Absorption and efficiency of insulin after oral administration of insulin-loaded nanocapsules in diabetic rats

Poly(isobutylcyanoacrylate) nanocapsules have been shown to decrease the blood glucose level after oral administration to streptozotocin-induced diabetic fasted rats after 2 days [Diabetes 37 (1988) 246]. Yet, the absorption of insulin in the blood of rats has not been characterised. The aim of this work was to evaluate the biological activity of insulin given orally as nanocapsules. Humalog-loaded nanocapsules (50 IU/kg) were administered by gavage to streptozotocin-induced diabetic rats. Thirty minutes to 1 h after oral administration, significant levels of human insulin were detected in rat plasma. However, the concentrations were very heterogenous from one rat to another and no decrease of glycemia could be observed. In addition, parenteral injection of insulin in solution showed that high levels of the protein are necessary to decrease blood glucose concentration in diabetic rats. These concentrations were not reached after oral administration. The same dose of insulin decreased glycemia by 50% in normal rats and by only 25% in diabetics. This suggested that an insulino-resistance was developed by streptozotocin-induced diabetic rats.     

Pharmacologic profile and insulin secretagogue effect of linogliride (McN-3935), a new,orally effective hypoglycemic agent

Linogliride (McN-3935) [N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-4-morpholinecarboximidamide] was selected for clinical evaluation as a potential orally effective hypoglycemic agent for treatment of noninsulin-dependent diabetes mellitus. Linogliride is structurally unrelated to sulfonylureas and biguanides. It produced a dose-dependent hypoglycemic effect in nondiabetic rats, mice, and dogs. The minimum effective oral doses that lowered fasting blood glucose levels and improved glucose tolerance were 1–5 mg/kg. Comparison of the dose-response curves from fasting rat studies showed linogliride to be approximately two times more potent than the related compound pirogliride and approximately eight times more potent than tolbutamide. Tolerance to its hypoglycemic effect did not develop in rat and dog 3-day repeat dose studies. Linogliride did not alter plasma lactic acid levels in normal and streptozotocin-induced diabetic rats, and it improved glucose tolerance whether the glucose was administered orally or parenterally. In nondiabetic rats and dogs, decreases in fasting blood glucose levels following linogliride administration were associated with elevated (two- to fourfold) plasma insulin concentrations. Linogliride was inactive in depancreatized diabetic dogs. In genetically diabetic (db/db) mice and streptozotocin-induced diabetic rats, linogliride (25–100 mg/kg p.o.) produced variable, nondose-dependent reductions of blood glucose levels, unlike the sulfonylureas, which were consistently ineffective in these diabetic rodent models. In conclusion, although the observed activity in diabetic rodent models is suggestive of a potential nonpancreatic mechanism, the experimental evidence to date indicates that the acute effectiveness of linogliride as a hypoglycemic agent is due primarily to stimulation of insulin release.     

Insulin-secretagogue activity of p-methoxycinnamic acid in rats, perfused rat pancreas and pancreatic beta-cell line

This study investigated the effect of p-methoxycinnamic acid (p-MCA) on plasma glucose and insulin concentrations in normal and streptozotocin-induced diabetic rats. In both fasting and glucose-loading conditions, an oral administration of p-MCA (40-100 mg/kg) significantly decreased plasma glucose and also increased plasma insulin concentrations in both normal and diabetic rats. The onset of the p-MCA-induced antihyperglycaemia/hypoglycaemia was observed at 1 hr after administration. In perfused rat pancreas, p-MCA (10-100 microM) stimulated insulin secretion about 1.4- and 3.1-fold of basal-control group. In addition, p-MCA (10 microM) enhanced glucose-induced insulin secretion. Moreover, p-MCA stimulated insulin secretion and increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in insulinoma-1 cells. Taken together, our findings suggested that p-MCA exerted antihyperglycaemic/hypoglycaemic effect by stimulating insulin secretion from pancreas and could be developed into a new potential for therapeutic agent used in type 2 diabetic patients.     

