in a recent issue of critical care , hermans and colleagues showed that intensive insulin therapy ( iit ) significantly reduces the incidence of electrophysiologic detection of neuromuscular complications in critically ill patients . these findings are consistent with data obtained from two randomized controlled trials using iit , which showed that iit decreases the incidence of critical illness polyneuropathy / critical illness myopathy ( cip / cim ) diagnosed by electroneuromyography as well as reducing the duration of mechanical ventilation and shortening the length of stay in the intensive care unit ( icu ) . improvements in electrophysiology presumably translate into improvements in respiratory muscle strength , decreasing the duration of mechanical ventilation and the length of icu stay it is important to note that our understanding of the mechanisms that lead to cip / cim is substantially limited . abundant data suggest that sepsis induces a myopathy characterized by reductions in muscle force - generating capacity ( force generation per cross - sectional area ) , loss of muscle mass and altered bioenergetics , but the mechanisms by which acute hyperglycemia induces prolonged or sustained alterations in the peripheral nervous system and in skeletal muscle are largely unknown . how does glucose damage tissues ? glucose toxicity has been explained by increased cellular glucose flux and mitochondrially generated oxidative stress . for example , nishikawa and colleagues showed that excessive mitochondrial superoxide generation is responsible for hyperglycemia - induced damage in endothelial cells . vincent and colleagues showed recently that 2 hours of high glucose exposure results in severe oxidative stress , mitochondrial disruption , activation of caspase 3 and apoptosis in cultured neurons . glucose overload and subsequent oxidative stress , therefore , may account for damage to neuronal tissue during acute hyperglycemia . this mechanism can not account for acute hyperglycemia - induced changes in skeletal muscle , however , because glucose uptake in skeletal muscle is insulin dependent whereas glucose flux in neurons is insulin independent . in fact , if the skeletal muscle glucose uptake was sufficient , hyperglycemia would not occur . as such , it is reasonable to postulate that the mechanisms of hyperglycemia - induced muscle dysfunction are likely to be different from those that mediate hyperglycemia - induced neuronal injury . what is the evidence that hyperglycemia produces derangements in skeletal muscle that result in weakness ? it is critical to understand that overall muscle strength depends on muscle - specific force generation ( that is , force generation per muscle mass or force per cross - sectional area ) and on total muscle mass . these two parameters represent distinct aspects of muscle function , and the processes that modulate force generation and muscle mass are different . in this context , only a few studies have examined the effects of more prolonged hyperglycemia on skeletal muscle contractile function , with some showing reductions in muscle - specific force generation whereas others show no change . it is therefore unclear whether hyperglycemia alters muscle force generation . on the other hand , du and colleagues have shown that hyperglycemia results in skeletal muscle caspase 3 activation , degradation of myofibrillar proteins ( specifically actin ) , and subsequent activation of the ubiquitin  proteasomal degradation pathway , leading to muscle atrophy . similarly , russell and colleagues recently demonstrated in cultured myotubes that high glucose induces protein loss via activation of caspase 3 , oxidative stress , and decreased protein synthesis . in addition , studies evaluating hyperglycemia - induced mitochondrial alterations in skeletal muscle reveal inconsistent data  with some showing normal function , while other studies show decrements in oxidative phosphorylation . moreover , data suggest that mitochondrial ultrastructure , complex activity , and muscle protein content are preserved in patients treated with iit . does acute hyperglycemia alter neurons and skeletal muscle in such a way as to produce sustained weakness in patients who survive critical illness ? cheung and colleagues show that many acute respiratory distress syndrome survivors have persistent functional impairment with decreased exercise tolerance , muscle weakness and muscle wasting up to 2 years after icu discharge . over the past decade , the concept of metabolic memory has described the phenomenon that hyperglycemia produces ongoing sustained damage in target tissues even after blood glucose levels are normalized . is it possible that acute hyperglycemia induces metabolic memory in neurons and/or in skeletal muscle and produces the prolonged weakness we see in our patients ? it is conceivable that hyperglycemia - induced mitochondrial free radical generation , irreversible modification of mitochondrial proteins and mitochondrial dna damage   might induce ongoing injury in neurons and skeletal muscle . if this is true , perhaps cip / cim develops because of an acquired mitochondrial myopathy . while entirely speculative , such possibilities should be entertained . in summary , substantial evidence supports that iit reduces the incidence of cip / cim . the proposed mechanisms by which insulin therapy protects neurons and skeletal muscle are related to its anabolic effects and anti - inflammatory effects . while iit remains the only intervention shown to reduce the occurrence of cip / cim , many patients develop prolonged weakness even with iit , indicating that other processes are involved . future studies to elucidate the mechanisms responsible for cip / cim should also address the role of hyperglycemia in these processes . importantly , if ongoing trials reveal that iit imparts a prohibitive risk in icu patients , then this information is crucial . cip / cim : critical illness polyneuropathy / critical illness myopathy ; icu : intensive care unit ; iit : intensive insulin therapy . the present work was supported by nih grants r01 hl80609 ( lac ) , r01 hl80429 ( gss ) , and r01 hl081525 ( gss ) .