| BackgroundIt is well accepted that alterations in glucose metabolism, especially theoccurrence of hyperglycemia associated with insulin resistance is common incritically ill patients after over a century of research. The acute insulin resistance(AIR), or ‘diabetes of injury’, now more commonly referred to as ‘critical illnessdiabetes’, can occur in patients without a history of diabetes.Increased metabolic rate is a common response in critical illness to meet thebody’s higher requirement of energy. Raised blood glucose level during criticalillness has long been considered essential for providing fuel for vital organs andhence was interpreted as a beneficial adaptation or was neglected as aparaphenomenon. However, evidence is now growing against this notion ashyperglycemia is identified as an independent risk factor for adverse outcomes ofcritical illness, such as increased vulnerability to infectious complications,impaired recovery of organ failure, myocardial dysfunction, neuromuscular weakness, mitochondrial dysfunction and mortality. Besides hyperglycemia,variability of blood glucose concentration is also reported as an independent riskfactor for mortality. Therefore, there is a new emphasis on efforts to control bloodglucose level, as well as to reduce glucose excursion in the treatment of criticalillness nowadays.Van den Berghe and his colleagues reported that intensive insulin therapy(IIT) to control blood glucose levels between4.4–6.1mM significantly reducedmortality and complications. However, subsequent clinical trials examining theeffects of IIT have conflicting results. Meanwhile, the risk of hypoglycemia doesexist and often results in poor outcomes in critically ill patients. Moreover, theoptimal timing of therapy is another contentious issue. Clearly, these conflictingresults indicate a need for better understanding the underlying mechanisms ofacute hyperglycemia and associated insulin resistance, which will allow a moretargeted approach to treat critically ill patients.Aims1. To observe characteristics of early hyperglycemia following severe burninjury in rats and explore the relationship between hyperglycemia andmortality.2. To prove the existence of acute insulin resistance and further investigate itsclinical significance.MethodsEighty male Sprague-Dawley (SD) rats weighing200-220g were randomizedinto sham-operated group (in37°C water), burn injury group (immersing theback of rats for15s and abdomen for5s in95°C water), early insulin treatment group (immediately subcutaneous injection following burn injury,2.5IU/kg) andlate insulin treatment group (subcutaneous injection at2.5h post burn injury,2.5IU/kg). Full-thickness third-degree burn injury comprising40%of total bodysurface area was produced and anti-shock treatment (saline,40ml/kg bodyweight) was administered.1. Blood glucose, serum insulin, serum glucagon and serum cortisol levels weremeasured at0min,30min,1h,3h,6h and12h post burn injuryrespectively.2. HOMA-IR index was calculated at given time points. The intraperitonealglucose tolerance test (IPGTT) and insulin sensitivity test (IST) wereperformed at3h and10h after burns respectively.3. To evaluate the cardiovascular function, mean arterial blood pressure(MABP), left ventricular systolic pressure (LVSP), heart rate (HR), and theinstantaneous first derivation of LVP (+dP/dtmaxand dP/dtmax) were derivedfrom computer algorithms3h post burn injury.4. Meanwhile, superficial palm skin blood flow (capillary blood flow) wasmeasured using laser Doppler perfusion imaging technique.5. The expressions of Akt, GSK-3β, eNOS and the phosphorylations of Akt,eNOS, GSK-3β were measured at given time points using western blot.6. Survival states (survival rate, weight and insulin sensitivity) were recorded2wk post burn injury.Results1. Two peaks of intermittent hyperglycemia were observed at30min (named H1)and3h (named H2) respectively after severe burns. Compared with the basallevel (6.5±0.1mM, n=22), H1was increased13%(7.4±0.3mM, n=32, P<0.05) and H2was increased35%(10.0±1.0mM, n=31, P<0.01).Specifically, H2was in a positive linear relationship with H1(H2=2.47×H1-8.23, mM) evaluated by Pearson’s simple correlation (r2=0.78,P<0.01). To further investigate the relationship between blood glucose leveland mortality, rats were classified into two groups based on H2values, with8mM (median value) as a threshold. The survival rate of rats with lower bloodglucose (<8mM,92%) was significantly higher than that in rats with higherblood glucose (>8mM,44%) within12h (n=12-16, P<0.01).2. Levels of serum glucagon were increased at30min,1h and3h post-burn(n=6, P<0.05). Levels of serum cortisol were increased at all time pointsmeasured within12h after burns (n=6, P<0.01). Serum insulin levels wereincreased2-to5-fold at all time points measured within12h post-burn,especially from30min to3h (n=6, P<0.05).3. Insulin resistance index assessed by HOMA-IR score was increased2-to9-fold and fluctuated after burns (n=6, P<0.05). Consistent with HOMA-IRscores, there was significant insulin resistance after burns, much more seriousat3h (n=6, P<0.05). These results suggested that significant insulinresistance occurred with a certain dynamic profile following severe burns.4. As the main regulator of glucose metabolism, Akt phosphorylation wasgradually increased due to elevated serum insulin level after burns andreached maximum value at1h post-burn in both hearts and skeletal muscles(n=4, P<0.05). It was then decreased due to aggravated insulin resistance andtended to be stable after6h post-burn in both hearts and skeletal muscles(n=4, P<0.05). The change of GSK-3β phosphorylation level was consistentwith that of Akt phosphorylation (n=4, P<0.05), while eNOSphosphorylations level showed a similar trend but without significant changes (n=4, P>0.05). These results indicated that insulin signaling activation wassignificantly impaired at3h post burn injury.5. In company with the severity of insulin resistance at3h post burn injury,cardiovascular function was impaired as evidenced by reduced MABP, LVSP,HR,±dP/dtmaxand decreased superficial capillary blood flow.6. After early insulin treatment, blood glucose concentration at30min wasdecreased (n=13, P<0.01) and no peak blood glucose level was detectedwithin12h after burns. Early insulin treatment improved insulin sensitivityboth at3h and10h post burn injury assessed by IPGTT and IST (n=6,P<0.05). Furthermore, it attenuated cardiac dysfunction and improvedsuperficial capillary blood flow (n=6, P<0.05). More importantly, the survivalrate of rats with early insulin treatment (93%, n=43) was significantly higherthan that in rats without treatment (71%, n=34) within12h (P<0.01).7. In late insulin treatment group, there was no increase of blood glucoseconcentration at3h post-burn (n=12, P>0.05). However, another peak ofblood glucose level was detected at around8h with a similar increase to thatof H2in rats without treatment. Late insulin treatment failed to improve thesurvival rate within12h (55.6%, n=18, p>0.05) post burn injury and had noprotective effects in long term (survival rate, weight and insulin sensitivity,2wk later)(n=18, P>0.05).ConclusionsThese results demonstrate for the first time that intermittent hyperglycemiaand acute insulin resistance (AIR) immediately occurred following severe burns,which had a definite pattern over time and amplitude. Early insulin treatmenthelped alleviate AIR and reduce mortality following severe burns while late insulin treatment had no protective effects. |
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