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Transgenic mice with muscle-specific insulin resistance develop increased adiposity, impaired glucose tolerance, and
D E Moller1, P Y Chang, B B Yaspelkis
1Department of Medicine, Beth Israel Hospital, Boston, Massachusetts, USA. david_moller@merck.com
Abstract:
Impaired skeletal muscle insulin receptor function is a feature of common forms of insulin resistance, including obesity and noninsulin-dependent diabetes mellitus. However, the extent to which this defect accounts for impaired muscle glucose disposal or altered in vivo glucose homeostasis remains to be established. We recently showed that transgenic mice that overexpress dominant-negative insulin receptors specifically in striated muscle have a severe defect in muscle insulin receptor-mediated signaling and modest hyperinsulinemia. Here we performed hindlimb perfusion studies to determine the impact of this defect on muscle glucose uptake and metabolism. Maximal rates of insulin-stimulated muscle 3-O-methylglucose transport were reduced by 32-40% in transgenic mice with proportional defects involving total hindlimb [14C]glucose uptake, lactate production, and muscle glycogen synthesis. To address the hypothesis that muscle insulin resistance could promote an increase in the accretion of body fat, carcass analysis was performed using two independent lines of transgenic mice. Although body weights were normal, transgenic mice had a 22-38% increase in body fat, with a reciprocal decrease (10-15%) in body protein. Mean gonadal fat pad weight was also increased in transgenic mice. Skeletal muscle histology and fiber type distribution were not affected. To determine whether muscle-specific insulin resistance was sufficient to cause impaired glucose tolerance, oral glucose tolerance tests were performed with 6-month-old transgenic and control mice. Fasting glucose levels were increased by 25%, and peak values were 22-40% higher in transgenic mice. Transgenic mice also had a 37% decrease in plasma lactate levels and modest increases in levels of plasma triglycerides and FFA (29% and 15%, respectively). We conclude that 1) severe defects in muscle insulin receptor function result in impaired insulin-stimulated glucose uptake and metabolism in this tissue; 2) muscle-specific insulin resistance can contribute to the development of obesity; and 3) a "pure" defect in insulin-mediated muscle glucose disposal is sufficient to result in impaired glucose tolerance and other features of the insulin resistance syndrome, including hyperinsulinemia and dyslipidemia.
Insights
Skeletal muscle insulin resistance impairs glucose uptake and metabolism, contributing to obesity and glucose intolerance. This study demonstrates that defects in muscle insulin receptors are sufficient to cause insulin resistance syndrome features.
Area of Science:
- Metabolic Research
- Physiology
- Endocrinology
Background:
- Impaired skeletal muscle insulin receptor function is a hallmark of insulin resistance, obesity, and type 2 diabetes.
- The precise contribution of muscle insulin resistance to overall glucose homeostasis and metabolic dysfunction remains unclear.
Purpose of the Study:
- To investigate the impact of severe defects in skeletal muscle insulin receptor function on glucose uptake, metabolism, and systemic glucose homeostasis in vivo.
- To determine if muscle-specific insulin resistance is sufficient to induce obesity and features of the insulin resistance syndrome.
Main Methods:
- Hindlimb perfusion studies in transgenic mice overexpressing dominant-negative insulin receptors in striated muscle.
- Carcass analysis to assess body composition (fat and protein content).
- Oral glucose tolerance tests and measurement of plasma metabolites (lactate, triglycerides, FFA).
Main Results:
- Transgenic mice exhibited a 32-40% reduction in maximal insulin-stimulated 3-O-methylglucose transport in muscle.
- Significant defects were observed in muscle glucose uptake, lactate production, and glycogen synthesis.
- Transgenic mice showed increased body fat (22-38%) and decreased body protein (10-15%) despite normal body weight.
- Impaired glucose tolerance, elevated fasting glucose, and increased plasma triglycerides and FFA were observed.
Conclusions:
- Severe defects in muscle insulin receptor function lead to impaired insulin-stimulated glucose uptake and metabolism.
- Muscle-specific insulin resistance can promote obesity and contribute to the development of the insulin resistance syndrome.
- A primary defect in muscle insulin signaling is sufficient to cause impaired glucose tolerance and associated metabolic dysregulation.