Effect Of Streptozotocin Diabetes Research Articles

The effect of streptozotocin-diabetes on β-endorphin level and proopiomelanocortin gene expression in the rat pituitary

Streptozotocin-induced diabetes for 4 weeks resulted in a decrease in proopiomelanocortin (POMC) mRNA in both the anterior lobe (AL) and the neuro-intermediate lobe (NIL) of the rat pituitary. The β-endorphin levels decreased in the NIL but not in the AL. It is concluded that the synthesis of POMC in the pituitary is inhibited in diabetic rats and that there is a decrease in β-endorphin release from the anterior pituitary.

Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse

Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse

Effect of streptozotocin-diabetes on knee joint inflammation-induced changes in substance P and nerve growth factor in the rat

Given the involvement of the sensory nervous system in the aetiology of neurogenic inflammation, we have investigated the effect of experimental diabetes and any associated sensory nerve dysfunction on the development of complete Freund's adjuvant-induced inflammation in the rat knee. Twenty-four hours after induction of inflammation in non-diabetic rats, γ-preprotachykinin mRNA expression was increased in the L 4/L 5 dorsal root ganglia. Substance P levels were increased in dorsal root ganglia and sciatic nerve whilst synovial levels of substance P were significantly decreased. Nerve growth factor, which regulates expression of γ-preprotachykinin mRNA, was significantly increased in synovium and sciatic nerve after induction of inflammation. After 24 weeks of streptozotocin-diabetes, there was a non-significant reduction in γ-preprotachykinin mRNA expression whilst substance P levels in dorsal root ganglia, sciatic nerve and synovium and nerve growth factor levels in the sciatic nerve were significantly decreased. Conversely, synovial levels of nerve growth factor were significantly increased. Injection of complete Freund's adjuvant into the knee of diabetic rats produced diminished joint swelling compared to that observed in non-diabetic rats. Substance P levels were unaltered compared to non-arthritic diabetic rats whilst nerve growth factor levels were significantly increased in synovium and sciatic nerve suggesting an uncoupling of substance P from nerve growth factor control in the inflammatory response in diabetic rats. The results show a significant reduction in the inflammatory response in rats with chronic streptozotocin-diabetes. Deficits in γ-preprotachykinin mRNA expression and substance P and the altered levels of nerve growth factor indicate sensory neuronal dysfunction may play a major role in this abnormal response.

Differential effects of diabetes and glomerulonephritis on glomerular basement membrane composition.

The hallmark of renal diseases involving the glomerulus is the presence of proteinuria. While the routes of pathogenesis of proteinuria have not been established, alterations in the barrier function of the glomerular basement membrane (GBM) have been implicated. We evaluated the effect of streptozotocin diabetes and passive Heymann nephritis (PHN) over time on the macromolecular composition of rat GBM to determine if changes in composition correlate with proteinuria. Six to twelve rats from each group (control, diabetic, and PHN) were sacrificed 1, 5, 28, 56, or 84 days after induction of disease. Identical amounts of GBM were subjected to a sequential extraction procedure, and type IV collagen, entactin, laminin, fibronectin, and anionic charge content were quantitated in the extracts. Type IV collagen and entactin content did not change with time or disease. Both laminin and fibronectin contents increased with time in GBM in all groups, but this increase was significantly greater in diabetic GBM. A significant decrease in anionic charge content of GBM coincided with the onset of albuminuria at Day 28 in diabetes, but no change was seen in PHN. In diabetic rats, the increase in laminin content over control preceded the onset of albuminuria, while the increase in fibronectin was not apparent until after albuminuria was present. In PHN, no differences in type IV collagen, entactin, laminin, fibronectin, or anionic charge content of GBM were found compared with control, even though profound albuminuria was evident from Day 5 through 84. Thus, while alterations in laminin and fibronectin content may contribute to the loss of glomerular permselectivity in streptozotocin diabetes, such changes apparently are not involved in PHN.

Effect of streptozotocin diabetes on polysomal aggregation and protein synthesis rate in the liver of pregnant rats and their offspring.

