Susceptibility of fetal rat endocrine pancreas to the diabetogenic action of cyproheptadine

The susceptibility of fetal endocrine pancreas to the diabetogenic action of cyproheptadine was investigated. Cyproheptadine (5 or 11 mg/kg) or water (control) was given orally once daily to pregnant rats on Days 13.5-20.5 or on Days 19.5-20.5 of gestation. Fetuses were obtained by cesarean section 24 hr after the last dose. Serum and pancreatic immunoreactive insulin and serum glucose from maternal and fetal animals were measured. Differences in maternal pancreatic insulin, serum insulin, and glucose between control and treated groups were not detected. In contrast, fetal pancreatic and serum insulin concentrations in animals exposed to 2 or 8 doses of cyproheptadine were less than 50% those of control. Drug treatment did not alter fetal pancreatic glucagon, pancreatic somatostatin, serum glucose, pancreas weight, or body weight. The drug-related depletion of fetal pancreatic insulin was reversible; the level returned to normal 3 days after cessation of the drug treatment. A similar depletion of fetal insulin was observed after 8 oral doses (11 mg/kg) of desmethylcyproheptadine, a metabolite which lacks the antiserotonin-antihistaminic properties of the parent compound. In vitro experiments showed that cyproheptadine inhibited the biosynthesis and release of insulin in fetal rat pancreas. These results indicate that cyproheptadine, when given to pregnant rats using a dose which produces no apparent effects in the maternal endocrine pancreas, causes abnormalities in the function of the insulin-secreting B cells in the fetal endocrine pancreas.     

Effect of Withania somnifera on insulin sensitivity in non-insulin-dependent diabetes mellitus rats

We investigated the effect of an aqueous extract of Withania somnifera (WS) on insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (100 mg/kg) to 2 days old rat pups. WS (200 and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e. 75 days after streptozotocin injection). A group of citrate control rats (group I) were also maintained that has received citrate buffer on the second day of their birth. A significant increase in blood glucose, glycosylated haemoglobin (HbA(1)c) and serum insulin levels were observed in NIDDM control rats. Treatment with WS reduced the elevated levels of blood glucose, HbA(1)c and insulin in the NIDDM rats. An oral glucose tolerance test was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with WS. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. WS treatment significantly improved insulin sensitivity index (K(ITT)) that was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas WS treatment significantly prevented the rise in HOMA-R in NIDDM-treated rats. Our data suggest that aqueous extract of WS normalizes hyperglycemia in NIDDM rats by improving insulin sensitivity.     

Effects of selenium on the serum glucose and insulin levels in diabetic rats]

We investigated the effects of selenium (Se) on the serum glucose and insulin levels in rats with diabetes induced by streptozotocin (STZ, 75 mg/kg, i.p.) and pancreatectomized rats. Moreover, the direct action of Se on insulin release from the isolated pancreatic islets using a slight diabetic rat was studied. The following results were obtained: 1) Selenite at a dose of 173 micrograms/kg (78.9 micrograms/kg of Se base equivalent) drastically reduced the very high level of serum glucose in acute diabetic rats within 5 to 30 min after treatment. During this time period, the insulin level in the serum showed an increasing tendency. 2) The high serum glucose level in chronic diabetic rats returned to the original level with injection of selenite for 4 days, once a day. However, Se did not elicit a significant increase in serum insulin level. 3) Although there was a tendency for the serum glucose level to decrease when selenite was administered into pancreatectomized rats, no secretion of insulin into the serum was observed. 4) Insulin release from isolated pancreatic islets was dose-dependently accelerated by the addition of selenite. These data present the new finding that Se reduced the high level of serum glucose in diabetic rats.     

