Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Pathophysiology

Proinflammatory Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid Peroxidation in Patients With Hyperglycemic Crises

  1. Frankie B. Stentz,
  2. Guillermo E. Umpierrez,
  3. Ruben Cuervo and
  4. Abbas E. Kitabchi
  1. From the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
  1. Address correspondence and reprint requests to Frankie B. Stentz, PhD, Assistant Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Tennessee Health Science Center, 951 Court Ave., Room 340M, Memphis, TN 38163. E-mail: fstentz{at}utmem.edu
Diabetes 2004 Aug; 53(8): 2079-2086. https://doi.org/10.2337/diabetes.53.8.2079
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Abstract

Acute and chronic hyperglycemia are proinflammatory states, but the status of proinflammatory cytokines and markers of oxidative stress and cardiovascular risks is not known in hyperglycemic crises of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH). We studied 20 lean and 28 obese patients with DKA, 10 patients with NKH, and 12 lean and 12 obese nondiabetic control subjects. We measured 1) proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-6, IL1-β, and IL-8), 2) markers of cardiovascular risk (C-reactive protein [CRP], homocysteine, and plasminogen activator inhibitor-1 [PAI-1]), 3) products of reactive oxygen species (ROS; thiobarbituric acid [TBA]-reacting material, and dichlorofluorescein [DCF]), and 4) cortisol, growth hormone (GH), and free fatty acids (FFAs) on admission (before insulin therapy) and after insulin therapy and resolution of hyperglycemia and/or ketoacidosis. Results were compared with lean and obese control subjects. Circulating levels of cytokines, TBA, DCF, PAI-1, FFAs, cortisol, and GH on admission were significantly increased two- to fourfold in patients with hyperglycemic crises compared with control subjects, and they returned to normal levels after insulin treatment and resolution of hyperglycemic crises. Changes in CRP and homocysteine in response to insulin therapy did not reach control levels after resolution of hyperglycemia. We conclude that DKA and NKH are associated with elevation of proinflammatory cytokines, ROS, and cardiovascular risk factors in the absence of obvious infection or cardiovascular pathology. Return of these values to normal levels with insulin therapy demonstrates a robust anti-inflammatory effect of insulin.

  • AGE, advanced glycation end product
  • CRP, C-reactive protein
  • DCF, dichlorofluorescein
  • DKA, diabetic ketoacidosis
  • FFA, free fatty acid
  • GH, growth hormone
  • IL, interleukin
  • NKH, nonketotic hyperglycemia
  • PAI-1, plasminogen activator inhibitor-1
  • ROS, reactive oxygen species
  • TBA, thiobarbituric acid
  • TNF-α, tumor necrosis factor-α
  • UTHSC, University of Tennessee Health Science Center

Diabetes is a chronic inflammatory state associated with insulin resistance (1–3). Hyperglycemia has been shown to induce proinflammatory cytokines and chemokine genes in monocyctic cells (4). Certain cytokines, such as tumor necrosis factor-α (TNF-α), impair insulin action in peripheral tissue (5) and have a direct role in obesity-linked insulin resistance (6). Interleukin-6 (IL-6) also influences glucose metabolism by alteration of insulin sensitivity (7). Chronic hyperglycemia has been shown to be responsible for multiple micro- and macrovascular complications as a result of hyperglycemic damage through four major biochemical processes, including advanced glycation end products (AGEs), the polyol pathway, the hexosamine pathway, and activation of protein kinase C, as described by Brownlee (8) and King and Brownlee (9). Recent studies suggest that lipid infusion in normal subjects may also result in the alteration of some of the above pathways and may induce insulin resistance (10).

Hyperketonemia in patients with type 1 diabetes has also been associated with increased plasma lipid peroxidation (11). Increased blood levels of IL-6 are also reported in type 1 diabetes without clinical evidence of micro- or macrovascular complications (12). Furthermore, abnormal markers of endothelial dysfunction and oxidative stress have been demonstrated in children with type 1 diabetes with no clinical vascular disease (13). Obesity and insulin resistance are also associated with adipose tissue secretion of IL-6 and TNF-α (14). Additionally, interaction of AGEs with cellular receptors alters the level of gene expression, which leads to the development of vascular abnormalities and activation of the transcription factor nuclear factor-κB in polymorphonuclear leukocytes (15).

Furthermore, transient hyperglycemia (16) or hyperlipidemia (17) in normal subjects results in the activation of the generation of reactive oxygen species (ROS) and the reduction of certain antioxidants. It has also been reported that normoglycemic obese individuals as well as patients with type 2 diabetes have elevated levels of C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), free fatty acid (FFA), IL-6, and TNF-α expression (18–20). Thus, these cardiovascular risk factors may play important roles in predicting diabetes and are components of insulin resistance syndrome (21).

Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) are two acute hyperglycemic emergencies characterized by decreased effective concentrations of insulin, leukocytosis, dehydration, elevation of counterregulatory hormones, and derangement of electrolytes and mineral metabolism, with severe alteration of protein, lipid, and carbohydrate metabolism (22). Our recent study demonstrated in vivo activation of T-cells in patients with DKA who were exhibiting de novo emergence of growth factor receptors (insulin, IGF-1, and IL-2) in association with an increased level of lipid peroxidation (thiobarbituric acid [TBA]-reacting material and ROS such as dichlorofluorescein [DCF]) (23). We had also reported earlier that in obese and lean subjects with DKA and hyperglycemia, serum leptin levels on admission are markedly decreased, and that after 6 h of insulin treatment, leptin levels return to control values (24). Because leptin is an adipokine generated by fat tissue, we hypothesized that alteration of other adipokines, such as TNF-α and IL-1β, -8, and -6, might occur in patients with obese hyperglycemic crises. Therefore, because DKA occurs in both lean and obese subjects, and obesity itself may influence the generation of proinflammatory cytokines, we undertook the present study to evaluate two conditions, obesity and ketoacidosis, with comparable levels of hyperglycemia. We studied these cytokines, as well as markers of oxidative stress and cardiovascular risk factors, in lean and obese DKA and in obese NKH patients (before and after resolution of hyperglycemia) who did not have severe infection or discernable cardiovascular pathology, and we compared them to age- and weight-matched lean and obese control subjects. Our study indicates that plasma levels of proinflammatory cytokines, markers of oxidative stress, certain cardiovascular markers, and lipid peroxidation are elevated on admission in patients with hyperglycemic crises. These values, as well as levels of counterregulatory hormones, promptly returned to control values with the administration of insulin and resolution of hyperglycemia. The constellation of these findings constitutes the first report of such events in lean and obese subjects with acute hyperglycemic crises. Demonstration of salutary and anti-inflammatory effects of low-dose insulin in these conditions supports the latter role of insulin in other clinical conditions associated with hyperglycemia (25–28).

RESEARCH DESIGN AND METHODS

A total of 58 patients admitted to the Regional Medical Center (Memphis, TN) for DKA and severe hyperglycemia were treated on a low-dose insulin protocol using intravenous infusion of insulin with the established rate of 0.1 unit · kg body wt−1 · h−1 (29). Patients with DKA had an admission blood glucose >250 mg/dl (13.9 mmol/l), pH <7.3, bicarbonate <18 mmol/l, anion gap >15 mmol/l, and positive ketonemia and ketonuria. Patients with NKH were admitted with blood glucose >400 mg/dl (22.4 mmol/l), pH >7.3, and serum bicarbonate >18 mmol/l. There was no apparent infection or other known precipitating illness for DKA and/or hyperglycemia in any of the study subjects. We excluded patients with gastrointestinal bleeding, fever, obvious endocrine disorders, history of myocardial infarction, pregnancy, congestive heart failure, history of cardiovascular disease, chronic obstructive pulmonary disease, or chronic renal failure. The criteria for resolution was defined as blood glucose <250 mg/dl (13.9 mmol/l), HCO3 >18 mmol/l, pH >7.3, normal anion gap, and normal mental status. Blood was drawn on admission for diagnosis and clinical management of DKA and NKH and at 4-h intervals until total resolution of hyperglycemic crisis, which was at 20–24 h after initiation of insulin therapy. The patients were on intravenous fluids and received no food by mouth for the entire study. The total amount of insulin per kilogram of body weight was similar in all hyperglycemic patients (∼90 units until resolution of hyperglycemia/ketoacidosis). Laboratory tests included a complete metabolic profile, cell blood count, arterial pH, blood glucose, blood cultures, and other routine chemistries, which were performed in the hospital laboratory. The other specified assays in this report were performed in the endocrinology laboratory at the University of Tennessee Health Science Center (UTHSC). Blood specimens for these assays were drawn in citrated tubes on admission and at resolution of hyperglycemic crisis at 20–24 h. The specimens were centrifuged at 4°C, and plasma was separated and stored at −70°C until assayed. The consent forms for the protocol, which was approved by the institutional review board at UTHSC, were obtained from the patient or next of kin.

Determination of plasma cytokines, metabolic hormones, and markers of cardiovascular risks, oxidative stress, and lipid peroxidation.

Levels of proinflammatory cytokines (TNF-α and IL-1B, -6, and -8), markers of cardiovascular risks (high-sensitivity CRP and homocysteine), and metabolic hormones (growth hormone [GH], cortisol, and C-peptide) were measured in the plasma using a solid-phase, two-site sequential chemiluminescent immunometric assay on an Immulite analyzer (Diagnostic Products, Los Angeles). The coefficients of variation of the assays were all <5%. The instrument calibrations for the assays were performed as recommended by the manufacturers and were within the specifications.

