Insulin resistance and muscle metabolism in chronic kidney disease
1Renal Division, Emory University School of Medicine, Woodruff Memorial Research Building, Room 338, 1639 Pierce Drive, Atlanta, GA 30322, USA.
Abstract:
Insulin resistance is a common finding in chronic kidney disease (CKD) and is manifested by mild fasting hyperglycemia and abnormal glucose tolerance testing. Circulating levels of glucocorticoids are high. In muscle, changes in the insulin signaling pathway occur. An increase in the regulatory p85 subunit of Class I phosphatidylinositol 3-Kinase enzyme leads to decreased activation of the downstream effector protein kinase B (Akt). Mechanisms promoting muscle proteolysis and atrophy are unleashed. The link of Akt to the ubiquitin proteasome pathway, a major degradation pathway in muscle, is discussed. Another factor associated with insulin resistance in CKD is angiotensin II (Ang II) which appears to induce its intracellular effects through inflammatory cytokines or reactive oxygen species. Skeletal muscle ATP is depleted and the ability of AMP-activated protein kinase (AMPK) to replenish energy stores is blocked. How this can be reversed is discussed. Interleukin-6 (IL-6) levels are elevated in CKD and impair insulin signaling at the level of IRS-1. With exercise, IL-6 levels are reduced; glucose uptake and utilization are increased. For patients with CKD, exercise may improve insulin signaling and build up muscle. Treatment strategies for preventing muscle atrophy are discussed.
Insights
Insulin resistance in chronic kidney disease (CKD) involves impaired insulin signaling and muscle wasting. Exercise may reverse these effects, improving glucose metabolism and muscle health in CKD patients.
Area of Science:
- Nephrology
- Endocrinology
- Metabolism
Background:
- Insulin resistance is prevalent in chronic kidney disease (CKD), characterized by hyperglycemia and impaired glucose tolerance.
- Elevated glucocorticoids and angiotensin II (Ang II) contribute to insulin resistance and muscle catabolism in CKD.
- Inflammatory cytokines like Interleukin-6 (IL-6) are increased in CKD, further disrupting insulin signaling.
Purpose of the Study:
- To elucidate the molecular mechanisms of insulin resistance in skeletal muscle of CKD patients.
- To explore the role of key signaling pathways, including phosphatidylinositol 3-Kinase (PI3K)/protein kinase B (Akt) and AMP-activated protein kinase (AMPK).
- To discuss potential therapeutic strategies, including exercise, for mitigating muscle atrophy and improving metabolic dysfunction in CKD.
Main Methods:
- Review of molecular changes in insulin signaling pathways within skeletal muscle.
- Analysis of the impact of elevated hormones (glucocorticoids, Ang II) and cytokines (IL-6) on muscle metabolism.
- Discussion of the interplay between insulin resistance, muscle proteolysis, and energy depletion.
Main Results:
- Increased p85 subunit of PI3K leads to reduced Akt activation, promoting muscle proteolysis and atrophy.
- Angiotensin II (Ang II) induces intracellular effects via inflammatory cytokines and reactive oxygen species, depleting skeletal muscle ATP.
- Elevated IL-6 levels impair insulin signaling at the IRS-1 level, while exercise can reduce IL-6 and enhance glucose uptake.
Conclusions:
- CKD-associated insulin resistance involves complex molecular derangements in skeletal muscle.
- Interventions targeting inflammatory pathways and promoting muscle anabolism are crucial for managing CKD.
- Exercise presents a viable strategy to improve insulin sensitivity, combat muscle atrophy, and enhance overall metabolic health in CKD patients.
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