Hypoglycemic effect of syringin from Eleutherococcus senticosus in streptozotocin-induced diabetic rats

Eleutherococcus senticosus (Araliaceae ) is a very powerful adaptogenic agent. In the present study, the effects of syringin, an active principle of this herb, on plasma glucose levels in streptozotocin-induced diabetic rats (STZ-diabetic rats) were investigated. Thirty minutes after syringin was intravenously injected into fasting STZ-diabetic rats, plasma glucose levels dose-dependently decreased. In normal rats, syringin at the effective dose (1.0 mg/kg) significantly attenuated the increase in plasma glucose caused by an intravenous glucose challenge. Syringin dose-dependently (0.01 to 10.0 micromol/L) stimulated glucose uptake in soleus muscle isolated from STZ-diabetic rats. Syringin treatment of hepatocytes isolated from STZ-diabetic rats enhanced glycogen synthesis . The ability of syringin to enhance glucose utilization and lower plasma glucose level in rats suffering from insulin deficiency suggest that this chemical may be useful in the treatment of human diabetes.     

Modification of GABAergic activity and thyrotropin secretion in male rats

The effect of GABA on basal and stimulated TSH secretion was studied in male rats. The effects of drugs on basal TSH levels were not consistent. Muscimol(0.5 mg/kg subcutaneously, but not 2 mg/kg) increased whereas baclofen (10 mg/kg intraperitoneally), amino-oxyacetic acid (AOAA, 20 mg/kg intraperitoneally) and bicuculline (2 mg/kg intraperitoneally, but not 1 or 4 mg/kg) decreased basal TSH concentrations. Muscimol, AOAA and baclofen dose-dependently reversed the TSH cold-response, as did a large dose of di-n-propylacetate (DPA, 400 mg/kg intraperitoneally) and 500 mg/kg (but not 50, 100 or 1500 mg/kg intraperitoneally) of GABA itself. Bicuculline was not effective alone. Neither did it modify the effects of muscimol, AOAA and GABA on the cold-stimulated TSH response. None of the drugs studied (AOAA, GABA, bicuculline) modified TRH-induced (100 ng intraperitoneally) TSH-response. GABA injected into the third ventricle (5-50 microgram/rat) or into the medial basal hypothalamus (MBH, 5 microgram/rat) had no effect on the basal TSH levels. However, the TSH cold-response was inhibited when GABA (5 microgram/rat) was infused into the MBH but not when it was infused into the third ventricle (5-50 microgram/rat). The results suggest that GABAergic pathways may have an inhibitory effect on the stimulated TSH secretion in male rats. The locus of this inhibition is not situated in the anterior pituitary, but possibly in the MBH.     

Effects of Aminooxyacetic Acid and Baclofen on the Catalepsy and on the Increase of Mesolimbic and Striatal Dopamine Turnover Induced by Haloperidol in Rats

Abstract Effects of aminooxyacetic acid (AOAA) and baclofen on the catalepsy and on the increase of mesolimbic and striatal dopamine turnover induced by haloperidol were studied in rats. AOAA (25 mg/kg intraperitoneally) which increases the cerebral concentration of δ–aminobutyric acid (GABA) and baclofen (10 mg/kg intraperitoneally), a structural analogue of GABA, did not induce catalepsy by themselves but potentiated the catalepsy caused by haloperidol (0.1 mg/kg subcutaneously). AOAA and baclofen did not alter the haloperidol–induced striatal homovanillic acid increase. AOAA and baclofen decelerated the dopamine disappearance caused by α–methyl–p–tyrosine (αMT) both in mesolimbic nuclei and striatum. Haloperidol accelerated the αMT–induced dopamine disappearance in these structures. AOAA and baclofen prevented this stimulatory effect of haloperidol on the dopamine turnover. These results support the earlier suggestions that GABAergic pathways have an inhibitory effect on the mesolimbic and striatal dopaminergic pathways.     

Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin

Effects of atorvastatin and pravastatin on glucose tolerance in mildly induced diabetic rats by streptozotocin at 24 mg/kg, i.v. were studied. Non-diabetic and diabetic rats were given orally 0.5% carboxymethylcellulose (control), 8 mg/kg atorvastatin or 8 mg/kg pravastatin once a day for 6 weeks. An oral glucose tolerance test (OGTT) was carried out 1, 2, 3, and 6 weeks after the administration. The blood glucose and plasma insulin levels measured before OGTT in the diabetic rats were not different from those in the non-diabetic rats. However, the hyperglycemic response to OGTT in the diabetic rats significantly exceeded that in the non-diabetic rats. The plasma insulin increased by OGTT in the diabetic rats appeared to be lower than that in the non-diabetic rats. Statin treatments for 1 week did not modify the OGTT-induced hyperglycemia appreciably, although there were some significant differences. More than 2 weeks after administration, the blood glucose levels at several time points after a glucose intake in the atorvastatin-treated diabetic rats were significantly higher than the respective levels in the control diabetic rats. Neither atorvastatin nor pravastatin modified the OGTT-induced insulin secretion. Statins, especially atorvastatin, may influence the glucose tolerance in mildly induced diabetic rats without alterations of insulin secretion.     

Clonazepam increases in vivo striatal extracellular glucose in diabetic rats after glucose overload

Hyperglycemia modulates brain function, including neuronal excitability, neurotransmitter release and behavioral changes. There may be connections between the GABAergic system, glucose sensing neurons and glucose in the neuronal environment that shed light on the mechanism by which GABA(A) agents influence depressive behavior in diabetic rats submitted to the forced swimming test. We aimed to investigate whether clonazepam (CNZ), a GABA(A) receptor positive modulator, modifies in vivo striatal extracellular glucose levels in diabetic rats under fasting condition or after oral glucose overload. Streptozotocin diabetic and nondiabetic rats were submitted to in vivo striatal microdialysis. Perfusate samples were collected at baseline, during fasting and following administration of CNZ (0.25 mg/kg) and oral glucose overload. Blood glucose and striatal extracellular glucose were measured simultaneously at several time points. Fasting striatal glucose levels were higher in diabetic than in nondiabetic rats and the differences between these animals were maintained after glucose overload. The increases in extracellular striatal glucose after glucose overload were around 40% and blood to brain transference was decreased in diabetics. CNZ treatment paradoxically increased striatal glucose after glucose overload in diabetic rats, which may mark the dysfunction in brain glucose homeostasis.     

Abnormal incorporation and utilization of alpha-tocopherol in erythrocyte membranes of streptozotocin-induced diabetic rats

Alpha-tocopherol is a well-known lipophilic-free radical scavenger that is mainly localized in biomembranes. In this study, we investigated the changes in the incorporation and utilization of alpha-tocopherol in erythrocyte membranes of streptozotocin-induced diabetic rats and the effects of insulin to control hyperglycemia on these changes. Diabetes was experimentally induced by the injection of streptozotocin (60 mg/kg, i.v.). Blood was collected to determine the concentrations of alpha-tocopherol and its oxidative metabolite (alpha-tocopherolquinone) in plasma or erythrocyte membranes after streptozotocin injection. In streptozotocin-induced diabetic rats, alpha-tocopherol concentrations were decreased in erythrocyte membranes and increased in plasma. The ratio of alpha-tocopherol in erythrocyte membranes to that in plasma, which reflects the incorporation of alpha-tocopherol into erythrocyte membranes, was dramatically decreased in streptozotocin-induced diabetic rats. Moreover, the ratio of alpha-tocopherolquinone to alpha-tocopherol in erythrocyte membranes, which reflects the utilization of alpha-tocopherol, was increased in streptozotocin-induced diabetic rats. These changes were prevented by insulin to control hyperglycemia. These findings suggest that the abnormalities in the incorporation and utilization of alpha-tocopherol in erythrocyte membranes of streptozotocin-induced diabetes can be restored to normal by insulin therapy to control hyperglycemia.     