Assays for markers of oxidative stress and lipid peroxidation were determined by TBA assay (30), and ROS were determined by DCF assay (31). FFA (32) and β-hydroxybutyrate levels (33) were determined by the methods established in this laboratory, as previously described. PAI-1 was assayed using the Zymutest PAI-1 activity enzyme-linked immunosorbent assay (Hyphen BioMed, Andresy, France), which measures only active PAI-1 (34–37). The normal range for fasting normal subjects for this assay was established to be <5 ng/ml. Absorbances of the enzyme-linked immunosorbent assay were determined on an HTS 7000 Plus microplate reader (Perkin-Elmer, Norwalk, CT) and the HTS data analysis software.

Normal fasting values of lean control subjects established in this laboratory for the cytokine assays are as follows: TNF-α <5.0 pg/ml, IL-1β <3.0 pg/ml, IL-6 <5.0 pg/ml, and IL-8 <10 pg/ml. Normal fasting values for the other assays measured in this laboratory are listed in Tables 1, 2, and 3.. Two levels of assay controls were determined with each assay for each analyte, and all control values were within the established ranges.

Data analysis.

The mean ± SE were calculated for all continuous variables. Baseline demographics and clinical characteristics between groups were compared using ANOVA and Scheffe’s method for continuous variables, with log transformations when necessary. χ2 analyses were performed for comparison of categorical variables. A two-tailed P value of <0.05 was considered statistically significant. StatView version 5.0.1 (SAS Institute, Cary, NC) was the statistical software used for the analysis.

RESULTS

Table 1 shows the clinical characteristics of study subjects. The groups consisted of 28 obese DKA subjects, 20 lean DKA subjects, and 10 obese subjects with NKH. In addition, 12 obese and 12 lean nondiabetic subjects, matched for age, BMI, and ethnicity, served as control subjects. All subjects were African American. None of the subjects had elevated temperature or a white blood cell count >16 × 106 cell/ml or a recognized precipitating cause of DKA. The mean HbA1c level on admission was 12.1%.

Table 2 shows the admission laboratory values before insulin therapy and at resolution of DKA or NKH, as well as baseline values in lean and obese control subjects. As previously shown (38), patients with DKA had lower levels of C-peptide than those with NKH. With insulin therapy, levels of counterregulatory hormones were significantly decreased at resolution of DKA and/or hyperglycemia.

Figure 1A–D shows levels of inflammatory cytokines (TNF-α and IL-8, -6, and -1β) on admission and at resolution of the hyperglycemic state. The values for lean and obese control subjects are also included. All values (in pg/ml) are means ± SE. Figure 1A shows the relationship of IL-8 at admission and resolution for the three groups of patients and the control subjects. The admission and resolution levels, respectively, for the groups are lean DKA: 29.3 ± 3.4 and 10.6 ± 2.3 pg/ml; obese DKA: 27.4 ± 3.8 and 11.9 ± 2.8 pg/ml; obese hyperglycemic: 25.8 ± 3.4 and 9.3 ± 2.8 pg/ml; lean control subjects: 4.9 ± 1.4 pg/ml; and obese control subjects: 5.5 ± 1.7 pg/ml. Figure 1B shows the relationship between the admission and resolution levels, respectively, of IL-6 of the groups: lean DKA: 14.9 ± 2.6 and 3.9 ± 1.1 pg/ml; obese DKA: 12.6 ± 2.1 and 4.3 ± 0.6 pg/ml; obese hyperglycemic: 10.2 ± 1.7 and 3.3 ± 0.7 pg/ml; lean control subjects: 1.8 ± 0.2 pg/ml; and obese control subjects: 2.1 ± 0.3 pg/ml. Similarly, Fig. 1C shows this relationship for TNF-α in these groups: lean DKA: 22.7 ± 3.6 and 4.6 ± 0.9 pg/ml; obese DKA: 28.3 ± 2.8 and 5.9 ± 0.7 pg/ml; obese hyperglycemic: 24.3 ± 3.1 and 5.1 ± 1.3 pg/ml; lean control subjects: 1.7 ± 0.2 pg/ml; and obese control subjects: 3.9 ± 0.6 pg/ml. This relationship of IL-1β levels can also be seen for each group at admission and resolution in Fig. 1D: lean DKA: 9.8 ± 2.3 and 2.1 ± 0.2 pg/ml; obese DKA: 13.7 ± 2.1 and 2.4 ± 0.3 pg/ml; obese hyperglycemic: 11.4 ± 0.8 and 3.1 ± 0.4 pg/ml; lean control subjects: 1.3 ± 0.2 pg/ml; and obese control subjects: 1.9 ± 0.3 pg/ml. In all patients, levels of cytokines on admission were significantly higher than at resolution or with matched control subjects. TNF-α levels were significantly higher in the obese DKA than the lean DKA subjects on admission and were correlated significantly with their BMI (r = 0.81, P < 0.05). The other cytokines did not demonstrate significant correlation with BMI (data not shown). The cytokine levels at resolution of hyperglycemia with insulin therapy were reduced to levels not significantly different from the lean or obese control subjects. Admission levels of TNF-α and IL-8 were greater than those of IL-1β and -6.

