The db/db mouse is a widely utilized animal model in biomedical research because it is genetically predisposed to develop conditions like obesity and diabetes, which mirror human health issues. This allows scientists to study disease progression and test potential treatments in a controlled setting.
The Genetic Basis of db/db Mice
The designation “db/db” refers to a homozygous mutation in the gene for the leptin receptor (`Lepr`), meaning the mice have two copies of a defective gene. This mutation, `Lepr^db`, renders the receptor for the hormone leptin non-functional. Leptin is produced by fat cells and signals the brain to suppress appetite when the body has sufficient energy stores.
In db/db mice, the brain cannot receive the leptin signal, even though their bodies produce high levels of the hormone. This inability to recognize satiety creates a constant sensation of starvation. As a result, the mouse is compelled to eat far more than it requires for its energy needs.
Physiological Characteristics
The inability to detect leptin results in uncontrolled eating (hyperphagia), which begins around three to four weeks of age. This constant overconsumption of food leads directly to severe obesity as the excess energy is stored as fat. This rapid weight gain is a defining characteristic of the db/db mouse.
Obesity causes the mouse’s cells to become less responsive to insulin, a condition known as insulin resistance. To compensate, the pancreas produces more insulin, but this demand eventually becomes unsustainable. This process leads to chronically elevated blood sugar levels (hyperglycemia), which mirrors type 2 diabetes in humans.
As the condition advances, the insulin-producing beta cells in the pancreas begin to fail from exhaustion. This dysfunction marks a progression from insulin resistance to insufficient insulin production. The result is severe, uncontrolled diabetes that mimics the progression seen in many human patients.
Role in Metabolic Research
The predictable traits of the db/db mouse make it a useful tool for studying human metabolic diseases. Researchers use this model to investigate the interactions between obesity, insulin resistance, and the development of type 2 diabetes. Observing the disease’s progression in these mice helps scientists understand how these conditions unfold in humans.
The db/db mouse model is also used in the preclinical phase of drug development. It allows for testing new therapeutic compounds designed to treat metabolic syndrome by evaluating their effectiveness at improving insulin sensitivity, lowering blood glucose, or promoting weight loss. This provides data on a drug’s potential efficacy and safety before human clinical trials.
Comparison with ob/ob Mice
To understand the db/db mouse, it is useful to compare it to the ob/ob mouse, another model for obesity. While both models exhibit similar outward signs of obesity and diabetes, their underlying genetic causes are different. The db/db mouse has a defective leptin receptor and cannot respond to it, whereas the ob/ob mouse has a mutation in the leptin gene (`Lep^ob`) and cannot produce the hormone.
An experiment known as parabiosis demonstrated this difference. The circulatory systems of a db/db and an ob/ob mouse were surgically connected, allowing hormones to circulate between them. The ob/ob mouse received leptin from the db/db mouse’s blood, which suppressed its appetite and caused it to lose weight.
The db/db mouse, however, was unaffected by the shared circulation. Its non-functional receptors still prevented it from detecting the abundant leptin. This experiment confirmed the issue in db/db mice is an inability to sense the hormone, not a lack of it, which distinguishes the model from the ob/ob mouse.