Sham-operated Diabetic Rats Research Articles

Evidence that chronic administration of 17β-oestradiol decreases the vasopressor responses to adrenergic system stimulation in streptozotocin-diabetic female rats

In vitro studies have indicated that 17β-oestradiol exerts beneficial effects on the cardiovascular system by activating the nitric oxide pathway. However, these effects have not been demonstrated in vivo in the systemic vasculature of rats made diabetic through streptozotocin induction. Therefore, the goal of this study was to determine the effect of 17β-oestradiol on vasopressor responses induced by sympathetic stimulation or i.v. injections of noradrenaline, methoxamine and B-HT 933 in sham-operated or ovariectomised, diabetic or non-diabetic female rats. Thus, rats were ovariectomised or sham-operated for this experiment. One week later, the animals were treated with streptozotocin (60mg/kg, i.p.) or its vehicle. Two weeks later, these rats were treated daily with 17β-oestradiol (10μg/kg, s.c.) or its vehicle for five weeks. Next, under anaesthesia, the animals were pithed and prepared for blood pressure and heart rate measurements. 17β-oestradiol failed to modify the vasopressor responses to (i) sympathetic stimulation, noradrenaline, methoxamine or B-HT 933 in sham-operated non-diabetic rats; (ii) sympathetic stimulation or B-HT 933 in sham-operated diabetic rats; (iii) noradrenaline or methoxamine in ovariectomised non-diabetic rats. In contrast, 17β-oestradiol significantly decreased the vasopressor responses to (i) noradrenaline and methoxamine in sham-operated diabetic rats; (ii) sympathetic stimulation or B-HT 933 in ovariectomised non-diabetic rats; and (iii) sympathetic stimulation, noradrenaline, methoxamine or B-HT 933 in ovariectomised diabetic rats. These results suggest that chronic administration of 17β-oestradiol decreases the vasopressor responses to adrenergic system stimulation in streptozotocin-induced diabetic rats. This report describes the first in vivo study reporting this effect of 17β-oestradiol in diabetes.

The protective role of hydrogen sulfide in myocardial ischemia–reperfusion-induced injury in diabetic rats

BackgroundHydrogen sulfide (H2S) displays anti-inflammatory and cytoprotective activities to attenuate myocardial ischemia–reperfusion (MIR)-induced injury, but its role in MIR in diabetics is not known. This study was undertaken to investigate whether H2S plays a protective role in MIR in diabetic rats. MethodsDiabetes was induced by streptozocin in Wistar rats, which were subjected to myocardial ischemia by blocking the left circumflex artery for 30min, followed by 2h reperfusion. dl-propargylglycine (PAG) and sodium hydrosulfide (NaHS) were administered to the rats to investigate their effects on severity of MIR-induced injury. ResultsDiabetic rats had smaller myocardial infarct sizes and higher serum levels of H2S (both P<0.05) than non-diabetics when they underwent MIR. MIR significantly increased the serum level of H2S (49.5±7.1μM), H2S-synthesizing activity (7.4±1.6nmol/mg) and the myocardial infarct size (44.0±7.2%), compared with sham-operated diabetic rats (21.7±2.1μM, 0.15±0.4nmol/mg and 1.2±0.4%, respectively). Administration of NaHS increased the H2S level (65.8±6.9μM) and had little effect on H2S production activity (6.5±2.2nmol/mg), while PAG reduced both the H2S level (29.2±5.0μM) and H2S-synthesizing activity (2.2±1.8nmol/mg). NaHS significantly reduced the myocardial infarct size (31.2±4.7%), inhibited the production of lipid peroxidation, MPO activity, and cell apoptosis, and downregulated expression of caspase-3, Fas, FasL, and TNF-α, which had been elevated by MIR, while PAG further increased the myocardial infarct size (58.3±5.9%), and displayed opposite effects. ConclusionsThe study indicates that H2S may play a protective role in MIR-induced myocardial injury in diabetics by its anti-apoptotic, anti-oxidative and anti-inflammatory activities.

Early Improvement of Glucose Tolerance after Ileal Transposition in a Non-obese Type 2 Diabetes Rat Model

Surgical operations which shorten the intestinal tract between the stomach and the terminal ileum result in an early improvement in type 2 diabetes, and one possible explanation is the arrival of undigested food in the terminal ileum. This study was designed to evaluate the role of the distal ileum in the improvement of glucose control in type 2 diabetic patients who underwent bariatric surgery. An ileal transposition (IT) to the jejunum was performed in lean diabetic Goto-Kakizaki (GK) rats. The IT was compared to sham-operated diabetic rats and a control group of diabetic rats. Non-diabetic controls were age-matched Sprague-Dawley (SD) rats, which underwent IT and no operation. Food intake and body weight were measured. An oral glucose tolerance test (OGTT) was performed 10 days before the operation and 10 days, 30 days and 45 days after the surgery. GLP-1 and insulin were measured during the OGTT 45 days after surgery. An insulin tolerance test (ITT) was performed 50 days after surgery. Glucose tolerance improved in the IT diabetic group compared with both the sham-operated animals and control diabetic group 30 days and 45 days after surgery (P=0.029 and P=0.023, respectively). Insulin sensitivity, as measured by an ITT, was not significantly different between diabetic groups and the normal groups respectively after surgery. No differences in basal glucose and glucose tolerance were noted between non-diabetic operated animals and control non-diabetic rats. No differences were recorded between the diabetic rat groups and the non-diabetic rats in terms of weight and food intake. GLP-1 levels were significantly higher in the IT diabetic group compared with the sham-operated rats (P=0.05). Ileal transposition is effective in inducing an improvement in glucose tolerance in lean diabetic rats without affecting weight and food intake. The possible mechanism underlying the early improvement of diabetes after bariatric surgery may be due to the action of the terminal ileum through an insulin-independent action.

