipid hydroperoxides and a decrease in plasma insulin, and enzymic antioxidants viz., superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase. Combined administration of tetrahydrocurcumin (80 mg/kg BW) and chlorogenic acid (5 mg/kg BW) to diabetic rats for 45 days, reversed the biochemical changes to near normal. The above findings were supported by histological observations of the liver and kidney. Together the present study clearly reflects that combined dosage of tetrahydrocurcumin and chlorogenic acid augments enzymic antioxidants with a concomitant decrease in lipid peroxidation and protects against streptozotocin–nicotinamide-induced type 2 diabetes in experimental rats.     

Inhibitory effects of somatostatin analogs on prolactin secretion in rats pretreated with estrogen or haloperidol

The effect on prolactin (PRL) secretion of acute administration of new octapeptide analogs of somatostatin (SS) with an enhanced and prolonged growth hormone inhibitory activity was investigated in rats under various pretreatment conditions with estrogen and antidopaminergic drugs. Analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), at a dose of 5 micrograms/100 g body wt, did not decrease basal PRL levels in thiopental-anesthetized female rats, untreated or treated with estrogen benzoate (EB) (8 micrograms/rat) for 5 days. When haloperidol was used to elevate PRL level, a single injection of RC-121 inhibited PRL release in EB-pretreated female rats or untreated female and male rats. Analog D-Phe-Cys-Trp-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), which has a potency similar to RC-121 in the tests on inhibition of GH, in a dose of 0.2 microgram/100 g body wt, did not lower the elevated PRL level induced by alpha-methyl-p-tyrosine and/or pretreatment with EB (100 micrograms/rat, 3 and 6 days before) in pentobarbital-anesthetized male rats. However, both analogs RC-121 and RC-160, in doses of 0.2 microgram/100 g body wt, decreased the PRL levels elevated by prolonged pretreatment with EB (100 micrograms/rat, twice a week for 3 weeks) in male rats. These results indicate that acute administration of these SS analogs can induce a prolonged inhibition of PRL release when PRL is acutely elevated by haloperidol or chronically elevated by 3 weeks of estrogen administration. Future additional studies are required to investigate the effects of chronic administration of these SS analogs on PRL levels.     

Effect of somatostatin analogs on gastric acid secretion in dogs and rats

The effects of several superactive analogs of somatostatin on gastric acid response to various exogenous and endogenous stimulants were investigated in conscious dogs and rats with gastric fistulae (GF). The inhibition was compared to that induced by somatostatin-14 (S-S-14) at two dose levels. Several octapeptide analogs of somatostatin including D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), which were superactive in tests on suppression of GH levels, were 4-5 times more potent than S-S-14 in inhibiting desglugastrin-stimulated gastric acid secretion in GF dogs. The analog RC-160 also reduced the rise in serum gastrin levels and gastric acid secretion induced by sham feeding (SF) in dogs with gastric and esophageal fistulae (EF), but did not decrease food consumption. Gastric acid secretion induced by histamine (80 micrograms/kg/h) in dogs was not affected by 1-5 micrograms/kg/h of analog RC-121 or by 5 micrograms/kg/h of S-S-14. Analogs RC-160, RC-121, and RC-98-I (D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2) and others also powerfully inhibited desglugastrin-induced potent as S-S-14 in dogs but its activity was higher in rats. The results indicate that octapeptide analogs which are superactive in GH-inhibition tests are also more potent than S-S-14 in suppressing gastric acid secretion. These findings may be of clinical value.