Figure 2 shows serum levels of CRP, homocysteine, PAI-1, TBA, DCF, and FFAs on admission and at resolution of DKA and NKH. As can be seen, admission levels were significantly higher in all groups than after insulin therapy and resolution of hyperglycemia. The actual values for these parameters are presented in Table 3. After resolution, levels of DCF, TBA, PAI-1, and FFAs were reduced to near control values, whereas reductions in circulating levels of CRP and homocysteine were not as robust and remained above control values. It is of interest that homocysteine was not decreased significantly with resolution of DKA/hyperglycemia and insulin treatment.

DISCUSSION

Hyperglycemia in subjects with or without a history of diabetes is a common finding in hospitalized patients admitted to critical care settings (39,40) and is associated with greater morbidity and mortality compared with those diagnosed with diabetes (39). The reason for greater mortality may be related to the delay in diagnosis of diabetes and/or its proper therapy (39). On the other hand, numerous prospective studies in diabetic and nondiabetic subjects admitted to critical care units have clearly shown a salutary effect of insulin, improving clinical outcome through correction of hyperglycemia and inflammation (41–45). Some of these studies have shown direct correlation between high blood glucose levels and increased mortality (45). A more recent study in such patients has demonstrated the salutary effect of insulin to be attributable to its anti-inflammatory properties (27).

Although previous studies have suggested an elevation of IL-6 and TNF-α in uncontrolled diabetes (46), elevation of IL-1B and -8 along with an increase in counterregulatory hormones and cardiovascular markers, to our knowledge, have not been recorded before. Of interest is our finding that these significant elevations of proinflammatory cytokines as well as cortisol, GH, TBA, PAI-1, DCF, and FFAs are all reduced to normal levels promptly in response to insulin therapy and normalization of blood glucose. The times for resolution of DKA and NKH were remarkably close, with both reaching total resolution within ≤24 h. Increased levels of these markers occurred in both ketotic and nonketotic hyperglycemic patients with similar blood glucose (i.e., >600 mg/dl.).

We must therefore conclude that hyperglycemia and ketoacidosis independently induce changes in proinflammatory cytokines, oxidative stress, and cardiovascular markers without synergistic effects of one or the other. It is of note that lean DKA patients exhibited as much of an increase in cardiovascular risk markers, oxidative stress, counterregulatory hormones, and cytokines as obese ketoacidotic patients. The only exception to this statement was the level of TNF-α, which was significantly greater in obese DKA than either lean DKA or NKH subjects. Although TNF-α values exhibited high correlation with BMI (r = 0.81, P < 0.05) in all three groups, other cytokines did not demonstrate such a correlation.

To our knowledge, this is the first report demonstrating increased levels of GH, cortisol, cytokines, cardiovascular risk markers, and oxidative stress in obese and lean patients with DKA (in the absence of any history or evidence of cardiovascular events, trauma, or severe infection) and their prompt suppression in response to intravenous insulin. Although previous studies support the association of DKA with oxidative stress and have studied possible mechanisms for the generation of ROS (47–49), it is not clear whether there is a causal relationship between markers of oxidative stress and acute diabetes complications, since the majority of these markers have been demonstrated in plasma.

Of interest is our finding in regard to homocysteine concentration and the fact that elevated levels of this risk factor did not respond to insulin as robustly as FFA, PAI-1, TBA, and DCF, all of which returned to control levels with resolution of DKA and hyperglycemia by insulin treatment. Homocysteine is regulated by many factors, and its levels are affected by various drugs (50), but its lack of response may be similar to the observations of Fonseca et al. (51), in that homocysteine levels in diabetic patients, unlike nondiabetic subjects, do not respond to insulin because these patients are insulin resistant. Our study confirms this phenomenon and extends these findings to patients in hyperglycemic crises.

In a more systematic study in type 1 diabetes, a variety of markers of oxidative stress were measured, including TBA, organoperoxide, vitamin E, vitamin C, glutathione, and glutathione peroxidase. The results suggest that most markers are not associated with long-term complications of diabetes (52,53) and that intracellular determination of these markers may be a better method of assessment of oxidative stress.