Neutral red changes arginine-induced glucagon and insulin response in the rat

Rats were treated with neutral red (amino-dimethyl-amino-toluaminozine hydrochloride, NR) twice weekly, 5 ml/kg b.wt.-1 of a 2% solution, for five weeks in order to investigate damage to pancreatic A-cells. After 1-5 weeks of treatment plasma glucagon levels were increased to about two times control values. Plasma glucose was maintained at control values. Following arginine stimulation, 8 micrograms intravenously 100 g b.wt.-1 min.-1 for 30 min., plasma glucagon and insulin concentrations increased 10-fold in normal rats. After NR treatment for 1 and 2 weeks the arginine induced glucagon response was reduced to a two-fold increase, after 5 weeks NR treatment arginine again increased glucagon concentrations 10-fold. There was no change in the 10-fold increase of insulin concentrations from arginine infusion during the NR treatment. Immunohistochemical examination of pancreas demonstrated unchanged number and size of Langerhans' islets. The insulin immunoreactivity of the B-cells appeared constant 0-5 weeks during NR treatment, while glucagon immunoreactivity appeared to lower in the A-cells from animals treated for one or two weeks with NR. After three to five weeks of NR treatment, pancreatic glucagon immunoreactivity appeared restored. We conclude that NR leads to a release of glucagon from pancreatic A-cells, with subsequent hyperglucagonaemia, maintained during repeated administrations. Such repeated administrations lead to a transient "glucagon insufficiency" on top of the hyperglucagonaemia, consisting of restricted ability to further release of glucagon, presumably because of pancreatic A-cell glucagon depletion.     

Precipitation by yohimbine of the withdrawal syndromes of clonidine, guanfacine, and methyldopa in the spontaneously hypertensive rat

In conscious spontaneously hypertensive (SH) rats, continuously infused with clonidine (500 micrograms/kg/day s.c.) for 12 days, yohimbine (3 or 10 mg/kg i.p.) dose dependently precipitated an overshoot of heart rate and other withdrawal symptoms, such as blood pressure upswings, diarrhea, ptosis, body shivering, jumping, and wet-dog shakes. Naloxone (3 or 30 mg/kg i.p.) or prazosin (1 mg/kg i.p.) did not evoke withdrawal signs in clonidine-treated SH rats. In SH rats treated for 12 days with guanfacine (10 mg/kg/day s.c.), the administration of yohimbine elicited a withdrawal pattern similar in severity and appearance to that observed in clonidine-treated rats. In methyldopa-treated (200 mg/kg/day) SH rats, the yohimbine-precipitated withdrawal symptoms were much less pronounced than those observed in the clonidine- and guanfacine-treated animals, despite the equipotency of the infusions in reducing mean arterial pressure. These results indicate that the clonidine-withdrawal syndrome can be precipitated by acute alpha 2-adrenoceptor blockade. The previously observed minor severity of the guanfacine-discontinuation syndrome in the rat should be attributed to the longer half-life of this drug as compared to clonidine. On the other hand, alpha-methylnoradrenaline much less intensively triggers the mechanisms underlying withdrawal symptoms than clonidine or guanfacine.     

Lithium inhibits the development of physical dependence to clonidine in mice

Based on our previous finding that chronic lithium treatment reduced naloxone-precipitated withdrawal syndrome in morphine-treated mice, the effect of chronic lithium treatment was evaluated on the development of dependence to clonidine. Dependence was induced by injection of either morphine (50, 50 and 75 mg/kg, intraperitoneally with 3 hr interval for 3 consecutive days), or clonidine (2 mg/kg/day, intraperitoneally for 10 days). Naloxone (4 mg/kg, intraperitoneally) precipitated withdrawal signs in both morphine- and clonidine-treated mice. Yohimbine (5 mg/kg, intraperitoneally) precipitated withdrawal signs in the clonidine-treated mice, similar to morphine withdrawal signs; but failed to precipitate any significant sign in the morphine-treated mice. Coadministration of lithium was carried out by adding lithium chloride to drinking water (600 mg/l for 20 days; 10 days before the beginning of clonidine administration and 17 days before the administration of morphine to allow the lithium concentration to reach steady-state). The results indicated that chronic lithium administration significantly attenuated the withdrawal signs, precipitated either by yohimbine or naloxone, in clonidine-treated mice. As a conclusion, clonidine withdrawal signs are very similar to opioid withdrawal signs, and lithium is able to prevent the development of physical dependence to clonidine.     

