STZ: Type 1 or Type 2 Diabetes?
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When discussing our unique NASH-HCC model STAM with clients, we are so often asked: What type of diabetes does the streptozotocin induce?
Since streptozotocin (an N-acetyl-β-D-glucosaminidase inhibitor; STZ) is cytotoxic to pancreatic beta cells, STZ-induced diabetes models are often considered as a model for Type 1 diabetes mellitus (T1D) which is in definition caused by autoimmune destruction of islet beta cells and characterized by the complete lack of insulin.
Indeed, classical STZ models aim to mimic the system of T1D, where insulin is totally deficient and complicated with ketosis. In such models, STZ is typically injected to adult rats or mice at a relatively high dose (160−170 mg/kg) to damage the beta cells and induce hyperglycemia due to the lack of insulin function .
There is another, later reported STZ model, with the toxin given to neonatal animals (at a dose of 80-100 mg/kg), and thus is called nSTZ . The nSTZ model is distinguished from the adult models in that insulin secretion is low but still remains, and that the impairment is reversible – the features more alike Type 2 diabetes mellitus (T2D). There is evidence supporting the T2D-like characteristics of nSTZ model, including the presence of insulin resistance (IR), impaired glucose tolerance, diabetic complications such as cataract , and response to anti-diabetic agents .
Interestingly, it is known that susceptibility of beta cells to STZ varies with species, strains, ages or genders . Consequently, by selecting an appropriate combination of animal and dosing regimen of STZ, one can induce multiple diabetic conditions: ranging from the complete abolishment of insulin section like in T1D, to a partial impairment of insulin function seen in early to late T2D.
SMC’s STAM™ model (a NASH-HCC model) is produced by a combination of STZ injection and high-fat diet feeding. STZ is used neonatally to generate mild systemic inflammation and a hyperglycemic condition, which in turn “prime” the liver for the subsequent diet challenge. The dose of STZ is carefully titrated, aiming for not the complete depletion but partial impairment of insulin secretion (thus, even after the exposure to STZ, insulin-producing beta cells are found in the pancreas). The observed phenotype can be categorized as an advanced T2D in which beta cells are functionally exhausted and can no longer secrete insulin at the normal level. Supportive data has been published by Van der Schueren and colleagues, reporting that HOMA-IR (an index for IR) was elevated in STAM mice . The result suggested the existence of IR in this model, despite its hypoinsulinemic state.
So, there you have it. STZ can be utilized to induce both Type 1, and Type 2 Diabetic phenotypes, the latter of which is seen in our NASH model.
Further questions? Get in touch below!
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- Srinivasan K and Ramarao P. (2007). Animal models in type 2 diabetes research: an overview. Indian J Med Res. 125:451-72.
- Patil MA. et al., (2014). Evaluation of neonatal streptozotocin induced diabetic rat model for the development of cataract. Oxid Med Cell Longev. 2014:463264.
- Rossetti L. et al., (1990). Effect of metformin treatment on insulin action in diabetic rats: in vivo and in vitro correlations. Metabolism. 39:425-35.
- Deeds MC. et al., (2011). Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim. 45:131-40.
6. Van der Schueren B. et al. (2015). Low cytochrome oxidase 4I1 links mitochondrial dysfunction to obesity and type 2 diabetes in humans and mice. Int J Obes. 39:1254-63.