Our study confirms the well-known phenomenon of leukocytosis in hyperglycemic crises, without obvious infection, on febrile events. Although the mechanism of this finding is not known, the proinflammatory state demonstrated here and elsewhere certainly could bring about such an event, as well as stimulation of sympathetic nervous system, secondary to stress of hyperglycemia. It is well known that in normal subjects, increased sympathetic activity results in leukocytosis and elevation of TNF-α and IL-6 (54). The latter cytokines, along with IL-1β, may regulate production of acute-phase protein by raising body temperature (55), and the organism may be undergoing a compensatory mechanism in the immune and hypothalamic-pituitary-adrenal axis (56). It is of interest that despite leukocytosis and elevation of cytokines and other signs of oxidative stress, the body temperature in DKA remains hypothermic in the absence of florid infection (23). After insulin treatment, however, the temperature returns to normal, concomitant with a reduction of leukocytosis. The mechanisms of this interesting phenomenon are not fully understood, but coupled with the present demonstration of a dramatic reduction of cytokines and mediators of oxidative stress with insulin, they deserve further investigation.

Our recent studies in patients with DKA demonstrated in vivo activation of T-cells, which led us to hypothesize that hyperglycemia and/or ketosis through production of ROS and generation of proinflammatory cytokines may result in de novo emergence of growth factor receptor insulin, IGF-1, and IL-B (24). In the present study, we report elevated levels of proinflammatory cytokines and ROS as markers of oxidative stress in conjunction with elevated levels of FFAs and glucose in our patients with DKA as well as NKH (Table 3).

Based on our present and previous studies as well as other work from other laboratories (10,17,57), we may expand our hypothesis by proposing that the initial activating event for T-cells may be the presence of high levels of both FFAs and glucose in patients with hyperglycemic crises, which may result in the generation of ROS through diacylglycerol/PKC-activated NAD(P)H, supporting earlier findings on the role of FFAs on human muscle cells (10). However, further studies are needed to establish the presence of several hypothetical intermediates, including diacylglycerol, protein kinase C, and activated NAD(P)H in activated T-cells in hyperglycemic patients. To our knowledge, however, the presence of these biochemical steps and intermediary metabolites have not been demonstrated in T-cells of DKA or NKH patients.

Multiple studies have now demonstrated not only the anti-inflammatory effect of insulin in vitro and in vivo, but also its profibrinolytic activity (25); its suppressive effects on endothelial growth factor, metaloproteinase-9 (26), plasma tissue factor, and PAI-1 (25); and its effect on activation of endothelial cells (58) and polymorphonuclear leukocytes (59). To our knowledge, however, studies on the effect of insulin on subpopulations of polymorphonuclear leukocytes such as CD-4 and CD-8 T-cells, where their in situ activation was demonstrated in DKA (23), has not been reported.

In conclusion, our study clearly demonstrates a hitherto undescribed phenomenon of anti-inflammatory effect of insulin in hyperglycemic crises concomitant with the reduction of multiple cytokines, markers of cardiovascular risk and oxidative stress, and counterregulatory hormones. Our findings thus extend the previous observation on the robust and prompt anti-inflammatory effect of insulin and other conditions not associated with DKA and NKH (25–28,58,59).

The present study, however, does not permit us to draw any definitive conclusion regarding cause and effect of these events because time-related assessment of these factors and isolation of the intermediate products were not planned in this protocol.

  • Download figure
  • Open in new tab
  • Download powerpoint
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 1.

The proinflammatory cytokine levels of IL-8 (A), IL-6 (B), TNF-α (C), and IL-1β (D) measured in the plasma at admission and resolution of the patients in hyperglycemic crisis. The bar graphs show the means ± SE for each of the patient groups: lean DKA (n = 20); obese DKA (n = 28); obese hyperglycemic (n = 10); and lean and obese control subjects (n = 12 each). ☆The admission and resolution levels are significantly different (P ≤ 0.01), and the admission levels are significantly different from the control subjects.

FIG. 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 2.

Markers of oxidative stress and cardiovascular risk markers determined in the plasma of the patient groups at admission and resolution of hyperglycemic crisis. The graphs show the means ± SE for each of the patient groups for each of the markers: high-sensitivity CRP, FFAs, homocysteine, DCF reactive, PAI-1, and TBA reactive. ▴, lean DKA (n = 20); ♦, obese DKA (n = 28); •, obese hyperglycemic (n = 10); and ×, lean; □, obese control subjects (n = 12 each). All markers were significantly different at admission compared with at resolution of hyperglycemic crisis except for homocysteine, where only the lean DKA values were significantly different.

