Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 308, Issue 8, Pages E662-E669Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00441.2014
Keywords
diabetes; beta-cell; glucose tolerance; zebrafish
Categories
Funding
- Vanderbilt Diabetes Research and Training Centers
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-088686]
- American Diabetes Association [1-13-BS-027]
- NIDDK [DK-02593]
- National Institutes of Health [CA-68485, DK-20593, DK-58404, HD-15052, DK-59637, EY-08126]
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Insulin resistance creates an environment that promotes beta-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies, and model systems that reflect the pathophysiology of disease progression are an important component toward this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant-negative IGF-IR. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle, confirming insulin resistance. In young animals, we observed an increase in the number of beta-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the beta-cell mass was reduced to that of control with the appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin-resistant animals have an increased fasting blood glucose compared with the control animals, demonstrating that the beta-cells in the insulin-resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.
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