Zucker Diabetic Fatty (ZDF) rats are a specialized type of laboratory rat widely used in biomedical research. These rats serve as an important animal model for understanding complex metabolic disorders. Their consistent physiological characteristics make them valuable tools for studying disease progression and evaluating potential treatments. This unique strain provides researchers with insights into conditions that mirror human health challenges.
Unique Biological Profile
ZDF rats originated from a mutation observed in a colony of outbred Zucker rats in the mid-1970s. They are characterized by a genetic mutation in the leptin receptor gene, known as fa/fa. This results in leptin resistance, leading to a predisposition for inherited obesity.
The fa/fa mutation causes ZDF rats to develop hyperphagia, or excessive eating, and subsequently become obese around 4 weeks of age. As they age, male ZDF rats develop glucose intolerance, hyperlipidemia, and hyperinsulinemia by 7 to 10 weeks of age. These conditions progress to overt type 2 diabetes, characterized by high blood glucose levels, which can reach 400 to 500 mg/dL and persist for at least six months. The development of diabetes is accelerated by feeding them a high-fat diet.
Modeling Metabolic Diseases
ZDF rats are used in research because their biological profile closely mimics human metabolic conditions. Their spontaneous development of inherited obesity, hyperlipidemia, and hyperinsulinemia makes them a valuable model for studying type 2 diabetes, obesity, and metabolic syndrome. The progression of insulin resistance in ZDF rats, where peripheral glucose disposal decreases significantly, mirrors human disease. For example, ten-week-old obese ZDF rats require an 89% lower glucose infusion rate to maintain normal blood sugar compared to lean littermates, indicating severe insulin resistance.
These rats also develop pancreatic beta-cell dysfunction, a hallmark of human type 2 diabetes. Initially, beta-cell mass increases in younger ZDF rats as compensation for insulin resistance, but this eventually fails, leading to decreased insulin output and progressive beta-cell failure in hyperglycemic animals. Similarities extend to complications like dyslipidemia. Researchers utilize ZDF rats to investigate the mechanisms behind these conditions, examining aspects like impaired glycogen synthesis and liver steatosis.
Advancing Therapeutic Strategies
Research using ZDF rats has contributed to understanding disease progression and developing new treatments for metabolic disorders. These rats have been used to evaluate the effectiveness of novel drugs and therapeutic approaches. For example, studies show that treatment with pioglitazone, an insulin sensitizer, reverses many metabolic signatures in diabetic ZDF rats, improving glycemic control and fatty acid profiles.
ZDF rats have also been used to test combination therapies for type 2 diabetes. A study demonstrated that icovamenib combined with low-dose semaglutide led to superior metabolic benefits in ZDF rats, including improved fasting blood glucose and glucose tolerance, compared to semaglutide alone. This combination also improved insulin sensitivity and enhanced beta-cell function, indicating potential for more effective human treatments. These insights from ZDF rat research inform the development of interventions for human health.