Streptozotocin (STZ) is a naturally occurring glucosamine-nitrosourea compound used extensively in metabolic research, particularly for studying diabetes. Isolated in the late 1950s from the soil bacterium Streptomyces achromogenes, STZ functions as both an antibiotic and a powerful alkylating agent. Its chemical structure allows it to target and damage the genetic material of cells, explaining its uses in medicine and scientific laboratories.
Dual Functionality as an Antibiotic and Chemotherapeutic Agent
STZ was initially recognized as a broad-spectrum antibiotic effective against certain Gram-negative bacteria. However, this application was abandoned because the compound’s potent toxicity to mammalian cells caused severe side effects, outweighing the benefits of its use. Researchers instead focused on its unique cytotoxic properties.
STZ found a specialized clinical role as an FDA-approved chemotherapeutic agent, marketed under the brand name Zanosar. It is specifically used to treat metastatic pancreatic neuroendocrine tumors (PNETs), also known as islet cell carcinoma. The drug’s efficacy against these rare cancers is linked to its ability to selectively destroy pancreatic islet cells, which often form these tumors.
In a clinical setting, STZ is typically administered intravenously, often combined with other chemotherapy drugs. This use leverages its alkylating action to damage tumor cell DNA, preventing cell division. Despite its utility, the treatment carries a substantial risk of serious adverse effects, most notably nephrotoxicity (kidney damage). This renal impairment is a dose-limiting factor that strictly controls its administration.
Mechanism of Selective Toxicity in Beta Cells
STZ’s selectivity for insulin-producing beta cells is a direct consequence of its chemical structure, which closely resembles glucose. This mimicry allows STZ to gain preferential entry into the beta cell via Glucose Transporter 2 (GLUT2). Beta cells naturally express high levels of GLUT2 to regulate glucose sensing, making them uniquely susceptible to STZ uptake compared to most other cell types.
Once inside, the STZ molecule breaks down, releasing a highly reactive methylnitrosourea group. This group acts as an alkylating agent, transferring a methyl group to the cell’s DNA. This action causes extensive DNA damage, including fragmentation, which overwhelms the cell’s repair mechanisms.
The widespread DNA damage activates the nuclear repair enzyme Poly ADP-ribose polymerase (PARP). PARP activation consumes large amounts of the cellular energy co-factor nicotinamide adenine dinucleotide (NAD+). This leads to depletion of cellular energy stores, including adenosine triphosphate (ATP), which is a major contributor to cell death and the diabetogenic effect.
STZ also contributes to cellular stress by acting as a nitric oxide (NO) donor within the pancreatic islets. Nitric oxide release exacerbates damage by inhibiting key metabolic enzymes, such as aconitase. The combined effects of DNA alkylation, NAD+ depletion, and oxidative stress ultimately destroy the beta cell through both programmed cell death (apoptosis) and uncontrolled cell death (necrosis).
Inducing Experimental Diabetes Models
The most common modern use of STZ is establishing controlled animal models of diabetes for biomedical research. By selectively destroying insulin-producing beta cells, researchers reliably induce insulin deficiency and subsequent hyperglycemia in rodents. These models are indispensable for studying disease mechanisms, testing new therapeutic drugs, and evaluating cell transplantation strategies.
Modeling Type 1 Diabetes (T1DM)
To model Type 1 Diabetes Mellitus (T1DM), which involves a near-total loss of insulin production, researchers use a high-dose, single-injection protocol. This regimen uses a single large dose (e.g., 50–65 mg/kg in rats or 120–250 mg/kg in mice), administered intravenously or intraperitoneally. The high concentration rapidly causes massive destruction of the majority of beta cells within days, leading to sustained, high blood glucose levels that mimic the human T1DM phenotype.
Modeling Type 2 Diabetes (T2DM)
Creating models that resemble Type 2 Diabetes Mellitus (T2DM) requires a different protocol, as T2DM is characterized by insulin resistance and partial beta-cell failure. This approach involves a low-dose, multiple-injection regimen (e.g., 25–45 mg/kg administered over four to five consecutive days). This gradual dosing causes only partial destruction of the beta-cell mass, allowing some insulin secretion to remain.
The low-dose STZ protocol is frequently combined with a High-Fat Diet (HFD) fed to the animals for several weeks. The HFD induces significant insulin resistance. The partial beta-cell damage ensures the animal develops the characteristic combination of insulin resistance and insufficient insulin secretion seen in human T2DM. These hybrid models allow scientists to investigate blood sugar control and the long-term complications associated with Type 2 diabetes.