View this table:
  • View inline
  • View popup
TABLE 1

Clinical characteristics of hyperglycemic patients on admission

View this table:
  • View inline
  • View popup
TABLE 2

Laboratory values at admission and resolution of patients in hyperglycemic crisis

View this table:
  • View inline
  • View popup
TABLE 3

Markers of cardiovascular risks and oxidative stress at admission and resolution of hyperglycemic crisis

Acknowledgments

This work was partially supported by a grant from the National Institutes of Health, Division of Research Resources (GCRC RR00211), and a grant from the American Diabetes Association (to G.E.U.).

We thank John Crisler for assay of chemicals and hormones and our patients who participated in this study.

Footnotes

  • G.E.U. is currently affiliated with the Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.

    • Accepted May 12, 2004.
    • Received February 11, 2004.
  • DIABETES

REFERENCES

  1. ↵
    Crook MA, Tutt P, Pickup JC: Elevated serum sialic acid concentration in NIDDM and its relationship to blood pressure and retinopathy. Diabetes Care16 :57 –60,1993
    OpenUrlAbstract/FREE Full Text
  2. Pickup JC, Crook MA: Is type II diabetes mellitus a disease of the innate immune system? Diabetologia41 :1241 –1248,1998
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Festa A, D’Agostino R, Howard G, Mykkanen L, Tracy RP, Haffner SM: Chronic subclinical inflammation as part of the insulin resistance syndrome. Circulation102 :42 –47,2002
    OpenUrl
  4. ↵
    Shanmugam N, Reddy MA, Guha M, Natarajan R: High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes52 :1256 –1264,2003
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Lang CH, Dobrescu C, Bagby GJ: Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology130 :43 –52,1992
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science259 :87 –91,1993
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Sandler S, Bendtzen K, Eizirik DL, Welsh M: Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. Endocrinology126 :1288 –1294,1990
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    Brownlee MB: Mechanism of hyperglycemic damage in diabetes. In Atlas of Diabetes. 2nd ed. Skyler J, Ed. Philadelphia, Lippincott Williams & Wilkins,2002 , p.125 –137
  9. ↵
    King GL, Brownlee MB: The cellular and molecular mechanisms of diabetic complications. Endo Metab Clin North Am25 :255 –270,1996
    OpenUrlPubMed
  10. ↵
    Itani SI, Ruderman NB, Schmieder F, Boden G: Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkB-α. Diabetes51 :2005 –2011,2002
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Jain SK, McVie R, Jackson R, Levine SN, Lim G: Effect of hyperketonemia on plasma lipid peroxidation levels in diabetic patients. Diabetes Care22 :1171 –1175,1999
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Targher G, Zenari L, Bertolini L, Muggeo M, Zoppini G: Elevated levels of interleukin-6 in young adults with type 1 diabetes without clinical evidence of microvascular and macrovascular complications. Diabetes Care24 :956 –957,2001
    OpenUrlFREE Full Text
  13. ↵
    Elhadd TA, Kennedy G, Hill A, McLaren M, Newton RW, Greene SA, Belch JJ: Abnormal markers of endothelial cell activation and oxidative stress in children, adolescents and young adults with type 1 diabetes with no clinical vascular disease. Diabetes Metab Res Rev15 :405 –411,1999
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G: Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol280 :E745 –E751,2001
    OpenUrl
  15. ↵
    Schiekofer S, Andrassy M, Chen J, Rudofsky G, Schneider J, Wendt T, Stefan N, Humpert P, Fritsche A, Stumvoll M, Schleicher E, Haring HU, Nawroth PP, Bierhaus A: Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor-κB in PBMCs. Diabetes52 :621 –633,2003
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Mohanty P, Hamouda W, Garg R, Alijada A, Ghanim H, Dandona P: Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab85 :2970 –2973,2000
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P: Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes52 :2882 –2887,2003
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Haffner S: Insulin resistance, inflammation and the prediabetic state: Am J Cardiol92 :18J –26J,2003
    OpenUrlPubMedWeb of Science
  19. Vinik AI, Erbas T, Park T, Nolan R, Pittenger GL: Platelet dysfunction in type 2 diabetes. Diabetes Care24 :1476 –1485,2001
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Fonseca V, Desouza C, Asnani S, Jialal I: Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev25 :153 –175,2004