Effects of isoprenaline and glucagon on insulin secretion from pancreatic islets

Summary The effects of isoprenaline and glucagon on insulin secretion from pancreatic islets were investigated. In the presence of high concentrations of isoprenaline (10–50 mol/l), glucose-induced (20 mmol/l) insulin secretion from isolated perifused mouse islets was inhibited. This inhibition was apparently mediated by ₂-adrenoceptors, as it was antagonized by rauwolscine. At low concentrations isoprenaline (0.1 or 1 mol/l) did not affect glucose-induced (2.5; 10 or 20 mmol/l) insulin secretion from perifused mouse or rat islets, even if ₂-adrenoceptors were blocked by rauwolscine. A stimulatory effect of isoprenaline on insulin secretion was also not observed in the perfused rat pancreas. However, when incubated mouse islets were exposed to glucose (10 mmol/l), insulin secretion was further enhanced by isoprenaline (0.5 mol/l). To elucidate the underlying mechanism, the effects of glucagon on insulin secretion were investigated, because glucagon is released from the pancreatic A-cells during stimulation with isoprenaline and is accumulated in the islets and the surrounding medium during incubations of pancreatic islets. Indeed, glucagon stimulated insulin secretion from perifused mouse islets in the presence of high glucose (10 or 15 mmol/l) concentrations but not of low glucose (5 mmol/l) concentrations. Thus it is concluded that direct -adrenergic stimulation of pancreatic B-cells does not occur in mouse or rat pancreatic islets. Augmentation of glucose-induced insulin secretion by isoprenaline observed in incubation systems can be explained as a result of stimulation by glucagon, which is released from pancreatic A-cells by isoprenaline.Some of the results described here were obtained during medical thesis work by S. Zielmann and g. Schütte     

Insulin-induced immunohistochemical and morphological changes in pancreatic beta-cells of streptozotocin-treated diabetic rats

This study was undertaken to investigate insulin-induced changes in the immunohistochemistry and morphometry of pancreatic beta-cells, plasma insulin and blood glucose concentrations of streptozotocin (STZ)-treated diabetic rats. Fifty male Wistar rats (200-250 g) were randomly divided into three experimental groups (viz., A: control group, B: STZ-treated group, and C: STZ+insulin-treated group). Diabetes was induced in group B and group C rats by single intraperitoneal injections of STZ (75 mg/kg body weight), while each animal in the "control" group A received equal volume of citrate buffer solution (pH 6.3) intraperitoneally. STZ+insulin-treated group C diabetic rats were additionally treated with subcutaneous injections of lente insulin (0.5 U/kg body weight) daily from Day 10 to Day 30 of our 40-day study period. The rats used were sacrificed at different time intervals (10th, 20th, 30th and up to the 40th day) following STZ treatment. Fragments of endocrine pancreas of each rat were randomly processed for immunohistochemistry staining and pancreatic insulin content. In diabetic state, pancreatic beta-cells showed a weak immunostaining for insulin on Day 10. Thereafter, insulin administration (in the group C rats) caused a significant decrease (p < 0.05) in the elevated blood glucose levels, and a significant increase (p < 0.05) in the serum insulin concentrations. The surviving beta-cells regenerated and virtually regained their normal immunostaining and functional status for insulin. On the 30th day, the pancreatic insulin contents of the insulin-treated group C rats showed approximately 45-fold increase in immunoreactivity when compared with the immunoreactivity of the same STZ+insulin-treated rats on Day 10 of the 40-day study period. The present study illustrates the sequence of morphological changes that occur in the islets of Langerhans following STZ administration and subsequent insulin treatment. The study also suggests that administration of a moderate single dose of STZ in Wistar rats produces specific necrosis of beta-cells, typical of type 1 insulin-dependent diabetes. The experimental evidence obtained in this study appears to suggest that induction of regenerative stimulus (by insulin treatment) in diabetic state triggers pancreatic regenerative processes, thereby restoring functional activities of the pancreas.     

