John H. Mennear

Effects of acute and subacute cadmium administration on carbohydrate metabolism in mice

Abstract The administration of single doses of cadmium acetate (2.0–6.0 mg/kg, ip) produces hyperglycemia and glucose intolerance in intact mice. Adrenalectomy prevents the hyperglycemic effect but not the glucose intolerance. Glucose intolerance is associated with a decreased pancreatic secretory activity as evidenced by decreased insulinogenic indices in Cd-treated mice. The administration of 4.0 mg/kg of Cd daily for 14 days produces tolerance to Cd-induced hyperglycemia. The subacute treatment did not produce changes in resting blood glucose levels, nor did it produce a decrease in glucose tolerance. A significant reduction in circulating serum insulin was detected after subacute Cd administration. It is suspected that a Cd-induced decrease in renal threshold to glucose masks the effect of lowered serum insulin concentrations.

Pancreatic metallothionein: Protection against cadmium-induced inhibition of insulin secretory activity

Abstract Mouse liver and pancreatic concentrations of metallothionein were determined by gel filtration at several intervals after the ip administration of cadmium acetate. Hepatic concentrations of the protein reached peak values 48 hr after the injection, whereas the pancreatic concentrations were highest at 6 hr. The exposure of mouse isolated pancreatic islets to a concentration of 1 × 10 −6 m cadmium significantly reduced glucose-stimulated insulin secretion. When mice were administered cadmium 6 hr prior to islet isolation, the time required for peak concentrations of metallothionein to develop in the pancreas, subsequent exposure to the metal did not reduce glucose-stimulated insulin secretion. The results suggest that the pancreas synthesizes metallothionein and that the protein serves a protective role against the acute effects of cadmium.

Effect of multiple doses of cadmium on glucose metabolism and insulin secretion in the rat.

The effect of multiple doses of cadmium on insulin secretion from the perfused pancreas was studied. In addition, urine and plasma glucose, plasma immunoreactive insulin, and the rate of evolution of respiratory 14CO2 after administration of [UL-14C]d-glucose were determined. The treated groups received two dose levels, 0.25 or 0.50 mg Cd/kg, ip every second day for 70 doses. Multiple doses of 0.50 mg/kg caused an inhibition in the amount of insulin secreted from the perfused pancreas, whereas multiple doses of 0.25 mg/kg caused a partial inhibition that was not statistically significant. With the exception of the plasma insulin concentration in animals receiving multiple doses of 0.50 mg/kg, statistically significant differences in the plasma glucose, plasma insulin, and insulinogenic index were not detected. A high glucose concentration as well as a high concentration of 14C in the urine of treated animals was found. Treated animals expired smaller amounts of 14CO2 than the controls. Animals receiving the higher dose showed significantly lower weights than either the controls or the animals receiving the lower dose, which did not differ significantly from each other.

The inhibitory effect of cadmium on the secretory activity of the isolated perfused rat pancreas

Abstract Perfusion of the isolated rat pancreas with cadmium (Cd) (1 × 10 −3 and 5 × 10 −4 m ) inhibits the insulin secretory response to glucose (300 mg/100 ml), tolbutamide (40 mg/100 ml), and potassium ions (30 mEq/liter). Cadmium inhibition of pancreatic secretory activity is immediate in onset, and not reversed by simple washout of the organ with perfusion medium. Perfusion of the inhibited organ with a combination of glucose and theophylline results in partial reversal of the inhibition. It is suspected that Cd-induced inhibition of insulin secretion may be mediated through interference with calcium uptake by the pancreatic beta cell.

The inhibitoty effect of DDT on insulin secretion in mice

Abstract A single oral dose of 50 mg/kg of DDT administered to mice 18 hr prior to experimentation was found to reduce glucose tolerance without affecting the basal blood concentration of glucose. Also, the treatment inhibited both d -glucose and tolbutamide-stimulated insulin release by isolated pancreatic islets. Hyperglycemia was not noted during the 18-hr period after DDT. The effect of DDT on glucose tolerance persisted for at least 1 week. Reduced pancreatic secretory activity after DDT administration is consistent with the increased activity of gluconeogenic enzymes as well as decreased glycogen synthetase activity reported by earlier workers.

