Original Contribution
Anti-inflammatory and organ protective effect of insulin in scalded MODS rats without controlling hyperglycemia

https://doi.org/10.1016/j.ajem.2017.07.070Get rights and content

Highlights

  • The effect of anti-inflammation of insulin do not depend on controlling hyperglycemia

  • The effect of anti-inflammation of insulin is in a dosage dependent manner

  • Different dosage of insulin could be used to treat inflammatory response by combination of insulin and glucose

  • Temporary traumatic hyperglycemia itself might not be detrimental to the body

Abstract

Background

Insulin, as an anti-inflammatory drug, could not be freely used in patients who experienced trauma according to the degree of inflammation, because of the side effect of hypoglycemia. In vivo experimental evidence is lacking concerning whether the effect is dosage dependent and whether it relies on controlling hyperglycemia.

Methods

By adjusting the dosage ratio of glucose and insulin, different dosages of insulin were used to treat severely scalded MODS rats to achieve uncontrolled or controlled hyperglycemia. One hundred forty rats with severe scalded were randomly divided into a hyperglycemia-controlled group, hyperglycemia-uncontrolled group, and control group. The levels of inflammation response indexes and major organ dysfunction indexes were measured and compared between groups.

Results

The blood indexes of inflammatory response and major organ dysfunction did not show statistical difference between hyperglycemia-controlled groups (A) and uncontrolled groups (B) in the same dosage of insulin (all P > 0.05). The blood indexes of inflammatory response and major organ dysfunction demonstrated statistical difference in different dosages of insulin with hyperglycemia-controlled groups (A1–A3 groups) and hyperglycemia-uncontrolled groups (B1–B3 groups) (all P < 0.01). The higher dosage of insulin, the better effect of anti-inflammation and organ protection it would demonstrate with or without controlling hyperglycemia.

Conclusions

The effect of anti-inflammation and organ protection of insulin is dosage dependent in vivo; it does not rely on controlling hyperglycemia. Temporary traumatic hyperglycemia itself might not be detrimental to the body. Adjusting the ratio of insulin and glucose could provide a novel train of thought for freely treating patients with severe traumatic injury with different dosages of insulin according to the degree of inflammation.

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

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    Zhu Zhongzhen and Hu Tian contributed equally to this work.

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