Hypoglycaemia downregulates endotoxin-induced production of tumour necrosis factor-α, but does not affect IL-1β, IL-6, or IL-10
Introduction
Proinflammatory cytokines, such as tumour necrosis factor-α (TNFα), interleukin-1β (IL-1β), and IL-6 are important mediators of the inflammatory response. Cytokines are elicited when the host is exposed to infectious organisms, [1] but may also appear in response to physical exercise, [2] trauma, [3] surgery, [4], [5] and resuscitation/haemorrhagic shock [6] as part of a stress response. Often, stressful events are followed by downregulated production of proinflammatory cytokines, which may be associated with release of adrenaline and cortisol, [7] with antiinflammatory effects of IL-10, [8], [9], [10] or with other factors [11], [12]. The downregulation of TNFα and IL-1β production capacity may be seen as a means to protect the host against excessive release of potentially deleterious cytokines. On the other hand, a decrease in cytokine production may increase vulnerability to secondary stressors, such as infections [13]. This higher susceptibility to (secondary) infections has been demonstrated in mice [14] and has been designated as ‘post-traumatic immune paralysis’ [15].
Hypoglycaemia is perceived as considerably stressful by the human body. Apart from glucagon release necessary to restore normoglycaemia, plasma adrenaline levels increase dramatically as do plasma levels of noradrenaline, cortisol, and growth hormone [16]. Most (insulin-treated) diabetic patients suffer from hypoglycaemic episodes more than once a week, especially since tight metabolic control has become standard in the management of diabetes [17], [18]. As far as we know, the effect of hypoglycaemia on cytokine kinetics has not been studied before. As a systemic stressor, hypoglycaemia may be expected to downregulate ex vivo cytokine production. Alternatively, downregulation may also occur as an effect of hypoglycaemia per se, because cytokine production capacity has been shown to depend directly on the ambient glucose level [19], [20]. The purpose of the present study was to determine the effect of in vivo hypoglycaemia, using a two-step hyperinsulinaemic hypoglycaemic clamp, on ex vivo endotoxin-induced cytokine production in healthy volunteers—having no prior hypoglycaemic experience—and in well-controlled Type 1 diabetic patients known to have frequent hypoglycaemic episodes. In addition, the role of the clamp procedure per se was investigated by a separate normoglycaemic time-control experiment, and the roles of insulin and adrenaline were investigated by separate in vitro studies.
Section snippets
Results
Prior to the clamp, plasma glucose levels were significantly higher in diabetic subjects than in healthy controls (11.2±0.1 versus 5.0±0.1 mmol l−1, P<0.001). Mean (±SD) glucose levels obtained at each glycaemic plateau during hypoglycaemia studies in both diabetic patients and healthy subjects were 5.0±0.1, 3.4±0.1, and 2.5±0.1 mmol l−1, respectively. During the normoglycaemia control study, plasma glucose remained 5.0±0.1 mmol l−1 throughout the experiment. Corresponding insulin levels were 930±132
Discussion
The main findings of our study were that insulin-induced hypoglycaemia specifically downregulated LPS-stimulated TNFα synthesis in a glucose concentration-dependent manner in healthy individuals. In type 1 diabetic patients, the effect was less accentuated and only significant at hypoglycaemic nadir. Under normoglycaemic conditions, the production capacity of TNFα was significantly lower in Type 1 diabetic patients than in healthy controls, whereas levels of circulating TNFα tended to be
Subjects
Written informed consent was obtained from 10 healthy individuals (six men and four women), mean (±SD) age 26.2±5.3 years, and eight Type 1 diabetic patients (four men and four women), age 34.5±2.9 years, duration of diabetes 15.0±2.1 years, and HbA1c 7.2±0.1%. Diabetic patients reported to have hypoglycaemic episodes at least once weekly and they were instructed to avoid hypoglycaemia for 3 days prior to the experiments. The study was approved by the hospital ethics committee of the University
Acknowledgements
We are indebted to Liesbeth Jacobs and Trees Verver-Jansen for their assistance with the cytokine determinations.
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