Elsevier

Cytokine

Volume 22, Issues 3–4, May 2003, Pages 71-76
Cytokine

Hypoglycaemia downregulates endotoxin-induced production of tumour necrosis factor-α, but does not affect IL-1β, IL-6, or IL-10

https://doi.org/10.1016/S1043-4666(03)00113-3Get rights and content

Abstract

The aim of the present study was to investigate the effect of hypoglycaemia on the production capacity of the proinflammatory cytokines tumour necrosis factor-α (TNFα) and interleukin-1β (IL-1β) in subjects with and without diabetes. Hyperinsulinaemic (360 pmol m−2 min−1) stepped hypoglycaemic (5.0–3.5–2.5 mmol l−1) glucose clamps were performed in eight diabetic patients and in six non-diabetic subjects, and hyperinsulinaemic normoglycaemia (5.0 mmol l−1) control experiments were performed in four non-diabetic subjects. Circulating levels of cytokines and endotoxin-induced production of TNFα, IL-1β, IL-6, and IL-10 were assessed. The effects of insulin and adrenaline were measured in separate in vitro experiments. In non-diabetic subjects, hypoglycaemia downregulated the production capacity of TNFα in a concentration-dependent fashion (P=0.007), but not of IL-1β, IL-6, or IL-10. Compared to controls, the production capacity of TNFα in diabetic patients was already suppressed at normoglycaemia (P=0.02) and only fell in response to hypoglycaemic nadir (P=0.04). The downregulation of TNFα could not be explained by increased insulin or adrenaline levels. We conclude that hypoglycaemia specifically downregulates TNFα production capacity. Diabetic patients already have a suppressed TNFα production capacity at non-hypoglycaemic levels.

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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