To study the effect of diabetes on hepatic protein synthesis and polysomal aggregation in pregnant rats, female rats were treated with streptozotocin prior to conception. Some animals were mated, and studied at day 20 of pregnancy, whereas, others were studied in parallel under non pregnant conditions. The protein synthesis rate measured with an "in vitro" cell-free system was higher in pregnant than in virgin control rats. It decreased with diabetes in both groups, although values remained higher in diabetic pregnant rats than in the virgin animals. The fetuses of diabetic rats had a lower protein synthesis rate than those from controls, although they showed a higher protein synthesis rate than either their respective mothers or virgin rats. Liver RNA concentration was higher in control and diabetic, pregnant rats than in virgin rats, and the effect of diabetes decreasing this parameter was only significant for pregnant rats. Liver RNA concentration in fetuses was lower than in their mothers, and did not differ between control and diabetic animals. The decreased protein synthesis found in diabetic animals was accompanied by disaggregation of heavy polysomes into lighter species, indicating an impairment in peptide-chain initiation.

Effect of streptozotocin diabetes on development of nitrosamine-induced pancreatic carcinoma when diabetes induction occurs after nitrosamine exposure.

Diabetes mellitus has been suggested as a possible risk factor for the development of pancreatic cancer in humans. Previous studies in our laboratory have shown, however, that streptozotocin (STZ) diabetes inhibits the development of cancer of the exocrine pancreas in hamsters when STZ is administered prior to treatment with the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP). It has been reported by others that the concurrent administration of BOP and STZ enhances pancreatic carcinogenesis in hamsters. The purpose of the present study was to determine the effect of STZ diabetes on the development of BOP-induced pancreatic carcinoma when STZ is given following exposure to BOP. Groups of Syrian golden hamsters were treated with either BOP only (single s.c. injection, 40 mg/kg body wt at week 0), BOP (single s.c. injection, 40 mg/kg body wt at week 0) plus STZ (50 mg/kg body wt x3 daily i.p. doses at weeks 10, 20 or 30), STZ only (50 mg/kg body wt x3 daily i.p. doses at weeks 10, 20 or 30), or neither BOP nor STZ. The experiment was terminated at 40 weeks after BOP treatment. No significant difference was seen in the incidence of pancreatic cancer between those animals receiving BOP only at week 0 and those receiving BOP at week 0 plus STZ at weeks 10, 20 or 30 of the study. The results would appear to indicate that STZ diabetes, established after BOP tumor initiation, plays no apparent role in the modulation of pancreatic carcinogenesis.

Effect of streptozotocin diabetes on motor and inhibitory transmission in rat anococcygeus.

The effect of streptozotocin diabetes of 4-week duration on the adrenergic motor transmission and on the nonadrenergic, noncholinergic, inhibitory transmission in the rat anococcygeus was investigated by recording contractile and relaxant activity of isolated muscle preparations taken from diabetic and age-matched control animals. The neurogenic contractile responses to electrical field stimulation were significantly reduced in the preparations from diabetic rats. The inhibitory transmission remained unaffected in the diabetic rats. Concentration--response curves showed no change in sensitivity of the diabetic anococcygei to noradrenaline. The maximum tension generated was also similar in preparations from diabetic and nondiabetic animals. The contractile responses to electrical field stimulation were significantly greater in preparations from diabetic rats treated for 4 weeks with either sorbinil (20 mg.kg-1.day-1 orally) or myo-inositol (667 mg.kg-1.day-1 orally) when compared with the untreated diabetic controls; the sensitivity to noradrenaline was identical in all three groups. It is concluded that streptozotocin diabetes causes a significant reduction of adrenergic contractile responses of the anococcygeus to electrical field stimulation by a prejunctional mechanism, and the reduction can be prevented by treating the animals with the aldose reductase inhibitor sorbinil or with myo-inositol.

The effect of streptozotocin diabetes on the vasoactive intestinal peptide receptor/effector system in membranes from rat ventral prostate.

All of the components of the neuropeptide vasoactive intestinal peptide (VIP) signal transduction system were underexpressed in rat prostatic membranes 6 weeks after streptozotocin-induced diabetes. Binding studies with [125I]VIP showed decreases of 86% and 62% in the binding capacity of the high and low affinity classes of VIP receptors in diabetes. Affinity labeling experiments indicated that the main form of VIP receptor was 51 kilodaltons in control rats and 45 kilodaltons in diabetic animals. The efficacy of VIP and forskolin in stimulation of adenylyl cyclase activity as well as the potentiating effect of GTP on VIP action were also reduced in diabetes, as was the expression of the alpha-subunit of the guanine nucleotide-binding regulatory proteins Gs and Gi (studied by ADP ribosylation with cholera and pertussis toxins). Gi function was lost in diabetes, as assessed with experiments on guanyl-5'-yl-imidodiphosphate potentiation of forskolin activity. These disturbances together with previous findings argue for VIP playing a role in the diabetic neuropathy of the genitourinary tract.

