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Current Protocols Apr 2021Streptozotocin (STZ) is an antibiotic that causes pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus...
Streptozotocin (STZ) is an antibiotic that causes pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this article are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition. © 2021 The Authors.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Insulin; Mice; Rats; Streptozocin
PubMed: 33905609
DOI: 10.1002/cpz1.78 -
Physiological Research 2001Alloxan and streptozotocin are widely used to induce experimental diabetes in animals. The mechanism of their action in B cells of the pancreas has been intensively... (Review)
Review
Alloxan and streptozotocin are widely used to induce experimental diabetes in animals. The mechanism of their action in B cells of the pancreas has been intensively investigated and now is quite well understood. The cytotoxic action of both these diabetogenic agents is mediated by reactive oxygen species, however, the source of their generation is different in the case of alloxan and streptozotocin. Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals. These radicals undergo dismutation to hydrogen peroxide. Thereafter highly reactive hydroxyl radicals are formed by the Fenton reaction. The action of reactive oxygen species with a simultaneous massive increase in cytosolic calcium concentration causes rapid destruction of B cells. Streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA. DNA damage induces activation of poly ADP-ribosylation, a process that is more important for the diabetogenicity of streptozotocin than DNA damage itself. Poly ADP-ribosylation leads to depletion of cellular NAD+ and ATP. Enhanced ATP dephosphorylation after streptozotocin treatment supplies a substrate for xanthine oxidase resulting in the formation of superoxide radicals. Consequently, hydrogen peroxide and hydroxyl radicals are also generated. Furthermore, streptozotocin liberates toxic amounts of nitric oxide that inhibits aconitase activity and participates in DNA damage. As a result of the streptozotocin action, B cells undergo the destruction by necrosis.
Topics: Alloxan; Animals; Antibiotics, Antineoplastic; Diabetes Mellitus, Experimental; Islets of Langerhans; Rats; Streptozocin
PubMed: 11829314
DOI: No ID Found -
The New England Journal of Medicine Jun 2012Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment.
METHODS
We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival.
RESULTS
For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.
CONCLUSIONS
Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Mitotane; Quality of Life; Streptozocin; Young Adult
PubMed: 22551107
DOI: 10.1056/NEJMoa1200966 -
International Journal of Molecular... Jan 2023The main cause of morbidity and mortality in diabetes mellitus (DM) is cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood....
The main cause of morbidity and mortality in diabetes mellitus (DM) is cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial in exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has been widely used to produce experimental models of both type 1 and type 2 DM (T1DM and T2DM). Here, we compared these two models for their effects on cardiac structure, function and transcriptome. Different doses of STZ and diet chows were used to generate T1DM and T2DM in C57BL/6J mice. Normal euglycemic and nonobese sex- and age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR and RNA-seq were employed to compare hearts from the three animal groups. STZ-induced T1DM and T2DM affected left ventricular function and myocardial performance differently. T1DM displayed exaggerated apoptotic cardiomyocyte (CM) death and reactive hypertrophy and fibrosis, along with increased cardiac oxidative stress, CM DNA damage and senescence, when compared to T2DM in mice. T1DM and T2DM affected the whole cardiac transcriptome differently. In conclusion, the STZ-induced T1DM and T2DM mouse models showed significant differences in cardiac remodeling, function and the whole transcriptome. These differences could be of key relevance when choosing an animal model to study specific features of DCM.
Topics: Mice; Animals; Diabetic Cardiomyopathies; Streptozocin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36674648
DOI: 10.3390/ijms24021132 -
Autophagy Feb 2023Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major...
Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants of DN. However, the underlying mechanisms of podocyte injury remain poorly understood. The cytosolic protein TNFAIP2/M-Sec is required for tunneling nanotubes (TNTs) formation, which are membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 and form TNTs, but the potential relevance of the TNFAIP2-TNT system in DN is unknown. We studied TNFAIP2 expression in both human and experimental DN and the renal effect of deletion in streptozotocin-induced DN. Moreover, we explored the role of the TNFAIP2-TNT system in podocytes exposed to diabetes-related insults. TNFAIP2 was overexpressed by podocytes in both human and experimental DN and exposre of podocytes to high glucose and AGEs induced the TNFAIP2-TNT system. In diabetic mice, deletion exacerbated albuminuria, renal function loss, podocyte injury, and mesangial expansion. Moreover, blockade of the autophagic flux due to lysosomal dysfunction was observed in diabetes-injured podocytes both and and exacerbated by deletion. TNTs allowed autophagosome and lysosome exchange between podocytes, thereby ameliorating AGE-induced lysosomal dysfunction and apoptosis. This protective effect was abolished by deletion, TNT inhibition, and donor cell lysosome damage. By contrast, overexpression enhanced TNT-mediated transfer and prevented AGE-induced autophagy and lysosome dysfunction and apoptosis. In conclusion, TNFAIP2 plays an important protective role in podocytes in the context of DN by allowing TNT-mediated autophagosome and lysosome exchange and may represent a novel druggable target. AGEs: advanced glycation end products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: diabetic nephropathy; FSGS: focal segmental glomerulosclerosis; HG: high glucose; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: tumor necrosis factor, alpha-induced protein 2; TNTs: tunneling nanotubes; WT: wild type.
