Cited by 1,961Adipokines, Inflammation, and Metabolic DiseasesAdvanced Glycation End Products researchDiabetes Management and Research

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Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress

Esposito, Katherine, Nappo, Francesco, Marfella, Raffaele, Giugliano, Giovanni, Giugliano, Francesco, Ciotola, Myriam, Quagliaro, Lisa, Ceriello, Antonio, Giugliano, Dario·2002·Circulation

DOI 10.1161/01.cir.0000034509.14906.ae

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Abstract

Background— Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-α, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results— Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-α, and IL-18 levels rose ( P <0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher ( P <0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-α levels higher ( P <0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P <0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher ( P <0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses. Conclusions— Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.

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Effect of Atorvastatin and Irbesartan, Alone and in Combination, on Postprandial Endothelial Dysfunction, Oxidative Stress, and Inflammation in Type 2 Diabetic Patients
Ceriello, A., Assaloni, R., Da Ros, R., Maier, A., Piconi, L., Quagliaro, L., Esposito, K., & Giugliano, D. (2005) · Circulation · doi:10.1161/01.cir.0000165070.46111.9f · Cited by 298
Self-citation
The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation
Kolb, H., & Mandrup-Poulsen, T. R. (2009) · Diabetologia · doi:10.1007/s00125-009-1573-7 · Cited by 299
“Increased activation of NFκB was found in response to glucose or a bread meal [13], and there was an increase in circulating levels of IL-6 and TNF-α during a hyperglycaemic clamp [14].”
BackgroundInfluential
Role of NF-κB in the pathogenesis of diabetes and its associated complications
Patel, S., & Santani, D. D. (2009) · Pharmacological Reports · doi:10.1016/s1734-1140(09)70111-2 · Cited by 300
Role of Diet in Chronic Obstructive Pulmonary Disease Prevention and Treatment
Scoditti, E., Massaro, M., Garbarino, S., & Toraldo, D. M. (2019) · Nutrients · doi:10.3390/nu11061357 · Cited by 299
“In addition to increasing the risk of obesity, hyperglycemia may trigger oxidative stress-related inflammatory responses [138], is associated with impaired lung function [139] and poor COPD outcomes [140], and may promote pulmonary infection, at least in part, by an effect on airway glucose concentrations [141].”
Background
The inflammatory consequences of psychologic stress: Relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II
Black, P. H. (2006) · Medical Hypotheses · doi:10.1016/j.mehy.2006.04.008 · Cited by 289
“interferon c and/or LPS), are also reduced during weight loss [61,88].”
Background
Glucose metabolism and hyperglycemia
Giugliano, D., Ceriello, A., & Esposito, K. (2008) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/87.1.217s · Cited by 284
Self-citation
Nutrition, inflammation and liver-spleen axis
Barrea, L., Somma, C. D., Muscogiuri, G., Tarantino, G., Tenore, G. C., Orio, F., Colao, A., & Savastano, S. (2017) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2017.1353479 · Cited by 317
“2005), have been extensively evaluated (Esposito et al. 2002; Steckhan et al. 2016; Feliciano Pereira, das Graças de Almeida, and Alfenas Rde 2014).”
BackgroundInfluential
Hyperglycemia Exacerbates Brain Edema and Perihematomal Cell Death After Intracerebral Hemorrhage
Song, E.-C., Chu, K., Jeong, S., Jung, K., Kim, S. H., Kim, M., & Yoon, B. (2003) · Stroke · doi:10.1161/01.str.0000088060.83709.2c · Cited by 263
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“(Esposito et al. 2002) and IL6 in non-diabetic and T2DM subjects (Ruge et al.”
Background
Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses: position statement of the T-Cell Workshop Committee of the Immunology of Diabetes Society
Mallone, R., Mannering, S. I., Brooks‐Worrell, B., Durinovic‐Belló, I., Cilio, C., Wong, F. S., & Schloot, N. C. (2010) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2010.04272.x · Cited by 261
Luteolin protects against diabetic cardiomyopathy by inhibiting NF-κB-mediated inflammation and activating the Nrf2-mediated antioxidant responses
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Oxidative stress as a therapeutic target in diabetes: revisiting the controversy
Wiernsperger, N. F. (2003) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70072-1 · Cited by 260
“In glucose-intolerant (IGT) subjects, the increased level of inflammatory cytokines is linked to oxidative processes [57].”
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New insights into insulin: The anti-inflammatory effect and its clinical relevance
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Inflammageing and metaflammation: The yin and yang of type 2 diabetes
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“Post-prandial hyperglycaemia is known to be associated with a transient pro-inflammatory response in both humans and mice (Dror et al., 2017; Esposito et al., 2002).”