    OpenUrlCrossRefPubMedWeb of Science
  21. ↵
    Barzilay JI, Freedland ES: Inflammation and its relationship to insulin resistance, type 2 diabetes mellitus and endothelial dysfunction. Metabol Syndrome Related Dis1 :155 –167,2003
    OpenUrlPubMed
  22. ↵
    Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, Wall BM: Management of hyperglycemic crises in patients with diabetes mellitus. Diabetes Care24 :131 –153,2001
    OpenUrlFREE Full Text
  23. ↵
    Kitabchi AE, Stentz FB, Umpierrez GE: Diabetic ketoacidosis induces in vivo activation of human T-lymphocytes. Biochem and Biophys Res Commun315 :404 –407,2004
    OpenUrlPubMed
  24. ↵
    Kitabchi AE, Umpierrez GE: Changes in serum leptin in lean and obese subjects with acute hyperglycemic crisis. J Clin Endocrinol Metab88 :2593 –2596,2003
    OpenUrlCrossRefPubMed
  25. ↵
    Aljada A, Ghanim H, Mohanty P, Kapur N, Dandona P: Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab87 :1419 –1422,2002
    OpenUrlCrossRefPubMedWeb of Science
  26. ↵
    Dandona P, Aljada A, Mohanty P, Ghanim H, Bandyopadhyay A, Chaudhuri A: Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care26 :3310 –3314,2003
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G: Intensive insulin therapy exerts anti-inflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Meta88 :1082 –1088,2003
    OpenUrlCrossRefPubMedWeb of Science
  28. ↵
    Dandona P, Aljada A, Mohanty P: The anti-inflammatory and potential antiatherogenic effect of insulin: a new paradigm. Diabetologia45 :924 –930,2002
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    American Diabetes Association: Hyperglycemic crises in diabetes (Position Statement). Diabetes Care27 :S94 –S102,2004
  30. ↵
    Kitabchi AE, McCay PB, Carpenter MP, Trucco RE, Caputto R: Formation of malonaldehyde in vitamin E deficiency and its relation to the inhibition of gulonolactone oxidase. J Biol Chem235 :1591 –1598,1960
    OpenUrlFREE Full Text
  31. ↵
    Bass DA, Parce Ja, Dechatelet LR: Flow cytometric studies of oxidative product formation by neutrophils a graded response to membrane stimulation. J Immunol130 :1910 –1917,1983
    OpenUrlAbstract
  32. ↵
    Lawson V, Young R, Kitabchi AE: Maturity-onset diabetes of the young: an illustrative case for control of diabetes and hormonal normalization with dietary management. Diabetes Care4 :108 –112,1981
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Kitabchi AE, Ayyagari V, Guerra S, Medical House Staff: The efficacy of low dose versus conventional therapy of insulin for treatment for diabetic ketoacidosis. Ann Intern Med84 :633 –638,1976
  34. ↵
    Declerck PJ, Alesse MC, Verstreken M, Kruihof EK, Juhan-Vague I, Collen D: Measurement of plasminogen activator inhibitor-1 in biologic fluids with a murine monoclonal antibody based enzyme linked immunosorbent assay. Blood71 :220 –225,1998
    OpenUrl
  35. Smith FB, Lee AJ, Rumley A, Fowles GR, Lowe GOR: Tissue plasminogen activator, plasminogen activator inhibitor and risk of peripheral arterial disease. Artheriosclerosis115 :35 –43,1995
    OpenUrl
  36. Loskutoff DJ, Samad F: The adipocyte and hemostatic balance in obesity: studies on PAI-1. Artheriosl Thromb Vasc Biol18 :1 –6,1998
  37. ↵
    Macy E, Meilan E, Declerck P, Tracy R: Sample Preparation for plasma measurement of plasminogen activator inhibitor-1 antigen in large population studies. Arch Pathol Lab Med117 :67 –70,1993
    OpenUrlPubMedWeb of Science
  38. ↵
    Umpierrez GE, Kelly JP, Navarrete JE, Casals MMC, Kitabchi AE: Hyperglycemic crisis in urban blacks. Arch Int Med157 :669 –675,1997
    OpenUrlCrossRef
  39. ↵
    Umpierrez G, Isaacs S, Bazargan N, You X, Thaler L, Kitabchi A: Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes: J Clin Endocrinol Metab87 :978 –982,2002
    OpenUrlCrossRefPubMedWeb of Science
  40. ↵
    Montori VM, Bistrian BR, McMahon MM: Hyperglycemia in acutely ill patients. JAMA288 :2167 –2169,2002
    OpenUrlCrossRefPubMedWeb of Science
  41. ↵
    Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L: Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol26 :57 –65,1995
    OpenUrlCrossRefPubMedWeb of Science
  42. Chaudhuri A, Janicke D, Wilson MF, Tripathy D, Garg R, Bandyopadhyay A, Calieri J, Hoffmeyer D, Syed T, Ghanim H, Aljada A, Dandona P: Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation109 :849 –854,2004
    OpenUrlAbstract/FREE Full Text
  43. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med345 :1359 –1367,2001
    OpenUrlCrossRefPubMedWeb of Science