Cyclosporine pharmacokinetics and effect in the type I diabetic rat model

Recent clinical studies have demonstrated the potential benefit of the T-cell-specific immunosuppressant, cyclosporine, in the treatment of Type I insulin-dependent diabetes. In the present study, steady-state cyclosporine pharmacokinetics, fasting glucose and insulin levels and renal function were examined in stable insulin-dependent diabetic rats and compared to non-diabetic rats. Mean creatinine clearance 30 days following diabetes induction was not significantly different from saline controls. Cyclosporine treatment (5 mg/kg/day i.v. for 13 days) did not significantly alter creatinine clearance in either group; however, renal function of vehicle-treated diabetic rats was markedly reduced compared to other groups. Serum insulin concentrations were significantly greater in diabetic rats treated with cyclosporine compared to the control group (35.1 +/- 22.7 vs. 16.0 +/- 8.1 microU/ml; P less than 0.05). Glucose levels were proportionately reduced in diabetic rats treated with cyclosporine. Area under the concentration-time curve, half-life and volume of distribution of cyclosporine were significantly reduced in diabetic rats compared to non-diabetic controls. In summary, the pharmacokinetics and pharmacodynamics of cyclosporine were significantly different in the insulin-dependent diabetic rat model compared to normal controls. Furthermore, short-term cyclosporine therapy reduced the extent of experimental diabetic nephropathy observed in this model.     

Interaction between phencyclidine (PCP) and Gaba-ergic drugs: Clinical implications

Pretreatment (IP) of mice with (?) baclofen, muscimol, 4,5,6,7-tetrahydroisoxazolo (S,4-c) pyridin-3-ol hydrate (THIP), aminooxyacetic acid (AOAA) or γ-acetylenic GABA caused a dose-dependent inhibition of the locomotor stimulant effect of phencyclidine (PCP, 8 mg/kg). Although (?) baclofen was found to be the most effective PCP antagonist, its (+) isomer was inactive. The maximum blocking effect of AOAA was seen in animals treated 3 and 6 hr earlier. Except for γ-acetylenic GABA, none of these drugs significantly blocked the locomotor stimulant effect of d-amphetamine (3 mg/kg, IP). Diazepam reduced d-amphetamine response, but failed to influence PCP-induced stimulation. The locomotor stimulant effect of PCP, unlike that of d-amphetamine, may be the result of a specific GABA antagonistic effect at certain dopamine-rich areas of the brain. It seems that (?) baclofen may prove to be useful in the management of PCP intoxication.Administration of higher doses of PCP (20 and 50 mg/kg) in mice pretreated with (?) baclofen resulted in the development of surgical anesthesia manifested as the loss of a) righting reflex, b) pain sensation and c) corneal reflex. The duration of the general anesthetic response was found to be a function of the doses of both (?) baclofen and PCP. The possible use of (?) baclofen as an adjuvant to general anesthetic is discussed.     

Stimulation of insulin release in rats by Die-Huang-Wan, a herbal mixture used in Chinese traditional medicine

Die-Huang-Wan is a herbal mixture widely used in Chinese traditional medicine to treat diabetic disorders. We have investigated the effect of Die-Huang-Wan on plasma glucose concentration in-vivo. Die-Huang-Wan was administered orally (5.0, 15.0 or 26.0 mg kg(-1)) to three rat models. Wistar rats were used as the normal animal model, rats with insulin-resistance (induced by the repeated thrice daily injection of human long-acting insulin) were used as the non-insulin-dependent diabetic model, and streptozotocin-induced diabetic rats were used as the insulin-dependent diabetic model. In normal rats, approximately 1 h after oral administration of Die-Huang-Wan the plasma glucose concentration decreased significantly in a dose-dependent manner, from 5 to 26.0 mg kg(-1). A similar effect was observed in rats with insulin-resistance. However, this effect was not observed in streptozotocin-induced diabetic rats, even at an oral dose of 26.0 mg kg(-1). These results suggested an insulin-dependent action, a view supported by the increase of plasma insulin-like immunoreactivity in normal rats receiving Die-Huang-Wan. The results indicated that Die-Huang-Wan had an ability to stimulate the secretion of insulin and this preparation seemed helpful in improving the diabetic condition, especially hyperglycaemia in type-II diabetes.     

