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

Lisette A Maddison; Kaitlin E Joest; Ryan M Kammeyer; Wenbiao Chen

doi:10.1152/ajpendo.00441.2014

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

Journal article

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

Lisette A Maddison, Kaitlin E Joest, Ryan M Kammeyer and Wenbiao Chen

American journal of physiology: endocrinology and metabolism, Vol.308(8), pp.E662-E669

04/15/2015

DOI: https://doi.org/10.1152/ajpendo.00441.2014

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https://hdl.handle.net/2376/102674

PMCID: PMC4398831

PMID: 25670827

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Abstract

Glucose Intolerance - metabolism

Receptor, IGF Type 1 - metabolism

Overnutrition - physiopathology

Cell Count

Muscle, Skeletal - metabolism

Glucose Intolerance - pathology

Green Fluorescent Proteins - genetics

Insulin-Like Growth Factor I - genetics

Recombinant Fusion Proteins - metabolism

Insulin-Secreting Cells - metabolism

Biological Transport

Glucose Intolerance - etiology

Aging

Insulin - genetics

Glucose Intolerance - physiopathology

Green Fluorescent Proteins - metabolism

Animals, Genetically Modified

Zebrafish Proteins - metabolism

Insulin Resistance

Zebrafish

Receptor, IGF Type 1 - genetics

Disease Progression

Insulin - metabolism

Animals

Glucose - metabolism

Recombinant Fusion Proteins - genetics

Luminescent Proteins - genetics

Hyperglycemia - etiology

Insulin-Secreting Cells - pathology

Zebrafish Proteins - genetics

Insulin-Like Growth Factor I - metabolism

Luminescent Proteins - metabolism

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.

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Title: Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner
Creators: Lisette A Maddison - Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and
Kaitlin E Joest - Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and
Ryan M Kammeyer - Indiana University School of Medicine, Indianapolis, Indiana
Wenbiao Chen - Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and wenbiao.chen@vanderbilt.edu
Publication Details: American journal of physiology: endocrinology and metabolism, Vol.308(8), pp.E662-E669
Academic Unit: Center for Reproductive Biology
Publisher: United States
Grant note: DK-02593 / NIDDK NIH HHS HD-15052 / NICHD NIH HHS P30 DK020593 / NIDDK NIH HHS DK-59637 / NIDDK NIH HHS DK-088686 / NIDDK NIH HHS EY-08126 / NEI NIH HHS R01 DK088686 / NIDDK NIH HHS DK-58404 / NIDDK NIH HHS T35 DK007383 / NIDDK NIH HHS DK-20593 / NIDDK NIH HHS CA-68485 / NCI NIH HHS
Identifiers: 99900546503001842
Language: English
Resource Type: Journal article