The effect of streptozotocin diabetes on the vasoactive intestinal peptide receptor/effector system in membranes from rat ventral prostate

All of the components of the neuropeptide vasoactive intestinal peptide (VIP) signal transduction system were underexpressed in rat prostatic membranes 6 weeks after streptozotocin-induced diabetes. Binding studies with [125I]VIP showed decreases of 86% and 62% in the binding capacity of the high and low affinity classes of VIP receptors in diabetes. Affinity labeling experiments indicated that the main form of VIP receptor was 51 kilodaltons in control rats and 45 kilodaltons in diabetic animals. The efficacy of VIP and forskolin in stimulation of adenylyl cyclase activity as well as the potentiating effect of GTP on VIP action were also reduced in diabetes, as was the expression of the alpha-subunit of the guanine nucleotide-binding regulatory proteins Gs and Gi (studied by ADP ribosylation with cholera and pertussis toxins). Gi function was lost in diabetes, as assessed with experiments on guanyl-5'-yl-imidodiphosphate potentiation of forskolin activity. These disturbances together with previous findings argue for VIP playing a role in the diabetic neuropathy of the genitourinary tract.

Effect of streptozotocin diabetes on the glycolytic flux and on fructose 2,6-bisphosphate levels in isolated rat enterocytes

In epithelial cells isolated from rat small intestine and incubated in the presence of 1 mM glucose, streptozotocin-induced diabetes reduced, by 46 and 29%, respectively, the rates of both glucose utilization and L-lactate formation. These effects were accompanied by a significant decrease of enterocyte fructose 2,6-bisphosphate concentration (about 50%) and of the glycolytic flux through the reaction catalyzed by 6-phosphofructo 1-kinase. The diminution of enterocyte fructose 2,6-bisphosphate levels caused by diabetes occurred in spite of an increase of hexose 6-phosphate concentration, and was associated with a reduction in the amount of active form of 6-phosphofructo 2-kinase; total activity of this enzyme was not significantly modified. Diabetes also caused an acceleration in the rate of 3-0-methyl-D-( 14C) glucose uptake and increased hexokinase activity in enterocytes. Lactate dehydrogenase, pyruvate kinase and 6-phosphofructo 1-kinase activities were not found to be significantly different in epithelial cells isolated from control or diabetic animals. Our results indicate that a reduction of the glycolytic flux in enterocytes could collaborate to increase intestinal glucose absorption in the diabetic state.

Effect of streptozotocin diabetes and insulin replacement on growth hormone in rats.

The effects of insulin deprivation on the growth rate, plasma and pituitary growth hormone (GH) and GH synthesis were investigated in male Wistar rats. Diabetes was induced by administration of streptozotocin (STZ), 7 mg/100 g bw, and plasma and pituitary GH levels were measured by means of a specific radioimmunoassay. GH synthesis was determined in pituitaries by the in vitro incorporation of [3H] leucine into specific immunoprecipitates. The body weight and the pituitary GH content of normally developing rats showed an almost linear increase throughout the observation period, whereas diabetic rats stopped growing immediately after receiving STZ, and remained smaller than age-paired controls. Pituitary GH content remained within the control range through the 5 days following STZ administration and thereafter decreased reaching 10% of control values by the 30th day. Furthermore, pituitaries from diabetic rats incorporated [3H] leucine into r-GH at a greatly reduced rate, which could explain the diminished r-GH storage in pituitaries of diabetic rats. Plasma GH concentrations remained within the normal range for 10 days after STZ, thereafter plasma GH were markedly reduced. Insulin treatment prevented the metabolic changes, and restored normal levels of plasma and pituitary GH in diabetic rats. These findings indicate that diabetes, in rat, is characterized by an inhibitory effect on GH secretion, probably via a diminished GH synthesis by the pituitary gland.