  44. Furnary A, Gao G, Grunkemeier G, Wu Y, Zerr KJ, Bookin SO, Floten HS, Starr A: Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg125 :1007 –1021,2003
    OpenUrlCrossRefPubMedWeb of Science
  45. ↵
    Finney SJ, Zekveld C, Elia A, Evans TW: Glucose control and mortality in critically ill patients. JAMA290 :2041 –2047,2003
    OpenUrlCrossRefPubMedWeb of Science
  46. ↵
    Pickup JC, Chesney GD, Thomas SM, Burt D: Plasma interleukin-6, tumor necrosis factor-α, and blood cytokine production in type 2 diabetes. Lifestyles67 :291 –300,2000
    OpenUrlPubMed
  47. ↵
    Gallou G, Ruelland A, Legras B, Maugendre D, Allannic H, Cloarec L: Plasma malondialdehyde in type 1 and type 2 diabetic patients. Clin Chim Acta214 :227 –234,1993
    OpenUrlCrossRefPubMedWeb of Science
  48. Sundaram RK, Bhaskar A, Vijayalongam S, Viswanathan M, Mohan R, Shanmugasundaram KR: Antioxidant status and lipid peroxidation in type 2 diabetes mellitus with or without complications. Clin Science90 :255 –260,1996
    OpenUrlPubMed
  49. ↵
    Carl GF, Hoffman WH, Passmore GG, Truemper EJ, Lightsey AL, Cornwell PE, Jonah MH: Diabetic ketoacidosis promotes a prothrombic state. Endocr Res29 :73 –82,2003
    OpenUrlCrossRefPubMed
  50. ↵
    Desanza C, Keebler M, McNamara D, Fonseca V: Drugs affecting homocysteine metabolism interaction on cardiovascular. Drugs62 :605 –616,2002
    OpenUrlCrossRefPubMedWeb of Science
  51. ↵
    Fonseca V, Madeline S, Schmidt B, Fink L, Kern P, Henry R: Plasma homocysteine concentration are regulated by acute hyperinsulinemia in nondiabetic but not type 2 diabetic subjects. Metabolism47 :686 –689,1998
    OpenUrlCrossRefPubMedWeb of Science
  52. ↵
    Chen MS, Hutchinson ML, Pecoraro RE, Lee WY, Labbe RF: Hyperglycemia-induced intracellular depletion of ascorbic acid in human mononuclear leukocytes. Diabetes32 :1078 –1081,1983
    OpenUrlAbstract/FREE Full Text
  53. ↵
    VanderJagt DJ, Harrison JM, Ratliff DM, Hunsaker LA, VanderJagt DL: Oxidative stress indices in IDDM subjects with and without long-term diabetic complications. Clin Biochem34 :265 –270,2001
    OpenUrlCrossRefPubMedWeb of Science
  54. ↵
    Goebel MU, Mills PJ, Irwin MR, Ziegler MG: Interleuken-6 and tumor necrosis factor-α production after acute psychological stress, exercise and infused isopraterenal: differential affects and pathway. Psychyosom Med62 :591 –598,2000
    OpenUrlPubMed
  55. ↵
    Suffredini AF, Fiantazzi G, Badolto R, Oppenheimer J, O’Grady N: New insights into the biology of the acute phase response. J Clin Immunol19 :203 –214,1999
    OpenUrlCrossRefPubMedWeb of Science
  56. ↵
    Selye H: The general adaptation syndrome and the diseases of adaptation. J Clin Endo6 :117 –230,1946
    OpenUrlPubMed
  57. ↵
    Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes49 :1939 –1945,2000
    OpenUrlAbstract
  58. ↵
    Aljada A, Ghanim H, Saadeh R, Dandona P: Insulin inhibits NF-kB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab86 :450 –453,2001
    OpenUrlCrossRefPubMedWeb of Science
  59. ↵
    Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmed S: Insulin inhibits intranuclear nuclear factor kappa-B and stimulates Ikappa-B in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect. J Clin Endocrinol Metab86 :3257 –3265,2001
    OpenUrlCrossRefPubMedWeb of Science
View Abstract
PreviousNext
Back to top

In this Issue

August 2004, 53(8)
  • Table of Contents
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Proinflammatory Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid Peroxidation in Patients With Hyperglycemic Crises
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Proinflammatory Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid Peroxidation in Patients With Hyperglycemic Crises
Frankie B. Stentz, Guillermo E. Umpierrez, Ruben Cuervo, Abbas E. Kitabchi
Diabetes Aug 2004, 53 (8) 2079-2086; DOI: 10.2337/diabetes.53.8.2079

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Proinflammatory Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid Peroxidation in Patients With Hyperglycemic Crises
Frankie B. Stentz, Guillermo E. Umpierrez, Ruben Cuervo, Abbas E. Kitabchi
Diabetes Aug 2004, 53 (8) 2079-2086; DOI: 10.2337/diabetes.53.8.2079
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • RESEARCH DESIGN AND METHODS
    • RESULTS
    • DISCUSSION
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo
  • Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation
  • CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα
Show more Pathophysiology

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.