title: Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner.
abstract: 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.
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors: Lisette A
authors: LA
authors: Maddison
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors: Kaitlin E
authors: KE
authors: Joest
authors: Indiana University School of Medicine, Indianapolis, Indiana.
authors: Ryan M
authors: RM
authors: Kammeyer
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and wenbiao.chen@vanderbilt.edu.
authors: Wenbiao
authors: W
authors: Chen
mesh_terms: D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D001692:Biological Transport; D002452:Cell Count; D018450:Disease Progression; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D044343:Overnutrition / Q000503:physiopathology*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D005947:Glucose; D049452:Green Fluorescent Proteins; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D008164:Luminescent Proteins; D017526:Receptor, IGF Type 1; D011993:Recombinant Fusion Proteins; D029961:Zebrafish Proteins; D000097573:Red Fluorescent Protein; C511797:IGF1RA protein, zebrafish; C485184:enhanced green fluorescent protein
keywords: diabetes; glucose tolerance; zebrafish; β-cell