Alteration of pancreatic B-cells in Wistar rats treated with non-diabetogenic doses of cyclosporin A.

We have investigated the effect of non-immunosuppressive cyclosporin A (CS-A) doses on glucose tolerance, pancreatic insulin content, insulin content of isolated islets and insulin secretion in vitro in response to glucose. Within 12 weeks animals treated permanently with a dose of 2.5 mg CS-A/kg b.wt. developed glucose intolerance (but not hyperglycaemia) accompanied by a decrease of pancreatic insulin content due to a decrease of islet insulin content, whereas the relative B-cell volume density was not changed. Isolated islets obtained from rats treated for 4 weeks had a diminished sensitivity for glucose, whereas islets obtained from animals treated for greater than 4 weeks showed a diminished half-maximum and maximum secretion rate. Rats treated for 12 weeks with 1.25 mg CS-A/kg b.wt. developed an impaired glucose tolerance after 8 weeks accompanied by a diminished pancreatic insulin content. Despite continued treatment the pancreatic insulin content was able to increase and the glucose tolerance to normalize, indicating an adaptation of pancreatic B-cells to CS-A. The results support the theory that a potential toxic effect of cyclosporin A can be diagnosed by functional tests (e.g. insulin secretion in response to a stepwise increase of glucose) before the irreversible (e.g. morphological) alterations occur.     

Alteration of Pancreatic B-Cells in Wistar Rats Treated with Non-Diabetogenic Doses of Cyclosporin A

Abstract: We have investigated the effect of non-immunosuppressive cyclosporin A (CS-A) doses on glucose tolerance, pancreatic insulin content, insulin content of isolated islets and insulin secretion in vitro in response to glucose. Within 12 weeks animals treated permanently with a dose of 2.5 mg CS-A/kg b.wt. developed glucose intolerance (but not hyperglycaemia) accompanied by a decrease of pancreatic insulin content due to a decrease of islet insulin content, whereas the relative B-cell volume density was.not changed. Isolated islets obtained from rats treated for 4 weeks had a diminished sensitivity for glucose, whereas islets obtained from animals treated for > 4 weeks showed a diminished half-maximum and maximum secretion rate. Rats treated for 12 weeks with 1.25 mg CS-A/kg b.wt. developed an impaired glucose tolerance after 8 weeks accompanied by a diminished pancreatic insulin content. Despite continued treatment the pancreatic insulin content was able to increase and the glucose tolerance to normalize, indicating an adaptation of pancreatic B-cells to CS-A. The results support the theory that a potential toxic effect of cyclosporin A can be diagnosed by functional tests (e.g. insulin secretion in response to a stepwise increase of glucose) before the irreversible (e.g. morphological) alterations occur.     

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

Aim： Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms.
Methods： Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine （10 mg/kg） and pravastatin （10 mg/d） or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line （INS-1） was used for measuring insulin secretion.
Results： In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 （Tph-1） mRNA levels. Treatment of INS-1 cells with paroxetine （5 and 10 μmol/L） significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin （10 μmol/L） significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine.
Conclusion： Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.     