Normalization of hyperglycaemia by oral vanadyl sulfate does not reverse diabetes-induced protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats

Streptozotocin- and galactose-induced diabetic rats are protected against nephrotoxic effects of cisplatin. While the mechanism remains to be defined, protection is associated with a decrease in the accumulation of platinum in renal cortical tissues of streptozotocin-diabetic versus non-diabetic rats. A physiological abnormality common to streptozotocin and galactosemic models of diabetes is hyperglycaemia, suggesting that elevated sugars are involved in mediating protection of diabetic kidney against cisplatin nephrotoxicity. The current study focused on the effect of normalization of hyperglycaemia by vanadyl sulfate trihydrate on the initiation of protection and accumulation of platinum in kidneys of streptozotocin-diabetic rats. Streptozotocin-diabetic rats were treated with 0.75 mg/ml of vanadyl sulfate trihydrate in drinking water to normalize streptozotocin-induced hyperglycaemia. Vanadyl sulfate treatment normalized plasma glucose and glycosylated haemoglobin levels in streptozotocin-diabetic rats to values observed for non-diabetic rats. Intraperitoneal administration of cisplatin (5 mg/kg body weight) increased blood urea nitrogen by a factor >2.5 over baseline in both untreated and vanadyl-treated non-diabetic groups. Cisplatin-induced increases in blood urea nitrogen were 1.6 times baseline in both untreated and vanadyl-treated streptozotocin-diabetic rats. Renal platinum accumulation was significantly lower in streptozotocin-diabetic versus non-diabetic rats regardless of vanadyl sulfate treatment. Renal vanadium levels in all groups of diabetic rats were not significantly different from each other. These results indicate that normalization of plasma glucose levels with vanadyl sulfate in streptozotocin-diabetic rats did not reverse protection of streptozotocin-diabetic kidney against cisplatin nephrotoxicity.     

Effects of Aminooxyacetic Acid and Baclofen on Catalepsy,Striatal Homovanillic Acid Increase and Antinociception Caused by Methadone in Rats

Abstract The effects of aminooxyacetic acid (AOAA) and baclofen on the catalepsy, striatal homovanillic acid (HVA) increase and antinociception caused by methadone were studied in rats. Antinociceptive responses were tested by the electric foot–shock method. A new type of stimulator unit which delivered nearly constant current over a wide range of output voltage and which was noiseless was designed and its construction is described. AOAA (25 mg/kg) which increases the cerebral concentration of δ–aminobutyric acid (GABA) and baclofen (10 mg/kg), a structural analogue of GABA, did not change the catalepsy induced by methadone (5 mg/kg). AOAA (25 and 50 mg/kg) alone did not alter the striatal HVA content and had no effect on the methadone– induced HVA increase. Baclofen (10 mg/kg) increased the striatal HVA content by 19% (P < 0.01) and reduced the methadone–induced HVA increase by 36 % (P < 0.01). AOAA (25 mg/kg) and baclofen (5 mg/kg) had no antinociceptive effect but they increased significantly the antinociception caused by methadone (2 and 5 mg/kg). These results suggest that narcotic analgesics might cause catalepsy and increase striatal dopamine turnover by some other mechanism than neuroleptics. The results support the suggestion that GABA might be involved in pain mechanisms.     

