Effects Of Streptozotocin Treatment Research Articles

Treatment with Streptozotocin (STZ) causes hypoglycemia and alters the stability of reference genes for real‐time PCR analysis in the liver of channel catfish

Genetically selected channel catfish for increased growth often develops phenotype similar to human obesity, suggesting that channel catfish may be a model organism to investigate human metabolic disorders. Streptozotocin (STZ) treatment induces hyperglycemia in mammals and some fish species. However, the effects of STZ treatment on blood glucose level as well as other physiological parameters in channel catfish have never been examined in detail. In this study, we tested the hypothesis that treatment with STZ affects body weight, blood glucose level, and hepatic expression of house‐keeping genes. Juvenile channel catfish (28.3 ± 2g) were treated with 0, 3.6, 36, 180, or 360 mg/kg STZ intraperitoneally on day 0 (n=4 fish/treatment). On day 7, blood glucose level was measured and blood, liver, muscle and brain samples were collected. Expression of five common housekeeping genes (beta‐macroglobulin, alpha‐tubulin, 18s ribosomal RNA, beta‐actin, and GAPDH) were measured using real‐time PCR. The weight of fish did not change between days 0 and 7 among all treatments. Blood glucose levels were lower in fish treated with 180 or 360 mg/kg STZ compared to fish treated with 0 mg/kg STZ. Treatment with STZ at higher doses altered expression of 4 housekeeping genes. Expression of beta‐macroglobulin, alpha‐tubulin, and beta‐actin mRNA was higher in fish treated with higher doses of STZ compared to 0 mg/kg STZ. In contrast, expression of GAPDH mRNA tended to be less in 360 mg/kg STZ than 0 mg/kg STZ. Expression of 18s rRNA was not affected by STZ treatment. Rather than causing hyperglycemia, treatment with high doses of STZ decreased blood glucose level in channel catfish, suggesting a difference in glucose metabolism exists between channel catfish and humans.Support or Funding InformationThis study is supported by APS IOSP fellowship program and Kansas Idea Network of Biomedical Research Excellence (P20GM10348).

Effects of streptozotocin on autoimmune diabetes in NOD mice.

Non-obese diabetic (NOD) mice develop autoimmunity that destroys their native beta cells causing diabetes. Their autoimmunity will also destroy syngeneic transplanted islets and transfer both autoimmunity and diabetes via spleen cells to non-diabetic mice. In this report, we studied the effects of streptozotocin (STZ) on the autoimmune diabetes in NOD mice. We transplanted NOD.SCID islets into three groups of NOD mice: (1) spontaneously diabetic NOD mice (NOD-sp.); (2) prediabetic NOD mice made diabetic by streptozotocin (NOD-stz); and (3) diabetic NOD mice also treated with streptozotocin (NOD-sp./stz). In the first group, the transplants were rejected within 3 weeks. In the second and third groups, the transplants survived indefinitely. Alloxan, a drug similar to streptozotocin, did not have the same effect as streptozotocin. The ability of streptozotocin to prevent diabetes in young NOD mice was reversed by anti-CD8 antibody treatment but not by anti-CD4 treatment. Streptozotocin also made spleen cells from diabetic NOD mice less effective transferring diabetes. These results indicate that streptozotocin treatment both prevents and reverses the islet destructive autoimmunity in NOD mice. We postulate that the effects of streptozotocin treatment may be mediated in part by regulatory T cells.

Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice.