An increase in cardiac alpha1-adrenoceptors following chronic clonidine treatment

Summary Chronic treatment (22 days) of rats with clonidine (0.5 mg/kg s.c. twice a day followed by 20 h of withdrawal) resulted in a significant increase in the specific [³H]WB4101 binding to ventricular and intraventricular septal ₁-adrenoceptors but no alteration of the atrial ₁-adrenoceptors. Scatchard analysis indicated that the increase in the [³H]WB4101 binding to the clonidine-treated cardiac tissues was due to an enhancement of the ₁-adrenoceptor density since there was a significant increase in the B _max value for the [³H]WB4101 binding to the treated ventricles without a change in the K _d value. The specific [³H]WB4101 binding to cardiac ₁-adrenoceptors was not altered by the acute (1 day) or 7 days treatment with clonidine. Chronic treatment with clonidine had no significant effect on the specific [³H](–)DHA binding to the atrial and ventricular -adrenoceptors. The noradrenaline (NA) concentrations in the clonidine-treated ventricles and intraventricular septae were decreased by 16–20%. These data provide biochemical evidence compatible with a significant reduction of sympathetic outflow to the ventricular myocardium by clonidine.     

Dual action of clonidine on insulin release: suppression,but stimulation when α2-adrenoceptors are blocked

Summary As shown previously clonidine reduces glucose-stimulated insulin release and this effect is mediated by inhibitory postsynaptic ₂-adrenoceptors.The present experiments demonstrate that clonidine has the additional property to also stimulate insulin release. This became evident when the a2-adrenoceptors of isolated islets were blocked by benextramine, and thus protected from being stimulated by clonidine.In the presence of benextramine, clonidine no longer reduced, but on the contrary enhanced, the release of insulin in response to glucose. In control experiments benextramine by itself failed to affect insulin release from isolated islets.These results show that the imidazoline derivative clonidine shares the property of other imidazoline compounds to enhance the insulin response to glucose. All of these agents may stimulate insulin by binding to imidazoline-preferring sites, that clearly differ from -adrenoceptors. Send offprint requests to A. Schulz at the above address     

小剂量阿司匹林对糖尿病大鼠胰腺功能和凋亡相关蛋白的研究

目的研究小剂量阿司匹林对糖尿病大鼠胰腺功能和凋亡相关蛋白的影响。方法雄性SD大鼠,尾静脉注射链脲佐菌素30mg/kg,造成1型糖尿病动物模型,随机分为糖尿病模型组和9 mg/kg阿司匹林治疗组(ASA治疗组),每组8只,另选8只健康雄性大鼠为正常对照组。各组大鼠灌服给药12周后,检测各组大鼠空腹血糖、血清胰岛素水平,免疫组化法检测分析Caspase-3、Bax和Bcl-2的表达情况。结果与正常对照组比较,糖尿病模型组大鼠空腹血糖提高、血清胰岛素水平降低,胰岛素抵抗指数升高;胰腺组织Caspase-3、Bax表达增强,Bcl-2的表达减弱,Bcl-2/Bax比值降低;ASA治疗组大鼠,血糖减低,胰岛素提高,减低Caspase-3、Bax表达,提升Bcl-2的表达,并明显提高Bcl-2/Bax比值。结论小剂量阿司匹林对糖尿病大鼠胰岛素分泌功能有保护作用,可能与调节胰腺细胞凋亡相关蛋白表达有关。     

The effect of clonidine on gastric acid secretion in rats and dogs

Summary The effect of clonidine on gastric acid secretion was investigated using rats and dogs. In the stomach lumen perfused rat basal gastric acid secretion was increased by clonidine in the anaesthetized rat but inhibited in the conscious animal. Clonidine also reduced the basal gastric acid secretion in rats with chronic gastric fistula, (ED₅₀ 12 g/kg p.o.). In addition, gastric secretion stimulated by insulin hypoglycaemia was inhibited by clonidine in anaesthetized stomach lumen perfused rats and in conscious dogs with gastric fistula. In the rat gastric secretion stimulated by electrical vagus stimulation was inhibited as well. However, clonidine had no effect on the gastric acid secretion stimulated by carbachol in stomach lumen perfused rats and in dogs with denervated fundic pouch.These results suggest that the inhibition of gastric acid secretion by clonidine probably is due to an inhibition of acetylcholine release at the vagus nerve endings. Additional central gastric antisecretory effects can, however, not be excluded by this study.     

