Critically ill patients show an adaptation of their metabolism to severe stress. This so-called postaggression metabolism leads to extensive changes in lipid, protein and carbohydrate metabolism [1-3]. The latter is characterized by enhanced gluconeogenesis and peripheral insulin resistance . The severity of insulin resistance can be determined in vivo using the euglycaemic hyperinsulinaemic clamp technique, which directly measures the effects of insulin to promote glucose utilization under steady-state conditions [5,6]. However, the performance of the euglycaemic hyperinsulinaemic clamp technique is time-consuming and associated with high costs. Alternatives for estimating insulin resistance include the Quantitative Insulin Sensitivity Check Index (QUICKI) and the Homeostasis Model Assessment (HOMA) [7,8]. QUICKI and HOMA are calculated indices of insulin resistance and have been developed by computer modelling and mathematical transformation of fasting glucose and insulin concentrations. Both indices are based on the fact that the relationship between glucose and insulin in the basal state reflects the balance between hepatic glucose output and insulin secretion, which is maintained by a feedback loop between liver and the β cells. Therefore, fasting glucose and insulin values contain crucial information about insulin sensitivity. QUICKI was developed after analysing data of glucose clamps and frequently sampled intravenous (i.v.) glucose tolerance tests of non-obese, obese and diabetic subjects . The approximation formula of HOMA was derived from a computer-solved model of insulin-glucose interaction . These indices have been evaluated in healthy subjects as well as in patients suffering from different diseases [7-12]. All these studies showed a significant correlation between QUICKI and/or HOMA and the euglycaemic hyperinsulinaemic clamp technique. These calculated indices of insulin sensitivity were described to be cheap and easy to apply in a large number of patients [7-12]. Thus, they seemed to be a reliable alternative to the clamp. Recently, HOMA was used to estimate insulin resistance in critically ill patients with acute renal failure . The authors conclude from their results that high HOMA values are indicative for the high prevalence of insulin resistance in critically ill patients although insulin resistance was not quantified by the euglycaemic hyperinsulinaemic clamp technique. However, these results have to be questioned since reliabilities of QUICKI and HOMA have never been evaluated in critically ill patients so far.
We, therefore, performed an observational study to assess the reliability of QUICKI and HOMA compared with the current gold standard method, the euglycaemic hyperinsulinaemic clamp technique, for the estimation of insulin resistance in critically ill medical patients.
Materials and methods
Thirty critically ill medical patients admitted to a medical ICU were included in this study. All patients were continuously sedated, mechanically ventilated and received a central venous catheter and an arterial line within the scope of routine monitoring on admission. Surgical patients and trauma patients as well as patients suffering from preexisting insulin-dependent diabetes were excluded.
According to our nutritional protocol patients received enteral nutrition from the admission day in the absence of contraindications (Nutrison® Standard; N. V. Nutricia-Zoetermeer, The Netherlands). Energy requirements for ICU patients were calculated with 25 kcal kg−1 bodyweight per day. Patients were prescribed 50% of calculated energy requirements on day 1, 75% on day 2 and 100% from day 3. The euglycaemic hyperinsulinaemic clamp was performed after an overnight fast (8 h) on the day after ICU admission as described by DeFronzo and colleagues . During the overnight fast, both artificial nutrition and fluids containing glucose were withheld from the patients. Patients with blood glucose levels above 180 mg dL−1 and patients developing spontaneous glucose levels below 60 mg dL−1 during the overnight fast were excluded. In these patients insulin therapy or glucose infusion could not be withheld. None of the included patients received subcutaneous or i.v. insulin therapy during the overnight fast.
