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Studies of insulin insensitivity in soleus muscles of obese mice
Abstract:
The isolated mouse soleus muscle is a suitable system to measure specific insulin binding and insulin effects. Studies in obese mice have pointed to discrete sites of insulin resistance of skeletal muscle in obesity: (1) A decrease in the number of insulin receptors, which may result in diminished insulin sensitivity (i.e., impaired responses to submaximally stimulating doses of insulin); and (2) Alterations that lay apart from, or beyond, the insulin receptor: thus, glucose transport (and/or phosphorylation) appears to be intrinsically altered and the stimulation by insulin of glycogen synthesis is markedly depressed. These alterations are responsible for the marked resistance to maximally stimulating doses of insulin. The serum from a patient with the syndrome of insulin resistance and acanthosis nigricans contains antibodies that inhibit insulin binding and exert insulin-like effects in muscle; this serum is, however, less effective than insulin in maximally stimulating glycogen synthesis, which suggests some differences in their mechanisms of action.
Insights
Obesity causes skeletal muscle insulin resistance through decreased insulin receptors and impaired glucose transport. These factors lead to reduced insulin sensitivity and glycogen synthesis, highlighting key mechanisms of insulin resistance.
Area of Science:
- Physiology
- Endocrinology
- Metabolism
Background:
- Skeletal muscle is a primary site for insulin action and glucose disposal.
- Obesity is associated with impaired insulin sensitivity and increased risk of type 2 diabetes.
- Understanding the molecular sites of insulin resistance is crucial for therapeutic development.
Purpose of the Study:
- To investigate the specific defects in insulin action within skeletal muscle of obese mice.
- To differentiate between insulin receptor-related and post-receptor defects in insulin resistance.
- To explore the role of serum factors in insulin resistance.
Main Methods:
- Utilized isolated mouse soleus muscle preparations.
- Measured specific insulin binding and insulin-stimulated glucose transport and glycogen synthesis.
- Analyzed serum from a patient with insulin resistance and acanthosis nigricans.
Main Results:
- Obese mice exhibited decreased insulin receptor numbers, reducing sensitivity to low insulin doses.
- Post-receptor defects, including impaired glucose transport and glycogen synthesis, caused resistance to high insulin doses.
- Patient serum inhibited insulin binding and showed insulin-like effects but was less effective in maximal glycogen synthesis stimulation.
Conclusions:
- Skeletal muscle insulin resistance in obesity involves both reduced insulin receptors and intrinsic post-receptor defects.
- These defects contribute to impaired glucose metabolism and glycogen synthesis.
- Differences in serum factor action suggest distinct mechanisms compared to insulin itself.