Normalization of Hyperglycaemia by Oral Vanadyl Sulfate Does Not Reverse Diabetes-Induced Protection against Cisplatin Nephrotoxicity in Streptozotocin-Diabetic Rats

Abstract: Streptozotocin- and galactose-induced diabetic rats are protected against nephrotoxic effects of cisplatin. While the mechanism remains to be defined, protection is associated with a decrease in the accumulation of platinum in renal cortical tissues of streptozotocin-diabetic versus non-diabetic rats. A physiological abnormality common to streptozotocin and galactosemic models of diabetes is hyperglycaemia, suggesting that elevated sugars are involved in mediating protection of diabetic kidney against cisplatin nephrotoxicity. The current study focused on the effect of normalization of hyperglycaemia by vanadyl sulfate trihydrate on the initiation of protection and accumulation of platinum in kidneys of streptozotocin-diabetic rats. Streptozotocin-diabetic rats were treated with 0.75 mg/ml of vanadyl sulfate trihydrate in drinking water to normalize streptozotocin-induced hyperglycaemia. Vanadyl sulfate treatment normalized plasma glucose and glycosylated haemoglobin levels in streptozotocin-diabetic rats to values observed for non-diabetic rats. Intraperitoneal administration of cisplatin (5 mg/kg body weight) increased blood urea nitrogen by a factor >2.5 over baseline in both untreated and vanadyl-treated non-diabetic groups. Cisplatin-induced increases in blood urea nitrogen were 1.6 times baseline in both untreated and vanadyl-treated streptozotocin-diabetic rats. Renal platinum accumulation was significantly lower in streptozotocin-diabetic versus non-diabetic rats regardless of vanadyl sulfate treatment. Renal vanadium levels in all groups of diabetic rats were not significantly different from each other. These results indicate that normalization of plasma glucose levels with vanadyl sulfate in streptozotocin-diabetic rats did not reverse protection of streptozotocin-diabetic kidney against cisplatin nephrotoxicitv.     

Improvement of glucose homeostasis by oral vanadyl or vanadate treatment in diabetic rats is accompanied by negative side effects.

Vanadate and vanadyl, two forms of vanadium, have been reported to exert insulin-like effects in vivo and in vitro. In the present study we compared the effectiveness of oral sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4) and vanadyl sulphate pentahydrate (VOSO4.5H2O) treatment in alleviating some signs of diabetes in streptozotocin-induced diabetic rats. Vanadium compounds were administered in aqueous solutions of NaCl (80 mM) at concentrations of 0.20 mg/ml (NaVO3), 0.50 mg/ml (Na3VO4), and 1.1 mg/ml (VOSO4.5H2O) for two weeks. Control rats, either diabetic or non-diabetic, drank solutions of NaCl (80 mM). Although some signs of diabetes (hyperglycaemia, hyperphagia, polydipsia) were significantly ameliorated by the vanadium treatment, negative side effects were also observed in all of the vanadium-treated diabetic rats. Those effects included some deaths, decreased weight gain, and tissue vanadium accumulation, which are consistent with the reported toxicity of vanadium in non-diabetic rats. Vanadyl sulphate was the most effective compound of those tested in normalizing blood glucose levels. However, the results here reported suggest that chronic administration of vanadyl or vanadate in the drinking water is not a viable alternative treatment to insulin in human diabetes.     

Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats

The antihyperglycemic action of myricetin, purified from the aerial part of Abelmoschus moschatus (Malvaceae), was investigated in streptozotocin-induced diabetic rats (STZ-diabetic rats). Bolus intravenous injection of myricetin decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats. Myricetin at the effective dose (1.0 mg/kg) significantly attenuated the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. A stimulatory effect of myricetin on glucose uptake of the soleus muscles isolated from STZ-diabetic rats was obtained in a concentration-dependent manner from 0.01 to 10.0 micromol/L. The increase of glucose utilization by myricetin was further characterized using the enhancement of glycogen synthesis in isolated hepatocytes of STZ-diabetic rats. These results suggest that myricetin has an ability to enhance glucose utilization to lower plasma glucose in diabetic rats lacking insulin.     