The clamp was started at 8.00a.m. on the day after ICU admission. After a 30-min baseline period, when basal glucose and insulin concentrations were determined, insulin infusion (Actrapid®; Novo Nordisk, Bagsvaerd, Denmark) was started in a primed continuous manner in order to raise and maintain plasma insulin levels at a new plateau for 120 min. The insulin infusate was prepared in isotonic saline to which 2 mL of the patient's blood per 50 mL infusate were added in order to prevent adsorption of insulin to plastic surfaces . For a 1 mU kg−1 min−1 clamp, an amount of 6 units of insulin per square metre of body surface area was added to the 50 mL infusate. Plasma glucose was maintained (‘clamped’) at its basal level by a variable rate of glucose infusion (Glucose 20%; Fresenius Kabi Pharma, Austria).
Arterial blood samples for monitoring plasma glucose were drawn every 10 min. Plasma glucose was measured at bedside using the glucose oxidase method (Beckman Glucose Analyzer II; Beckman Instruments Corporation, Anaheim, CA, USA).
Plasma insulin concentration was measured at minute 0, 30, 60, 90, 120 using a liquid radioimmunoassay (Pharmacia-Upjohn, Uppsala, Sweden). The steady-state period of the clamp was defined as the time from minute 60 to 120, when variation of plasma glucose and insulin was <5%. The M-value was calculated using the glucose infusion rate, the space correction and by correcting for eventual urinary loss as described previously .
Indices for insulin resistance were calculated for every patient as follows [7,8]:
where I0 = fasting plasma insulin concentration (μU mL−1), G0 = fasting plasma glucose concentration (mg dL−1).
where G0 = fasting plasma glucose concentration (mM L−1), I0 = fasting plasma insulin concentration (μU mL−1).
These two indices were calculated for all patients using baseline values of glucose and insulin concentrations, which were collected in the course of the clamp. The APACHE (Acute Physiology and Chronic Health Evaluation) III score is used for evaluation of severity of critical illness and was calculated for every patient included .
The study protocol conformed to the ethical guidelines of the Declaration of Helsinki. The study protocol was approved by the Local Review Board. According to the Austrian law and the guidelines of the Ethics Committee of the Medical University of Vienna post hoc informed consent was obtained from the patients when possible. Next of kin was informed about the study.
Data are expressed as means ± SD. Repeated measures ANOVA was used to calculate changes of parameters over time. If results were found to be significant, a Tukey's multiple comparison test was used for post hoc testing. Correlations between pairs of values of insulin sensitivity (M-value, QUICKI, HOMA) were assessed by means of Pearson's correlation coefficient (r2). Statistical analysis was carried out using the GraphPad Prism 4.00 software program (GraphPad Software Inc., San Diego, USA). A P-value of <0.05 was regarded to indicate statistical significance.
Thirty critically ill medical patients were included in this study. Clinical characteristics and laboratory parameters are shown in Table 1. Admission reasons of patients are given in Table 2. Baseline blood glucose concentration was 117 ± 27 mg dL−1 and remained unchanged throughout the whole clamp (Fig. 1). Baseline insulin concentration increased significantly during the priming period of the clamp (20.9 ± 19.3 μU mL−1 at baseline and 69.0 ± 26.6 μU mL−1 after 30 min; P < 0.01) and remained unchanged during steady state (70.2 ± 33.2 μU mL−1; Fig. 1). Patients received 4.6 ± 0.6 U of insulin during the clamp.
The M-value was 2.07 ± 0.64 mg kg−1 min−1. HOMA and QUICKI were 6.38 ± 6.43 and 0.319 ± 0.04, respectively. No association was found between QUICKI and the M-value (r2 = 0.008), as well as between HOMA and the M-value (r2 = 0.0005). A significant correlation was found between the M-value and the APACHE III score (r2 = 0.16; P < 0.05; Fig. 2). HOMA and QUICKI were not associated with the APACHE III score (r2 = 0.034 and 0.033, respectively).
