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. 1. Introduction Insulin resistance describes a physiological condition which is characterized by reduced tissue responses to the action of insulin for any given blood concentration of the hormone. It is a common finding in chronic kidney disease but it largely goes unrecognized. In nondiabetic patients with end stage renal disease, this is manifested by mild fasting hyperglycemia and abnormal glucose tolerance testing during an oral or intravenous glucose load. Patients may develop hyperglycemia or maintain normoglycemia at the expense of hyperinsulinemia [1, 2]. These changes are often masked by a decline in the metabolic clearance of insulin that occurs as the glomerular filtration rate drops below 15 to 20 mL/minute. Between glomerular filtration rates of 20 to 40 mL/minute, peritubular insulin uptake increases to maintain renal insulin clearance [3]. In uremia, degradation of insulin in nonrenal tissues such as liver and muscle is impaired and the half-life of insulin is prolonged. It is hypothesized that accumulation of uremic toxins may inhibit insulin degradation particularly by the liver. Although the latter is responsible for removal of approximately 50% of the insulin secreted into the portal circulation [4], the major site of insulin resistance is in the peripheral
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