Cytokines associated with insulin resistance in critically ill patients

Introduction

We examined the relationship between proinflammatory cytokines, adipocyte-derived adiponectin and hyperglycemia. Patients requiring long periods in the ICU have a relatively high mortality. Tight glucose control with insulin infusions has been shown to improve survival and prevent complications.

Methods

A prospective, observational study at an academic ICU. A sequential sample was taken over a 2-month period. Ethics approval was obtained from the University Ethics Committee.

Baseline bloods for TNFα, IL-6, adiponectin (Adipo), total cholesterol (TC), triglycerides (TG), insulin, C-peptide (CPep) and cortisol (Cort) were collected on admission (D0). These were repeated on day 3 (D3), day 7 (D7) and discharge (D/C). Routine bloods ordered were also used. Data on the ICU charts were also used. No changes to ICU protocols were required. Of note, insulin infusions were started for blood glucose concentrations greater than 6 mmol/l. Exclusion criteria included all patients with diabetes mellitus, chronic renal failure and liver failure or cirrhosis.

Results

Forty patients admitted to the ICU were enrolled and followed up to discharge. The median age was 35.5 years (minimum 18, maximum 66). The median APACHE II score was 10.5 (minimum 2, maximum 28) and the median duration was 6 days (minimum 1, maximum 43). D0, D3, D7 and D/C glucose concentrations did not differ (Kruskal–Wallis ANOVA, P = 0.98). TNFα peaked at D3 (4.9 pg/ml) and then started decreasing. Administered insulin (InsAd) accompanied the TNFα peak at D3 (32U) and then decreased. Adipo peaked at D7 (10,774 pg/ml) after the TNFα peak, which coincided with the TNFα decrease at D7 to 4.76 pg/ml. Endogenous insulin indicated by CPep peaked with Adipo at D7 (2.8 μg/l). TG levels increased in parallel with increasing TNFα from 0.7 mmol/l at D0 to 1.1 mmol/l at D3 and then declined. TC was lowest at D0 and increased up to D/C but remained relatively low. Table 1 shows several variables and their change over time from admission to discharge. Table 2 shows the correlations between these variables. Survivors had a lower median TNF than nonsurvivors (Mann–Whitney U test, P = 0.066).

Table 1 Changes in glucose, insulin, cytokines and lipids in the ICU over time

Table 2 Relevant Spearman correlations between the parameters

Conclusion

TNF contributes to increased insulin needs. TNF is known to cause insulin resistance. We have shown that TNF correlates inversely with Adipo. As Adipo increases, insulin needs are decreased (inverse correlation with InsAd). Also, TNF contributes to increase TG indicating increased free fatty acids (FFA) by lipolysis, which impairs glucose clearance. Adipo, an insulin sensitizing protein, is known to negatively regulate TNF levels as was indicated by our study. Adipo contributed to a decrease in TG indicating lower FFA and better glucose clearance. IL-6 at D/C also contributed to a higher glucose concentration at D/C. Increasing age contributed to lower Adipo levels at D/C, indicating lower insulin sensitivity. A higher BMI contributed to a higher glucose level at D0 and increased insulin needs at D0. Finally, a higher TNF level appears to be related to increased mortality