In critically ill patients intensive insulin therapy leading to normoglycaemia resulted in decreased morbidity and mortality in critically ill patients . Insulin resistance is one of the major causes of stress hyperglycaemia . These facts recently aroused rising awareness of insulin resistance in critically ill patients . The calculated indices of insulin resistance, QUICKI and HOMA, promised to be easily applicable methods for quantifying insulin resistance [7,8]. However, our results failed to show an association between the calculated indices of insulin resistance and the euglycaemic hyperinsulinaemic clamp in critically ill medical patients. Several reasons might be responsible for this failure. First of all, the lack of association could be explained by the finding that HOMA and QUICKI do not distinguish between hepatic and peripheral insulin resistance, whereas the euglycaemic hyperinsulinaemic clamp evaluates glucose disposal in peripheral tissues and, therefore, assesses peripheral insulin resistance only . Critical illness represents a state in which hepatic and peripheral insulin resistance are uncoupled . This finding is also supported by Thorell and colleagues , who showed that exogenous insulin administration could only reduce hepatic gluconeogenesis, but it had no influence on whole-body glucose disposal.
Secondly, QUICKI and HOMA use fasting insulin and glucose concentrations for calculation [7,8]. Fasting plasma glucose and fasting plasma insulin concentrations reflect basal insulin sensitivity and responsiveness. In contrast, the euglycaemic hyperinsulinaemic clamp reflects stimulated insulin sensitivity .
Another aspect might be that under hyperglycaemic conditions, as are often found in critically ill patients, some parts of the plasma glucose are eliminated in an insulin-independent manner. Therefore, the degree of glucose metabolism cannot exactly be estimated by the fasting glucose and insulin concentrations.
Furthermore, fasting plasma insulin and fasting plasma glucose levels do not depend on tissue insulin sensitivity only. Fasting plasma insulin concentration is also influenced by insulin secretion, insulin distribution and insulin degradation . Critically ill patients often show symptoms of impaired liver and renal function, what might influence insulin degradation. Laboratory parameters of our patients showed impaired renal function as well as hepatic disorders. We believe that critical illness with the concomitant postaggression metabolism is the major cause of insulin resistance in our critically ill medical patients. This statement is also supported by the finding that the M-value was associated with the APACHE III score, which is a reliable measure of the severity of illness. No association could be found between HOMA and QUICKI and the APACHE III score, which might be based on the insufficient quantification of insulin resistance of the two calculated indices in critically ill medical patients.
HOMA was prematurely used in critically ill patients with acute renal failure . However, as our study shows these calculated indices neither are as reliable nor are as accurate as the euglycaemic hyperinsulinaemic clamp technique, the current gold standard method for measuring insulin resistance in critically ill patients.
QUICKI has been established by Katz and colleagues  after analysing fasting insulin and glucose concentrations of healthy, obese and diabetic subjects, and its accuracy has been approved by comparison of QUICKI with the euglycaemic hyperinsulinaemic clamp and a frequently sampled i.v. glucose tolerance test. HOMA was developed by a computer model of fasting glucose-insulin interaction, and its reliability was confirmed in healthy and diabetic subjects by comparison with the results of a euglycaemic hyperinsulinaemic clamp, a hyperglycaemic clamp, and an i.v. glucose tolerance test . Studies including lean and obese subjects, pregnant women, as well as patients suffering from type 2 diabetes and arterial hypertension have shown excellent correlation between QUICKI, HOMA and the euglycaemic hyperinsulinaemic clamp [7-12,20].
A limitation of this study might be the low insulin infusion rate used in our patients, although a high insulin resistance could be expected. Moreover, the isotopic glucose method was not used in our euglycaemic hyperinsulinaemic clamps, which could have compensated for the incomplete suppression of hepatic gluconeogenesis. This could have caused an overestimation of insulin resistance by using the 1 mU min−1 kg−1 clamp technique. However, Chambrier and colleagues  have shown that this insulin infusion rate was able to suppress endogenous glucose production in septic patients. Therefore, we regarded the same infusion rate to be applicable in our critically ill medical patients.
In summary, our results show that QUICKI and HOMA indicated insulin resistance in the critically ill patients however, are not able to reliably quantify it. Consequently, both indices did not correlate with the M-value. Therefore, the euglycaemic hyperinsulinaemic clamp remains the gold standard for measuring insulin resistance in critically ill medical patients.
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