To investigate GH's role in diabetic end organ damage, experimental diabetes was induced with streptozotocin (STZ) in bovine GH (bGH) or bGH antagonist transgenic mice and in their nontransgenic (NTG) litter mates. Body growth, blood glucose, serum insulin-like growth factor-I levels, liver GH receptor (GHR) binding, and kidney histology of these animals were evaluated. After administration of multiple low doses of STZ, 90% of the mice developed hyperglycemia. The diabetic animals, especially those expressing GH and GH antagonist transgenes, demonstrated retarded body growth and reduced insulin-like growth factor-I levels when compared with their nondiabetic litter mates. Kidney histology revealed severe glomerulosclerosis in diabetic and nondiabetic bGH transgenic mice. Diabetic NTG mice exhibited moderate kidney lesions. Diabetic bGH antagonist transgenic mice possessed normal glomeruli indistinguishable from those seen in nondiabetic NTG mice. GHR-binding assays revealed that liver GHR-binding sites were significantly reduced in diabetic NTG mice and transgenic dwarf mice when compared with their nondiabetic controls. Conversely, liver GHR-binding ability was significantly increased in bGH transgenic mice as compared with their NTG littermates and remained high during diabetes. It is concluded that transgenic mice that express a GH antagonist are protected from diabetes and or GH-induced nephropathy.

Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice

To investigate GH's role in diabetic end organ damage, experimental diabetes was induced with streptozotocin (STZ) in bovine GH (bGH) or bGH antagonist transgenic mice and in their nontransgenic (NTG) litter mates. Body growth, blood glucose, serum insulin-like growth factor-I levels, liver GH receptor (GHR) binding, and kidney histology of these animals were evaluated. After administration of multiple low doses of STZ, 90% of the mice developed hyperglycemia. The diabetic animals, especially those expressing GH and GH antagonist transgenes, demonstrated retarded body growth and reduced insulin-like growth factor-I levels when compared with their nondiabetic litter mates. Kidney histology revealed severe glomerulosclerosis in diabetic and nondiabetic bGH transgenic mice. Diabetic NTG mice exhibited moderate kidney lesions. Diabetic bGH antagonist transgenic mice possessed normal glomeruli indistinguishable from those seen in nondiabetic NTG mice. GHR-binding assays revealed that liver GHR-binding sites were significantly reduced in diabetic NTG mice and transgenic dwarf mice when compared with their nondiabetic controls. Conversely, liver GHR-binding ability was significantly increased in bGH transgenic mice as compared with their NTG littermates and remained high during diabetes. It is concluded that transgenic mice that express a GH antagonist are protected from diabetes and or GH-induced nephropathy.

Behavioral and biochemical effects of an ICV injection of streptozotocin in old Lewis rats

Intacerebroventricularly (ICV) injected streptozotocin (STREP) decreases central glucose metabolism and energy metabolism, which has also been observed in patients with dementia. In the present study we examined the behavioral (open-field behavior and two-way active avoidance learning) and biochemical (hippocampal ChAT activity) effects of STREP treatment in old Lewis rats. The results suggest that hippocampal function was affected by STREP. STREP-treated rats acquired the two-way active avoidance task faster than the control rats, which indicates that STREP treatment does not lead to a general learning deficit. Hippocampal ChAT activity was decreased in STREP-treated rats. The present results suggests also that susceptibility to STREP amy not be related to age in Lewis rats.

Mechanisms of up-regulation of the liver insulin receptor in chronically hypoinsulinemic rats: assessment of receptor endocytosis

Chronic hypoinsulinemic states in rodents are known to cause an increase in the number of insulin receptors at the hepatocyte surface. To assess whether this change results from a reduced endocytosis of the receptors, the effects of streptozotocin treatment and fasting on the number and the subcellular distribution of hepatic insulin receptors have been evaluated in the rat. In streptozotocin-treated rats, insulin receptor number was increased by 25–40% in plasma membrane and total cellular membrane fractions, and by 60–130% in the light Golgi-endosomal (GE) fraction. In contrast, receptor number was unaffected in the intermediate GE fraction and decreased by 25–35% in the heavy GE fraction. Such changes were detectable at 12 h in GE fractions and at 2 days in other subcellular fractions, and lasted for at least 8 days. Streptozotocin treatment also led to a 3- to 4-fold decrease in the insulin content of GE fractions, indicating reduced hormone endocytosis. Fasting for 16 h elicited changes in receptor and ligand concentration in cell fractions comparable to those induced by Streptozotocin. It is concluded that, although endocytosis of hepatic insulin receptors is reduced in chronic hypoinsulinemic states, changes in receptor synthesis and/or degradation also occur in these states.