Phenothiazine-Induced Hyperglycemia: Relation to CNS and Adrenal Effects

Summary The ability of 4 phenothiazines to induce hyperglycemia, to decrease motor activity in mice, and to release catecholamines from isolated bovine adrenals, were not well correlated. Fluphenazine produced the greatest CNS depression with a minimal hyperglycemia. Chlorpromazine produced the greatest hyperglycemia but was not the best releasing agent in isolated adrenals. It appears that the hyperglycemic action of the phenothiazines may be minimized without sacrificing CNS activity by selecting the appropriate derivative. Variation in extra-adrenal effects on blood sugar may explain the lack of correlation between production of hyperglycemia and adrenal catecholamine release by the phenothiazines studied.

The inhibitory effect of dehydroascorbic acid on insulin secretion from mouse pancreatic islets

Abstract Intravenous doses of 200 mg/kg dehydroascorbic acid (DHA) produced hyperglycemia, hypoinsulinemia, and decreased glucose tolerance in mice. This effect of DHA is mediated, at least in part, through a direct inhibition of pancreatic insulin release. Exposure of isolated pancreatic islets to a concentration of 2.0 mg/dl DHA reduces the responsiveness of the islets to both glucose (300 mg/dl) and tolbutamide (6±10 −3 m ). Exposure of isolated islets to DHA in a high concentration of d -glucose (300 mg/dl) partially protected them against the inhibitory effect of DHA. Exposure of islets to 4.0 mg/dl of DHA causes a leakage of insulin. Similarly, islets isolated from mice which had been treated with 300 mg/kg DHA iv exhibited increased insulin release in the presence of only 60 mg/dl glucose. Intravenous administration of either 200 or 300 mg/kg DHA prior to islet isolation results in increased insulin secretion in response to 300 mg/dl glucose. The results show that the pancreatic effects of DHA are similar to those of the diabetogen, alloxan.

Inhibitory Effect of Diphenylhydantoin on the Diabetogenic Action of Alloxan in the Mouse

The effect of the pretreatment of mice with diphenylhydantoin (DPH) on the development of alloxan diabetes was studied. DPH, in intraperitoneal doses of 20 to 45 mg./kg., administered one hour prior to alloxan, was found to prevent the development of alloxan (75 mg./kg., intravenously) diabetes. Administration of DPH after alloxan had no effect. The initial hyperglycemie response to alloxan (measured forty-five minutes post-alloxan) was potentiated by DPH pretreatment. Intravenous glutathione, administered one minute prior to alloxan, inhibited both the initial and chronic hyperglycemia produced by alloxan. A structural similarity between DPH and alloxan suggests that DPH may be protecting pancreatic beta cell binding sites from alloxan.

Chlorpromazine-induced glucose intolerance in the mouse.

Summary Intraperitoneally administered chlorpromazine produced a dose-related increase in blood glucose levels in the mouse. The magnitude of the hyperglycemic response is related to liver glycogen levels, since fasting depleted liver glycogen and attenuated the hyperglycemic response. Mice quickly develop tolerance to the hyperglycemic effect of CPZ and 18 hr after a single dose of chlorpromazine a second dose of the drug is not hyperglycemic. Tolerance to chlorpromazine-induced hyperglycemia does not impart tolerance to the hyperglycemic effects of either epinephrine or alloxan. Chlorpromazine was also found to reduce glucose tolerance in mice, but the reduced glucose tolerance is not completely antagonized by pretreatment with CPZ. The authors thank Mrs. Judith Stilwell for providing excellent technical assistance.

The comparative glycemic effects of catecholamines in rats and mice

Abstract Epinephrine, norepinephrine and isoproterenol were administered to either normally fed or 18 hr-fasted mice. While fasting did not alter the magnitude of epinephrine-induced hyperglycemia, it abolished norepinephrine-induced hyperglycemia. Isoproterenol produced hyperglycemia and depletion of liver glycogen in fed mice and hypoglycemia in fasted mice. In fed rats isoproterenol had no effect on blood glucose but elicited hyperglycemia in 24 hr-fasted rats. Isoproterenol also induced hyperglycemia in adrenalectomized normally fed mice. The results suggest that hyperglycemia in the fed mouse is a reflection of isoproterenol-induced glycogenolysis in the liver. It is suggested that the hypoglycemia in fasted mice is due to isoproterenol-stimulated insulin secretion. This study accents the criticality of the species employed as well as the pretreatment regimen with respect to data interpretation.