Effects of Streptozotocin-Induced Hyperglycemia on Brain Damage Following Transient Ischemia

Hyperglycemia is known to aggravate ischemic brain damage. The present experiments were undertaken to explore whether hyperglycemia caused by streptozotocin-induced diabetes exacerbates brain damage following transient brain ischemia as it does in animals acutely infused with glucose. Experimental diabetes was induced by injection of streptozotocin in rats which were subjected to 10 min of forebrain ischemia either 1 week (1-wk) or 4 weeks (4-wk) after the induction of diabetes. Normoglycemic rats exposed to the same duration of ischemia and sham-operated diabetic rats served as controls. The animals underwent evaluation of clinical outcome and histopathological analysis of brain damage. Postischemic seizures developed in 35.3 and 42.1% of 1-wk and 4-wk diabetic hyperglycemic animals, respectively. The incidence of seizure was not different between the two groups. None of the diabetic animals with plasma glucose concentrations below 12 mM exhibited seizure activity. The extent and distribution of brain damage were similar between 1- and 4-wk diabetic animals. In the CA1 and in the subicular regions of hippocampus, both diabetic hyperglycemic and normoglycemic animals showed 70–80% cell death. Diabetic hyperglycemic animals had more severe neuronal necrosis in the parietal cortex than normoglycemic animals. In diabetic hyperglycemic animals, neuronal damage involved additional brain structures, e.g., cingulate cortex, thalamus nuclei, substantia nigra, pars reticulata, and the hippocampal CA3 sector, i.e., structures in which neurons were not affected in normoglycemic ischemic subjects at this duration of ischemia. These findings demonstrate that diabetic hyperglycemic animals frequently develop postischemic seizures and that streptozotocin-induced hyperglycemia results in exacerbated postischemic brain damage of the same density and distribution as in acutely glucose-infused animals.

Cardiovascular responses and central catecholamines in streptozocin-diabetic rats

Brain catecholamine levels, spinal cord levels of the norepinephrine metabolite methoxy-hydroxy-phenylglycol (MHPG), and heart rate were measured in nondiabetic and streptozocin-diabetic rats after sham surgery or bilateral carotid ligation. Although carotid ligation increased heart rate in both diabetic and nondiabetic rats, in diabetic animals the response did not differ from the response to sham surgery. Carotid ligation increased epinephrine concentrations in the medulla/pons of diabetic animals but was not associated with alterations in other central catecholamines. In all diabetic rats spinal ratios of MHPG/norepinephrine (an index of noradrenergic activity) were higher than in nondiabetics, and the change in heart rate (post-surgical-pre-surgical rate) correlated inversely with hypothalamic dopamine (R = -0.60). In sham-operated diabetic rats there were high inverse correlations of the change in heart rate with medullary epinephrine and of pre- and post-surgical heart rate with spinal MHPG/NE (R = -0.87 to -0.95). Central catecholamines and heart rate were not correlated in nondiabetic animals and correlated only weakly when nondiabetic and diabetic animals were pooled. Correlations in diabetic animals were usually abolished or reduced by carotid ligation. These findings suggest a link between central catecholamines and heart rate in diabetic rats subjected to surgical stress. Whether catecholaminergic neurons contribute to abnormal chronotropic responses in diabetic rats or respond to stimuli that affect both heart rate and neural function remains to be determined.

Medialbasal hypothalamic deafferentation modulates feeding response to insulin in rats

Medialbasal hypothalamic (MBH) deafferentation induces hypothalamic obesity accompanied by hyperphagia and hyperinsulinemia. Insulin is essential in developing and maintaining obesity, but the role of insulin in food intake in hypothalamic obesity is still unclear. The present study demonstrated that exogenous insulin increased food intake dose relatedly in MBH deafferented diabetic rats without developing hypoglycemia. Insulin administrations suppressed hyperphagia in the sham-operated diabetic rats. In contrast, in the MBH deafferented diabetic rats, insulin increased food intake in sow-related manner concomitant with a greater increased body weight gain than the sham-operated diabetic rats. The blood glucose levels of the MBH deafferented diabetic rats were at all time higher than those of the sham-operated diabetic rats and were hyperglycemic throughout the insulin treatment. These data indicate that insulin action on food intake mediated through the central nervous system is modulated by MBH deafferentation. This modulated insulin action may contribute to the pathogenesis on obesity in MBH deafferented animals.

Effects of diabetes on glucose oxidation in rat aorta after hypophysectomy and adrenalectomy.

The influence of diabetes, hypophysectomy and adrenalectomy on glucose oxidation in rat aorta was studied. Diabetes was induced in normal, adrenalectomized and hypophysectomized-cortisone substituted rats by streptozotocin (65 mg/kg body weight). The oxidation of glucose to CO2 was determined during incubation of rat aorta in vitro for 2-3 hours. The aortic glucose oxidation was reduced after hypophysectomy but was unaffected by adrenalectomy. After streptozotocin treatment the rise in blood glucose concentration was similar in normal, adrenalectomized and hypophysectomized-cortisone substituted rats. In shamoperated diabetic rats the aortic glucose oxidation was reduced after a diabetes duration of 4 days. In adrenalectomized diabetic rats the aortic glucose oxidation was not significantly affected after 4 days but was reduced after a diabetes duration of 14 days. When adrenalectomized diabetic rats were treated with hydrocortisone the aortic glucose oxidation was reduced after diabetes for 4 days. After incubation of normal rat aorta in vitro for 6 hours with cortisol (1 microgram/ml) in the incubation medium a decrease in the aortic glucose oxidation was found. Incubation of aorta with only growth hormone had no effect. These results suggest that cortisol is of importance for the lowered glucose oxidation in diabetic rat aorta.