The effect of streptozotocin diabetes on insulin binding by isolated rat kidney tubules

Preparations of kidney tubules were isolated from rat kidney cortex and were demonstrated to possess specific binding sites for insulin. The binding was time- and temperature-dependent and the label was displaced by bovine insulin, A 1-B 29 dodecoyl insulin, proinsulin and insulin A- and B-chains in proportion to their relative activity. Cell-associated degradation was studied by incubating tubules in the presence of fatty-acid-free albumin. The tubules showed high insulin-degrading activity, which was dependent on temperature, time and cell concentration. The number and affinity of insulin receptors on tubules isolated from kidneys taken from streptozotocin-diabetic rats was not significantly different from tubules isolated from untreated control or insulin-treated diabetic rats. Diabetes did not alter the kinetics of insulin degradation by the tubules. This lack of response by the tubules to changes in the concentration of circulating insulin supports the hypothesis that the kidneys do not play an active role in modulating the rate of insulin removal from the circulation.

Effect of streptozotocin-diabetes and insulin treatment on regulation of Leydig cell function in the rat.

The present study was performed to further clarify the possible role played by insulin deficiency on the steroidogenic capacity of the rat testis. Sprague-Dawley rats weighing 250-300 g were used in all experiments. Diabetes was induced by i.p. injection (40 mg/kg b.w.) of streptozotocin and was monitored at 2-day intervals by measuring body weight and serum glucose, glucosuria and ketonuria levels. The effect of insulin therapy on pituitary LH content and plasma LH concentrations, as well as on the cyclic AMP level in interstitial cell incubation medium and plasma testosterone concentrations, was measured 30 days after the induction of diabetes by radioimmunoassay. Streptozotocin-induced diabetes resulted in significantly reduced pituitary LH (16%, P less than 0.025) and plasma LH (34%, P less than 0.02); insulin treatment completely restored these levels. Similarly, the cyclic AMP content of interstitial cell incubation medium and the plasma testosterone concentrations were dramatically decreased in the diabetic state (50%, P less than 0.005 and 63%, P less than 0.025, respectively) and combined treatment with insulin plus hCG appeared slightly more effective than treatment with either of these hormones alone, suggesting a possible synergistic action. It is concluded that decreased testicular steroidogenesis in the diabetic rat may represent, at least in part, a direct consequence of insulin deficiency at the hypothalamic and/or pituitary levels. However, our findings would also be consistent with other reports suggesting that insulin may play a direct role in the rat testis.

Acute insulin treatment normalizes the resistance to the cardiotoxic effect of isoproterenol in streptozotocin diabetic rats. A morphometric study of isoproterenol induced myocardial fibrosis.

The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the cardiotoxic effect of high doses of isoproterenol (ISO) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood glucose after insulin treatment appeared. The myocardial content of catecholamines was estimated in these 8 day diabetic rats. The norepinephrine content was significantly increased while epinephrine remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this catecholamine resistance. The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the ISO resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in diabetic rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients.

Ovarian dysfunction in streptozotocin-induced diabetic rats.

The effect of streptozotocin diabetes on some ovarian functions in adult rats was examined. Diabetic diestrus animals showed reduced ovary weight and lower circulating levels of progesterone. Scatchard plots of binding data derived from ovarian particulate fractions of normal and streptozotocin diabetic rats revealed the presence of one class of binding sites with high affinity for 125I-hCG. The apparent association constant of the hCG receptors of diabetic ovaries was comparable to that of normal gonads. However, a marked decrease (42%) in the number of hCG binding sites was found in diabetic animals. With isolated luteal cells similar results were obtained, and the administration of insulin to streptozotocin diabetic rats restored to normality the number of hCG binding sites. The maximal response of progesterone production by luteal cells from control ovaries was obtained with 10(-10) M hCG. A 100-fold higher concentration of hCG was required for the maximum stimulation of cAMP synthesis. The cAMP response of cells from diabetic rats was significantly higher than that of control cells. However, luteal cells from diabetic rats showed some loss of sensitivity in the synthesis of progesterone during incubation with hCG. Most of the alterations seen in diabetic female rats could be restored with insulin therapy, indicating that insulin plays an important role in the regulation and maintenance of normal reproductive functions. It is suggested that the diminution of the LH receptor population causes the disruption of normal luteal cell function. This fact could be responsible for some of the reproductive alterations in the diabetic female rat.

Effect of streptozotocin diabetes on tissue ascorbic acid and dehydroascorbic acid.