Hypertensive Diabetic Rats: Different Effects of Streptozotocin Treatment on Blood Pressure in Adult SHR and in Neonatal SHR

The effect of streptozotocin (STZ) treatment on blood pressure in adult spontaneously hypertensive rats (SHR) was compared with that in neonatal SHR. Three-month-old SHR were intravenously given 10, 30 or 50 mg/kg of STZ. When STZ was given in adult SHR, weight loss, overt hyperglycemia and the reduction of blood pressure occurred dose dependently. Two-day-old pups from SHR were subcutaneously injected with 100 mg/kg of STZ. Neonatal STZ treatment did not attenuate the development of hypertension in SHR. Since neonatally STZ-treated SHR develop mild diabetic symptom with hypertension and develop mild diabetic glomerulosclerosis, they are a good model for studying vascular complications or other disorder relating to the synergism between hypertension and diabetes mellitus.

Glucose transport and metabolism in rat renal proximal tubules: multicomponent effects of insulin

Glucose transport and metabolism, and the effect of insulin thereon, was studied using suspensions of rat renal tubules enriched in the proximal component. (1) [U- 14C]Glucose oxidation is a saturable process ( K m 3.1 ± 0.2 mM; V max 14 ± 0.2 μmole 14CO 2 formed/g tissue protein per h.) Glucose oxidation and [ 14C]lactate formation from glucose are inhibited in part by phlorizin and phloretin: the data suggest that the rate-limiting entry of glucose into the cell metabolic pool occurs by both the Na-glucose cotransport system (at the brush border) and the equilibrating, phloretin-sensitive system (at the basal-lateral membrane). Raising external glucose from 5 to 30 mM markedly increases aerobic and anaerobic lactate formation. Gluconeogenesis from lactate is not affected by variations of glucose concentrations. (2) 24 h after streptozotocin administration, aerobic lactate formation is enhanced, as is the uptake of methyl α- d-glucoside by the tubules, while anaerobic glycolysis is depressed. Streptozotocin treatment (ST) increases both the K m and V max of glucose oxidation; gluconeogenesis and lactate oxidation are not affected. The effect of streptozotocin treatment on lactate formation are abolished by 1 mU/ml insulin. (3) Streptozotocin treatment increases tissue hexokinase activity, decreases glucose-6-phosphatase, but has no significant effect on fructose-1,6-diphosphatase, phospho enolpyruvate carboxykinase and pyruvate dehydrogenase. The data demonstrate fast streptozotocin-induced changes in cellular enzymes of carbohydrate metabolism. (4) The enhancing effect of streptozotocin on methyl α-glucoside uptake is transient: 8 days after administration of the agent, no significant difference from controls is found. (5) It is concluded that under the given experimental conditions insulin enhances the equilibrating glucose entry by the phloretin-sensitive pathway at the basal-lateral membrane, and transiently inhibits the Na-glucose cotransport system.

Reduced neurogenic inflammation in streptozotocin-diabetic rats due to microvascular changes but not to substance P depletion

The effect of streptozotocin treatment (65 mg/kg i.v.) on plasma protein extravasation, nociception, and the content of substance P immunoreactivity (SP-IR) and somatostatin immunoreactivity (SOM-IR) was investigated in the rat. Twelve days after treatment, the neurogenic plasma extravasation induced by 5% mustard oil was reduced by 67% in the skin of the hind paw. Extravasation caused by SP, a putative mediator of neurogenic inflammation, was also reduced by 61% in the abdominal skin. While calcitonin gene-related peptide (CGRP) potentiated the SP-induced extravasation in control rats, no potentiation was observed in diabetic rats. Thermonociception or chemonociception was unchanged after streptozotocin treatment. The content of SP-IR and SOM-IR in sensory nerves or spinal ganglia was also not altered. These results indicate that the impairment of neurogenic inflammation in diabetic rats is not the result of depletion of neurogenic mediators like SP. Changes of the microvasculature at the leakage site appear to account for the effects observed.