Topics: Humans; Mice; Animals; Podocytes; Diabetic Nephropathies; Autophagy; Diabetes Mellitus, Experimental; Streptozocin; Albuminuria; Phosphatidylinositol 3-Kinases; Tumor Necrosis Factors; Glycation End Products, Advanced; Glucose; Cytokines
PubMed: 35659195
DOI: 10.1080/15548627.2022.2080382 -
Journal of Advanced Research Nov 2022Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Broad knowledge about the genetics, epidemiology and clinical management of T1D has been achieved, but...
INTRODUCTION
Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Broad knowledge about the genetics, epidemiology and clinical management of T1D has been achieved, but understandings about the cell varieties in the bone marrow during T1D remain limited.
OBJECTIVES
We aimed to present a profile of the bone marrow cells and reveal the relationship of bone marrow and osteopenia in streptozotocin (STZ)-induced T1D mice.
METHODS
The whole bone marrow cells from the femurs and tibias of healthy (group C) and STZ-induced T1D mice (group D) were collected for single-cell RNA sequencing analysis. Single-cell flow cytometry and immunohistochemistry were performed to confirm the proportional changes among bone marrow neutrophils (BM-neutrophils) (Cxcr2, Ly6g) and B lymphocytes (Cd19). X-ray and micro-CT were performed to detect bone mineral density. The correlation between the ratio of BM-neutrophils/B lymphocytes and osteopenia in STZ-induced T1D mice was analyzed by nonparametric Spearman correlation analysis.
RESULTS
The bone marrow cells in groups C and D were divided into 12 clusters, and 249 differentially expressed genes were found. The diversity of CD45 immune cells between groups C and D were greatly affected: the proportion of BM-neutrophils showed a significant increase while the proportion of B lymphocytes in group D showed a significant decrease. X-ray and micro-CT analyses confirmed that osteopenia occurred in group D mice. In addition, the results of single-cell flow cytometry and correlation analysis showed that the ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice.
CONCLUSION
A single-cell RNA sequencing analysis revealed the profile and heterogeneity of bone marrow immune cells in STZ-induced T1D mice for the first time. The ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice, which may enhance understanding for treating T1D and preventing T1D-induced osteopenia.
Topics: Mice; Animals; Streptozocin; Diabetes Mellitus, Type 1; Bone Marrow; Diabetes Mellitus, Experimental; Bone Diseases, Metabolic; Sequence Analysis, RNA
PubMed: 36328744
DOI: 10.1016/j.jare.2022.01.006 -
International Review of Neurobiology 2016The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat and mouse models of type 1 diabetes. This chapter will review the creation... (Review)
Review
The study of diabetic neuropathy has relied primarily on the use of streptozotocin-treated rat and mouse models of type 1 diabetes. This chapter will review the creation and use of other rodent models that have been developed in order to investigate the contribution of factors besides insulin deficiency to the development and progression of diabetic neuropathy as it occurs in obesity, type 1 or type 2 diabetes. Diabetic peripheral neuropathy is a complex disorder with multiple mechanisms contributing to its development and progression. Even though many animal models have been developed and investigated, no single model can mimic diabetic peripheral neuropathy as it occurs in humans. Nonetheless, animal models can play an important role in improving our understanding of the etiology of diabetic peripheral neuropathy and in performing preclinical screening of potential new treatments. To date treatments found to be effective for diabetic peripheral neuropathy in rodent models have failed in clinical trials. However, with the identification of new endpoints for the early detection of diabetic peripheral neuropathy and the understanding that a successful treatment may require a combination therapeutic approach there is hope that an effective treatment will be found.
Topics: Animals; Antibiotics, Antineoplastic; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Humans; Neural Conduction; Rodentia; Streptozocin
PubMed: 27133146
DOI: 10.1016/bs.irn.2016.03.002 -
IARC Monographs on the Evaluation of... 1990
Review
Topics: Animals; Carcinogens; Humans; Molecular Structure; Streptozocin
PubMed: 2149865
DOI: No ID Found -
Communications Biology Apr 2022Loss of podocytes is a common feature of diabetic renal injury and a key contributor to the development of albuminuria. We found that podocyte Rho associated coiled-coil...
Loss of podocytes is a common feature of diabetic renal injury and a key contributor to the development of albuminuria. We found that podocyte Rho associated coiled-coil containing protein kinase 2 (ROCK2) is activated in rodent models and patients with diabetes. Mice that lacked ROCK2 only in podocytes (PR2KO) were resistant to albuminuria, glomerular fibrosis, and podocyte loss in multiple animal models of diabetes (i.e., streptozotocin injection, db/db, and high-fat diet feeding). RNA-sequencing of ROCK2-null podocytes provided initial evidence suggesting ROCK2 as a regulator of cellular metabolism. In particular, ROCK2 serves as a suppressor of peroxisome proliferator-activated receptors α (PPARα), which rewires cellular programs to negatively control the transcription of genes involved in fatty acid oxidation and consequently induce podocyte apoptosis. These data establish ROCK2 as a nodal regulator of podocyte energy homeostasis and suggest this signaling pathway as a promising target for the treatment of diabetic podocytopathy.
Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Humans; Mice; Podocytes; Streptozocin; rho-Associated Kinases
PubMed: 35396346
DOI: 10.1038/s42003-022-03300-4 -
Journal of Molecular Endocrinology Apr 2022Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The...
Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels are increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hyperglycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+channel-dependent Ca2+influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells.
Topics: Animals; Glucagon; Hyperglycemia; Kidney; Mice; Mice, Knockout; Receptors, G-Protein-Coupled; Streptozocin; Urotensins
PubMed: 35244607
DOI: 10.1530/JME-21-0199