Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects
Introduction
We have documented that severe hyperglycemia of diabetic ketoacidosis (DKA) or nonketotic hyperglycemia provokes elevation of counterregulatory hormones, proinflammatory cytokines (tumor necrosis factor [TNF]–α, interleukin [IL]-6, IL-8, and IL-1β), markers of reactive oxygen species (ROS) measured by dichlorofluorescein (DCF) or lipid peroxidation measured as malondialdehyde (MDA), cardiac risk factors including C-reactive protein, and free fatty acids (FFA). These parameters, which are 2- to 3-fold higher than normal, return to normal values within 24 hours of insulin therapy and resolution of hyperglycemia and dehydration [1]. We had previously suggested that these prompt responses to elevation of cytokines and counterregulatory hormones may be due to either anti-inflammatory effects of insulin or, more likely, responses to stress of hyperglycemia. Because patients with diabetes on antidiabetic agents experience hyperglycemia and hypoglycemia, these excursions may provoke various responses in the body. We have chosen hypoglycemia in distinction to hyperglycemia to investigate if such a stress would also produce similar responses to that of hyperglycemia. Herein, we present the results of insulin-induced hypoglycemia in 13 nondiabetic male subjects.
Section snippets
Participants
Healthy male subjects with no history of current infection, cardiovascular risk factors, metabolic syndrome, or abnormal glucose metabolism were invited to participate in the study that was approved by the ethics committee of Endocrinology and Metabolism Research Center of Tehran University. On admission, after physical examination including measuring the vital signs, blood was drawn between 8:00 and 9:00 am for the following tests: complete metabolic profile, cell blood counts with
Results
Table 1 demonstrates the baseline characteristics of the participants. During the ITT, no severe adverse events were detected; and infusion of 50% glucose was not required during the study, as hypoglycemia less than 30 mg/dL or intolerable hypoglycemic symptoms did not occur in any of participants. The mean nadir of hypoglycemia was 38.2 ± 4.3 mg/dL, which was recorded at 30 minutes. The levels of counterregulatory hormones (GH, ACTH, EP, and NE), WBC, proinflammatory cytokines, FFA, MDA, and
Discussion
In this study, we have demonstrated the responses of body to the stress of hypoglycemia; these include the well-known responses of counterregulatory hormones [2], [3] and previously unknown elevation of proinflammatory cytokines, markers of lipid peroxidation and ROS, as well as leukocytosis.
Based on the present findings, EP is a predictor of TNF-α and IL-8. Cortisol predicts the change of IL-1β. Corticotropin predicts IL-6 with borderline significance. Norepinephrine and cortisol are
Acknowledgment
We are grateful to our volunteers, whose participation made this study possible, and to Ms Brenda Scott for her secretarial assistance, Ms Cat Casey for her depiction of the results in the 5 figures, and Mr John Crisler for his assistance in laboratory assays.
None of the authors have any financial interests that might conflict with this study.
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2021, IBRO Neuroscience ReportsCitation Excerpt :Previous studies have reported that swim stress alone (Dal-Zotto et al., 2000; Himmerich et al., 2013) and 2-DG alone (Deak et al., 2005; Dréau et al., 2000; Horman et al., 2018) can increase blood levels of CORT and TNF-α in rodents. In the current study, serum levels of CORT increased following exposure to swim stress and to injections of 2-DG (Table 1), which is consistent with previous studies reporting increased CORT levels in response to forced swimming (Dal-Zotto et al., 2000) and experimentally-induced hypoglycemia (Deak et al., 2005; Horman et al., 2018; Razavi Nematollahi et al., 2009). Neither stressor alone significantly impacted TNF-α levels.