Evaluation of an oral insulin formulation in normal and diabetic rats

Aim:

As injection is not an ideal means for insulin delivery, various attempts have been made to administer insulin orally until now. The development of an oral dosage form of insulin would help diabetic patients and make the treatment more convenient. The aim of the present study is to evaluate the effectiveness of an oral insulin formulation containing polar and non-polar ingredients.

Materials and Methods:

New excipient for oral insulin administration in normal and diabetic rats was evaluated by measuring blood glucose concentrations in two groups (10 rats each) of normal and streptozotocin-induced diabetic rats. Oral insulin was administrated and blood glucose was measured by glucometer at 0, 1, 2, 3 and 4 h post-feeding. The data was compared by Student''s t test.

Results:

Oral insulin formulation significantly (P<0.05) reduced blood glucose from 100 mg/dl to 33.73 mg/dl and 451.66 mg/dl to 200.83 mg/dl at 4 h in normal and diabetic rats, respectively.

Conclusion:

The novel excipient used could protect insulin from gastric and pancreatic enzymes and reduce blood glucose concentration in both healthy and diabetic rats suggesting that oral delivery of insulin is feasible in a near future.KEY WORDS: Blood glucose, normal and diabetic rats, oral insulin     

Acute and chronic administration of SHR117887, a novel and specific dipeptidyl peptidase-4 inhibitor,improves metabolic control in diabetic rodent models

Aim:

Dipeptidyl deptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents. The purpose of this study was to assess the acute and chronic effects of SHR117887, a novel DPP-4 inhibitor, on metabolic control and pancreatic β-cell function in normal or diabetic rodent models.

Methods:

In the acute experiments, ICR mice, diet-induced obese (DIO) rats and ob/ob mice were subjected to an oral glucose tolerance test (OGTT) following a single oral administration of SHR117887 (0.1, 0.3, 1 or 3 mg/kg). Blood samples were collected to measure glucose, insulin, DPP-4 activity and active GLP-1 level. In the chronic experiments, ob/ob mice was administered SHR117887 (3, 10 or 30 mg/kg) twice daily for 33 d to assess the effects on metabolic control and pancreatic β-cell function. Vildagliptin (LAF237) was used as a positive control in all the experiments.

Results:

Acute oral administration of SHR117887 dose-dependently decreased the serum DPP-4 activity and improved glucose tolerance in ICR mice, DIO rats and ob/ob mice. This was accompanied by significant increases in the serum active GLP-1 and insulin levels. Chronic administration of SHR117887 significantly decreased fasting blood glucose level and improved the lipid profiles in ob/ob mice by reducing the serum triglyceride and free fatty acid levels, and its efficacy was comparable with that of vildagliptin at the same molarity. Moreover, chronic administration of SHR117887 increased the insulin staining of islet cells, which is suggestive of improved β-cell function.

Conclusion:

SHR117887 is a potent DPP-4 inhibitor that improves metabolic control and β-cell function in diabetic rodent models, suggesting that it could be a new therapeutic agent for the treatment of type 2 diabetes.     

Effects of subacute and chronic lead treatment on glucose homeostasis and renal cyclic AMP metabolism in rats

The effects of chronic oral ingestion of lead in doses ranging from 20–80 ppm were compared with those seen after the subacute exposure of rats to a 10 mg/kg daily dose of the heavy metal for 7 days. Irrespective of the treatment regimen used, lead treatment significantly increased the activities of renal pyruvate carboxylase, phosphoenopyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase. The observed enhancement of kidney gluconeogenic enzymes in chronically treated animal was associated with a stimulation of the adenylate cyclase-cyclic AMP system, a rise in blood glucose and urea as well as a depression in hepatic glycogen and serum immunoreactive insulin (IRI) levels. In contrast, subacute exposure to lead failed to significantly alter cyclic AMP metabolism and the concentrations of liver glycogen, blood glucose, serum urea or IRI. Whereas the insulinogenic index (the ratio of serum IRI to blood concentration) was markedly suppressed in chronically treated rats, this ratio remained within normal limits following subacute exposure to the heavy metal. However, a marked decrease in the insulinogenic index was observed in subacutely treated rats 15 min after the administration of a glucose load. The data provide evidence to show that increased glucose synthesis as well as suppressed pancreatic function may be responsible for lead-induced disturbances in glucose homeostasis.     

