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Published on: May 11, 2015
A Mouse Model of Beta-Cell Dysfunction as Seen in Human Type 2 Diabetes
Jacqueline H Parilla1,2, Joshua R Willard1, Breanne M Barrow1
1Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Abstract:
Loss of first-phase insulin release is an early pathogenic feature of type 2 diabetes (T2D). Various mouse models exist to study T2D; however, few recapitulate the early β-cell defects seen in humans. We sought to develop a nongenetic mouse model of T2D that exhibits reduced first-phase insulin secretion without a significant deficit in pancreatic insulin content. C57BL/6J mice were fed 10% or 60% fat diet for three weeks, followed by three consecutive, once-daily intraperitoneal injections of the β-cell toxin streptozotocin (STZ; 30, 50, or 75 mg/kg) or vehicle. Four weeks after injections, the first-phase insulin response to glucose was reduced in mice when high-fat diet was combined with 30, 50, or 75 mg/kg STZ. This was accompanied by diminished second-phase insulin release and elevated fed glucose levels. Further, body weight gain, pancreatic insulin content, and β-cell area were decreased in high fat-fed mice treated with 50 and 75 mg/kg STZ, but not 30 mg/kg STZ. Low fat-fed mice were relatively resistant to STZ, with the exception of reduced pancreatic insulin content and β-cell area. Together, these data demonstrate that in high fat-fed mice, three once-daily injections of 30 mg/kg STZ produces a model of β-cell failure without insulin deficiency that may be useful in studies investigating the etiology and progression of human T2D.
Insights
Researchers developed a new mouse model for type 2 diabetes (T2D) by combining a high-fat diet with streptozotocin (STZ) injections. This model effectively mimics early beta-cell dysfunction seen in human T2D without causing insulin deficiency.
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.
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