Effect of streptozotocin diabetes on tissue ascorbic acid and dehydroascorbic acid.

Effect of Streptozotocin Diabetes on the Pituitary-Testicular Axis in the Rat

Correction to: Effect of Streptozotocin Diabetes on the Pituitary-Testicular Axis in the RatHorm Metab Res 1982; 14(09): 479-482DOI: 10.1055/s-2007-1019052

Effect of streptozotocin diabetes on the pituitary-testicular axis in the rat.

The pituitary-testicular axis was investigated in the streptozotocin diabetic male rat to determine the relationship between hormonal alterations and steroidogenic activity. Male Sprague-Dawley rats weighing 250-300 g were used in all experiments. Diabetes was induced by intraperitoneal injection (40 mg/kg body wt.) of streptozotocin and they were studied with non-diabetic controls. The observations on these animals were compared to those from diabetic rats treated with 1-5 IU protamine zinc insulin. Steroidogenic activity was determined by measuring the per cent of [4-14C]-cholesterol converted to [4-14C]-pregnenolone and [4-14C]-progesterone. Plasma concentrations of LH, FSH and prolactin were measured by RIA. Streptozotocin induced diabetes resulted in significantly reduced plasma LH (34%, p less than 0.20) and prolactin (53%, p less than 0.001) but did not modify FSH concentrations. Insulin treatment completely and partially restored abnormal LH and prolactin release. The activity of the enzyme cleaving the side-chain of cholesterol (rate limiting step in steroidogenesis) was considerably reduced in the diabetic state (59%, p less than 0.002) and insulin treatment restored it to even supranormal levels (not significant). Our findings suggest that insulin may play a physiological and differential role in regulating the secretory activity of the anterior pituitary. The insulin is needed for normal LH and prolactin release and Leydig cells function but its role in FSH release and Sertoli cells function is not clear.

Effect of streptozotocin diabetes on some urea cycle enzymes

Streptozotocin induced diabetes in rats increased the activities of the three mitochondrial enzymes, carbamylphosphate synthetase, ornithine transcarbamylase and N-acetylglutamate synthetase, but not of the cytosolic N-acetylglutamate deacylase. Levels of both N-acetylglutamate and arginine, which are activators of carbamylphosphate synthetase and N-acetylglutamate synthetase respectively, increased in diabetes. These results serve to explain the increase both of mitochondrial citrulline and urea formation in hepatocytes and the increased urea excretion in diabetes.

Effect of streptozotocin diabetes on the hypothalamic-pituitary-thyroid axis in the rat.

Studies of the hypothalamic-pituitary-thyroid axis have been performed in streptozotocin (STZ)-diabetic Wistar rats and their controls. Plasma PBI concentration, plasma and pituitary TSH, contents, and hypothalamic TRH content were measured by RIA in basal and stimulated conditions. Compared to controls, rats made diabetic by 6.0 or 7.5 mg STZ/100 g BW showed decreased plasma PBI and TSH and diminished pituitary TSH content, with greater alterations in rats receiving the highest STZ dose. Both diabetic groups showed an almost 50% reduction of hypothalamic TRH content in comparison with the mean control value. After thyroidectomy, pituitary TSH secretion increased in diabetic, ad libitum fed, and semistarved animals, but it was lower in the diabetic group in which the reduction in plasma PBI was similar or greater. To evaluate pituitary sensitivity to the inhibitory action of L-T4 on TSH secretion in diabetes, thyroidectomized control (Thx-C), thyroidectomized diabetic (Thx-D), and thyroidectomized semistarved (Thx-S) rats were injected twice daily for 7 days with either saline or a fractional L-T4 dose of 0.25, 0.50, or 1.00 microgram/100 microgram/100 g BW. In Thx-D rats, a daily dose of 1.00 microgram L-T4 was sufficient to normalize pituitary TSH secretion, while a dose of 2.00 microgram was required to induce a similar effect in the Thx-C and Thx-S animals. Pituitary TSH content was increased in the Thx-C group with increasing T4 doses. No modification in this parameter was seen in the Thx-D and Thx-S animals. The fact that diabetes caused a reduction in the hypothalamic TRH content indicates that the primary cause of pituitary-thyroid alterations in STZ-diabetic rats lies in the hypothalamus, although the metabolic imbalance induced by diabetes and, in less degree, by undernutrition could also be partly responsible for some of the described modifications.