Original ContributionAnti-inflammatory and organ protective effect of insulin in scalded MODS rats without controlling hyperglycemia
Introduction
Multiple organ dysfunction syndrome (MODS) caused by wound infection, intestinal bacterial translocation and inflammation is the main cause of mortality in hospitalized patients with severe trauma, including burns and major surgical procedures [1], [2], [3], [4]. Posttraumatic hyperglycemia and MODS enhance each other, and severe traumatic hyperglycemia is positively correlated with the degree of multiple organ dysfunction [5], [6], [7]. Posttraumatic hyperglycemia would deteriorate MODS; however, severe posttraumatic MODS results in insulin resistance and dysfunction of the islet B cell, and enhances posttraumatic hyperglycemic reaction [8], [9], [10]. Insulin is the only hormone that could effectively promote the oxidation of glucose providing adenosine triphosphate. Studies reported that insulin could strictly control hyperglycemia of patients in the intensive care unit and improve the prognosis. In vitro experiments have also demonstrated that insulin has an anti-inflammatory effect by downregulation of the nuclear transcription factor NF-KB [11], [12], [13], [14]. However, because insulin in vivo could alleviate hyperglycemia, there is no direct evidence regarding whether insulin has a direct anti-inflammatory effect, or if there is a controlling effect of hyperglycemia. It is worth studying whether the anti-inflammatory effect of insulin is dosage dependent, as other anti-inflammatory drugs.
Because insulin is a low-cost drug, like other anti-inflammatory drugs, the dosage of insulin should be associated with the severity of inflammatory response and the severity of inflammation. However, an incorrect dosage of insulin could lead to hypoglycemia or even shock, limiting the use of insulin as an anti-inflammatory drug. To resolve the problem of using different dosages of insulin for anti-inflammation, and to observe the anti-inflammatory effect of insulin without controlling hyperglycemia, we rationally adjusted insulin and glucose ratio, and combined injection of insulin and glucose. The study not only can achieve treatment of different traumatic inflammation by different dosages of insulin, but also may control different severe posttraumatic blood glucose levels (normal blood glucose and hyperglycemia).
Section snippets
Materials
Healthy, clean Sprague-Dawley rats, weighing 200 ± 15 g, with half male and hale female (Jiangxi University of Traditional Chinese Medicine Experimental Animal Center, production license SCXK (Gan) 2013-0001, quality certificate 1308118); long glargine (Sanofi (Beijing) Pharmaceutical Co., LTD, specification 20,160,032, 3.0 mL:300 U). Endotoxin (LPS, lipopolysaccharide, Escherichia coli O111: B4, Sigma-Aldrich, USA). Blood glucose, alanine transaminase (ALT), creatinine (CRE), creatine kinase-MB
Surviving outcomes of rats in different groups
The 7-day survival rate in group C was 75.0%. There was no significant difference in the survival rates between all rats in the A and B groups (P > 0.05). See Table 1.
Blood glucose levels of rats in each groups
The blood glucose of MODS rats in group C was significantly higher than before injury (P < 0.01). The blood glucose levels in all subgroups of group A were lower than those of group C at all time points (all P < 0.01). The blood glucose levels in all subgroups of group B were higher than before injury at all time points (all P < 0.01),
Discussion
Severe posttraumatic MODS is usually involved in liver dysfunction, renal dysfunction, and changes of myocardial zymogram. The prognosis of patients with MODS could be improved to a certain extent with clinical detection and intervention at an early stage [17]. In our research, an animal model with severe traumatic MODS demonstrated high levels of relevant indicators of liver dysfunction, renal dysfunction, and myocardial enzymes for 7 consecutive days after injury. The average survival rate
Conclusions
Insulin could take the effect of anti-inflammatory and organ protection in a dosage-dependent way without hyperglycemia control. Temporary traumatic hyperglycemia itself might not be detrimental to the body. Patients with severe posttraumatic hyperglycemia could be treated with a combination of insulin and glucose. By adjusting the ratio of insulin and glucose, insulin could be used freely for anti-inflammation and organ protection in accordance with the severity of inflammation, without the
Disclosure
The authors declare that they have no competing interests, or other interests that might be perceived to influence the results and discussion reported in this paper.
Acknowledgments
This work was supported by the National Key R&D Program of China (2017YFC1103300), the Ph.D. Candidate Research Innovation Fund of Nankai University School of Medicine (2017011), National Science and Technology project (2008BAI52B03), Jiangxi Provincial Science and Technology project (2014ZBBG70004), Key Issues for the “Eleventh Five-Year” in Nanjing Military Region (06Z25), the Health Science and Technology project in Jiangxi Province (20173025). All the authors would like to express great
Reference (47)
- et al.
Bacterial translocation in an experimental model of multiple organ dysfunctions
J Surg Res
(2013) - et al.
The systemic immune response to trauma: an overview of pathophysiology and treatment
Lancet
(2014) - et al.
Dutch burn repository group, mortality and causes of death of Dutch burn patients during the period 2006–2011
Burns
(2015) - et al.
Effects of insulin combined with ethyl pyruvate on inflammatory response and oxidative stress in multiple-organ dysfunction syndrome rats with severe burns
Am J Emerg Med
(2016) - et al.
Tissue damage volume predicts organ dysfunction and inflammation after injury
J Surg Res
(2016) - et al.
Bacterial respiratory tract infections are promoted by systemic hyperglycemia after severe burn injury in pediatric patients
Burns
(2014) - et al.
Protective effect of glucose-insulin-potassium (GIK) on intestinal tissues after severe burn in experimental rats
Burns
(2012) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Cell
(2010)- et al.
HMGB-1 as a useful prognostic biomarker in sepsis-induced organ failure in patients undergoing PMX-DHP
J Surg Res
(2011) - et al.
Survivors versus nonsurvivors postburn: differences in inflammatory and hypermetabolic trajectories
Ann Surg
(2014)
Admission hyperglycemia is associated with higher mortality in patients with hip fracture
Eur J Emerg Med
Increasing blood glucose variability is a precursor of sepsis and mortality in burned patients
PLoS One
Time in blood glucose range 70 to 140 mg/dl > 80% is strongly associated with increased survival in non-diabetic critically ill adults
Crit Care
Evidence for the participation of soluble triggering receptor expressed on myeloid cells-1 in the systemic inflammatory response syndrome after multiple trauma
J Trauma
Inflammation and insulin resistance
J Clin Invest
IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB
Am J Physiol Endocrinol Metab
Intensive insulin therapy in the medical ICU
N Engl J Med
Insulin inhibits NF-kappaB and MCP-1 expression in human aortic endothelial cells
J Clin Endocrinol Metab
Insulin alleviates the inflammatory response and oxidative stress injury in cerebral tissues in septic rats
J Inflamm (Lond)
Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans
Am J Physiol Endocrinol Metab
Insulin protects against hepatic damage postburn
Mol Med
Influence of glucose-insulin-potassium on the levels of inflammatory cytokines and prognosis of MODS in the scalded rats
Zhonghua Shao Shang Za Zhi (in Chinese)
Pattern of cytokine (IL-6 and IL-10) level as inflammation and anti-inflammation mediator of multiple organ dysfunction syndrome (MODS) in polytrauma
Int J Burns Trauma
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Zhu Zhongzhen and Hu Tian contributed equally to this work.