Effect of tolbutamide on aminophylline-, 3,5-AMP-dibutyrate-or glucagon-induced insulin release from pancreatic islets after impairment of pyridine nucleotide metabolism caused by 6-aminonicotinamide (6-AN)

Summary The effect of tolbutamide on pyridine nucleotides and insulin secretion stimulated by aminophylline, 3,5-AMP-dibutyrate or glucagon was studied in pancreatic islets of rats previously treated with 6-aminonicotinamide (6-AN), an inhibitor of pyridine nucleotide synthesis.After being incubated for 60 min in a Krebs-Ringer-Bicarbonate-Buffer in the absence of glucose, pancreatic islets of rats i.p. injected with 35 mg/kg of 6-AN 6 hrs before pancreas removal contained about 30% less NADP and NADPH than did islets of control rats. No changes of NAD or NADH were observed in islets of 6-AN-treated animals. Addition of 16.5 mM glucose led to an increase of NADH, NADPH and a decrease of NADP in islets of both groups of animals; NAD levels remained unchanged. In vitro addition of tolbutamide to islets of control rats did not affect the levels of NADPH or NADP in the presence of 5.5 mM glucose. When 16.5 mM glucose were present, a decrease of NADPH and an increase of NADP was obvious. No effect of tolbutamide on insular NADPH or NADP was observed in islets of rats previously treated with 6-AN be it in the presence of 5.5 or 16.5 mM glucose.In islets of 6-AN-treated rats insulin release in response to aminophylline or 3,5-AMP-dibutyrate in the presence of 5.5 mM glucose was significantly depressed, when compared to islets of untreated controls. Addition of tolbutamide increased insulin release due to aminophylline, 3,5-AMP-dibutyrate or glucagon from islets of controls. Tolbutamide alone was without effect. In islets of 6-AN-treated rats aminophylline, 3,5-AMP-dibutyrate or glucagon stimulated insulin release only when tolbutamide was present.Our data suggest that there is no direct interference of tolbutamide with pyridine nucleotides of pancreatic islets, and that tolbutamide increases the secretory response of the -cell to aminophylline, 3,5-AMP-dibutyrate or glucagon when insulin release due to these agents is inhibited during decrease of insular NADP and NADPH, caused by 6-AN.Supported by the Deutsche Forschungsgemeinschaft.     

Effect of clonidine on the responsiveness of infant rats to maternal stimuli

Clonidine (0.1 mg/kg), an ₂-adrenoceptor agonist, stimulated ultrasonic callings in 10-day-old rats. Unlike normal isolated rat pups, the vocalizations of clonidine-treated rats appeared resilient to maternal cues. Thus, clonidine-induced vocalizations did not decrease during intraoral infusions with 10% sucrose, exposure to home cage bedding or tactile stimulation of the skin. Clonidine (0.05; 0.1; 0.2 mg/kg) also disrupted the attraction normally shown by infant rats to home cage odours in an olfactory place preference test. This effect by clonidine was not shared by raclopride (1–4 mg/kg), naltrexone (0.5–2.0 mg/kg) or propranolol (2.5–10.0 mg/kg). Clonidine-treated infants (0.05; 0.1; 0.2 mg/kg) also failed to apprehend and attach to the anaesthetized mother's nipple. The results raise the possibility that ₂-adrenoceptor activation blunts the infant's receptivity to maternal olfactory incentives and intensifies separation-induced responses.