Effects of streptozotocin-induced diabetes on xylazine-ketamine anesthesia

The effects of streptozotocin-induced diabetes and insulin on the duration of xylazine-ketamine anesthesia were studied in rats. The duration of anesthesia was significantly reduced in diabetic group as compared to control group. In contrast, the duration of anesthesia in insulin-treated non-diabetic group was not significantly different from control group. The plasma glucose level in control group was increased significantly during and upon recovery from anesthesia as compared to pre-anesthetic levels. The plasma glucose level in diabetic group was not changed during anesthesia; however, it was reduced significantly upon recovery. The plasma glucose level was significantly reduced in insulin-treated group as compared to pre-anesthetic levels. The reduction in duration of anesthesia in diabetic rats is possibly due to enhanced metabolism xylazine and/or ketamine and is independent of plasma glucose level.     

D-chiro-inositol found in Cucurbita ficifolia (Cucurbitaceae) fruit extracts plays the hypoglycaemic role in streptozocin-diabetic rats

Cucurbita ficifolia is commonly used as an antihyperglycaemic agent in Asia. However, the mechanism of its action is unknown. Chemically synthesized D-chiro-inositol (D-CI), a component of an insulin mediator, has been demonstrated to have antihyperglycaemic effects in rats. In this study, we found that C. ficifolia contained fairly high levels of D-CI, thus, C. ficifolia may be a natural source of D-CI for reducing blood glucose concentrations in diabetics. We evaluated C. ficifolia fruit extract, containing D-CI, for its antihyperglycaemic effect in streptozotocin-induced diabetic rats. Oral administration of C. ficifolia fruit extract containing 10 or 20 mg D-CI kg(-1) body weight for 30 days resulted in significantly lowered levels of blood glucose, and increased levels of hepatic glycogen, total haemoglobin and plasma insulin. An oral glucose tolerance test was performed in fasted diabetic and normal rats, in which there was a significant improvement in blood glucose tolerance in the diabetic rats treated with C. ficifolia fruit extract. The effects were compared with 20 mg kg(-1) body weight chemically synthesized D-CI. Findings from this study demonstrated that C. ficifolia fruit extract was an effective source of D-CI for its hypoglycaemic effects in rats, and therefore may be useful in the treatment of diabetes.     

Streptozotocin- and Alloxan-Induced Diabetes Modifies Total Plasma and Lipoprotein Lipid Concentration and Composition without Altering Cholesteryl Ester Transfer Activity

Abstract: The objectives of this study were to determine the total plasma and lipoprotein lipid concentration and composition and cholesteryl ester transfer activity in two diabetic animal models (alloxan-induced diabetes in rabbits and streptozotocin-induced diabetes in rats). Furthermore, we wanted to determine if the severity of diabetes influences lipoprotein lipid profiles and cholesteryl ester transfer activity. Rats and rabbits were randomly divided into non-diabetic and diabetic groups. Rats were administered either 55 mg/kg or 100 mg/kg of streptozotocin intravenously through the tail vein, while rabbits were administered 100 mg/kg or 200 mg/kg of alloxan intravenously through the marginal ear vein under light anesthesia. Hyperglycaemia was tested for at 48 hr following the doses. Total and lipoprotein cholesterol and triglyceride concentrations using enzymatic kits and cholesteryl ester transfer activity from low-density lipoproteins to high-density lipoproteins using ³H-cholesteryl ester incorporated into low-density lipoproteins were determined. Elevations in both total and lipoprotein cholesterol and triglyceride concentrations and alterations in lipoprotein lipid composition are observed following the onset of drug-induced diabetes in rats and rabbits compared to non-diabetics. However, these findings were observed only in animals administered the higher streptozotocin and alloxan dose. Furthermore, cholesteryl ester transfer from low-density lipoproteins to high-density lipoproteins is not significantly different in drug-induced diabetic compared to non-diabetic rats and rabbits, regardless of which streptozotocin and alloxan dose was used. These findings suggest that difference in lipoprotein lipid concentration and composition as a result of drug-induced diabetes is independent of cholesteryl ester transfer activity in both rats and rabbits. Furthermore, diabetic severity may influence lipoprotein metabolism in these animal models.