Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner.

Maddison LA, Joest KE, Kammeyer RM, Chen W
Am J Physiol Endocrinol Metab. 2015 308 (8): E662-9

PMID: 25670827 · PMCID: PMC4398831 · DOI:10.1152/ajpendo.00441.2014

Insulin resistance creates an environment that promotes β-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 β-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the β-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 β-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.

MeSH Terms (21)

Aging Animals Animals, Genetically Modified Biological Transport Cell Count Disease Progression Glucose Glucose Intolerance Green Fluorescent Proteins Hyperglycemia Insulin Insulin-Like Growth Factor I Insulin-Secreting Cells Insulin Resistance Luminescent Proteins Muscle, Skeletal Overnutrition Receptor, IGF Type 1 Recombinant Fusion Proteins Zebrafish Zebrafish Proteins

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