A Mouse Model of Beta-Cell Dysfunction as Seen in Human Type 2 Diabetes

Area of Science:

• * Endocrinology and Metabolism
• * Diabetes Research
• * Animal Models of Disease

Background:

• * Type 2 diabetes (T2D) is characterized by early loss of first-phase insulin release.
• * Existing mouse models often fail to replicate the specific early beta-cell defects observed in human T2D.
• * There is a need for a non-genetic model that accurately reflects early-stage T2D pathophysiology.

Purpose of the Study:

• * To create a non-genetic mouse model of T2D exhibiting impaired first-phase insulin secretion.
• * To develop a model that does not show a significant deficit in overall pancreatic insulin content.
• * To investigate the effects of diet and streptozotocin (STZ) on beta-cell function.

Main Methods:

• * C57BL/6J mice were fed either a 10% or 60% fat diet for three weeks.
• * Mice received daily intraperitoneal injections of streptozotocin (STZ) at 30, 50, or 75 mg/kg, or a vehicle control.
• * Insulin secretion, glucose levels, body weight, and pancreatic beta-cell area were assessed four weeks post-injection.

Main Results:

• * A high-fat diet combined with STZ (30, 50, or 75 mg/kg) reduced first-phase insulin response and second-phase insulin release.
• * Elevated fed glucose levels were observed in mice treated with high-fat diet and STZ.
• * High-fat diet with 50 or 75 mg/kg STZ decreased body weight, pancreatic insulin content, and beta-cell area; 30 mg/kg STZ did not significantly impact these parameters.

Conclusions:

• * Three daily injections of 30 mg/kg STZ in high fat-fed mice create a model of beta-cell failure.
• * This model successfully mimics early T2D defects, including reduced first-phase insulin release, without causing insulin deficiency.
• * This novel model is suitable for studying the etiology and progression of human type 2 diabetes.