Self-citation
The inflammatory status score including IL-6, TNF-α, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus
Daniele, G., Guardado‐Mendoza, R., Winnier, D. A., Fiorentino, T. V., Zuo, P., Cornell, J. E., Andreozzi, F., Jenkinson, C. P., Cersósimo, E., Federici, M., et al. (2013) · Acta Diabetologica · doi:10.1007/s00592-013-0543-1 · Cited by 252
“Although the relation between glycemic instability and the risk of cardiovascular disease and diabetic complications is complex, it has been demonstrated that repeated fluctuations of glucose produce increased circulating levels of inflammatory cytokines compared with stable high glucose in normal subjects and worsene…”
Background
Mechanisms underlying the effect of polysaccharides in the treatment of type 2 diabetes: A review
Wu, J., Shi, S., Wang, H., & Wang, S. (2016) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2016.02.040 · Cited by 244
Natural Honey Lowers Plasma Glucose, C-Reactive Protein, Homocysteine, and Blood Lipids in Healthy, Diabetic, and Hyperlipidemic Subjects: Comparison with Dextrose and Sucrose
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“28 Honey compared with dextrose reduced PGL and insulin in normal subjects.”
Elevated Interleukin-18 Levels Are Associated With the Metabolic Syndrome Independent of Obesity and Insulin Resistance
Hung, J., McQuillan, B., Chapman, C., Thompson, P. L., & Beilby, J. P. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000163843.70369.12 · Cited by 240
Chronic stress impacts the cardiovascular system: animal models and clinical outcomes
Golbidi, S., Frisbee, J. C., & Laher, I. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00859.2014 · Cited by 262
“secretion of inflammatory mediators possibly through an oxidative mechanism (86).”
Relationship Between Adiponectin and Glycemic Control, Blood Lipids, and Inflammatory Markers in Men With Type 2 Diabetes
Schulze, M. B., Rimm, E. B., Shai, I., Rifai, N., & Hu, F. B. (2004) · Diabetes Care · doi:10.2337/diacare.27.7.1680 · Cited by 235
“Hyperglycemia acutely increases circulating cytokine concentrations (38,39).”
‘Glycaemic variability’: a new therapeutic challenge in diabetes and the critical care setting
Ceriello, A., & Ihnat, M. A. (2010) · Diabetic Medicine · doi:10.1111/j.1464-5491.2010.02967.x · Cited by 236
Self-citation
Soft drinks and sweetened beverages and the risk of cardiovascular disease and mortality: a systematic review and meta-analysis
Narain, A., Kwok, C. S., & Mamas, M. A. (2016) · International Journal of Clinical Practice · doi:10.1111/ijcp.12841 · Cited by 223
Diet and inflammation: a link to metabolic and cardiovascular diseases
Esposito, K., & Giugliano, D. (2005) · European Heart Journal · doi:10.1093/eurheartj/ehi605 · Cited by 236
“These findings are in line with previous studies demonstrating that after oral or intravenous glucose challenges, in both normal subjects and patients with type 2 diabetes mellitus, there is an increased generation of ROS and raised circulating levels of inflammatory cytokines, such as tumour necrosis factor-a (TNF-a)…”
ResultSelf-citation
Klotho Depletion Contributes to Increased Inflammation in Kidney of the db/db Mouse Model of Diabetes via RelA (Serine)536 Phosphorylation
Zhao, Y., Banerjee, S., Dey, N., LeJeune, W. S., Sarkar, P. S., Brobey, R. K. B., Rosenblatt, K. P., Tilton, R. G., & Choudhary, S. (2011) · Diabetes · doi:10.2337/db10-1262 · Cited by 232
“Our rationale for selecting TNF-a as a diabetic milieu inflammatory stimulus was based on clinical and epidemiological data indicating a role for TNF-a in the initiation and progression of diabetes, including the following: 1) proinflammatory cytokines such as IL-6, TNF-a, IL-1b, and plasminogen activator inhibitor-1…”
Method
Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes
DiNicolantonio, J. J., Bhutani, J., & O’Keefe, J. H. (2015) · Open Heart · doi:10.1136/openhrt-2015-000327 · Cited by 243
“39 Further, Esposito et al 40 showed that in individuals with both normal (n=20) and IGT (n=15) intravenous glucose pulses caused a signi ﬁ cantly greater increase in mediators of subclinical in ﬂ ammation (interleukin-6 and tumour necrosis factor-α ) as compared to sustained hyperglycaemic periods.”
Result
Circulating Adiponectin Levels Are Associated with Better Glycemic Control, More Favorable Lipid Profile, and Reduced Inflammation in Women with Type 2 Diabetes
Mantzoros, C. S., Li, T., Manson, J. E., Meigs, J. B., & Hu, F. B. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0372 · Cited by 224
“Finally, the associations reported in this study are consistent with a large and accumulating body of evidence (20, 32, 33) on the role of adiponectin in metabolism and inflammation, but some weak associations, albeit statistically significant due to the high power of the study, may not be as clinically important.”
BackgroundResult
Hyperglycemia Is Associated With Adverse Outcomes in Patients Receiving Total Parenteral Nutrition
Cheung, N. W., Napier, B., Zaccaria, C., & Fletcher, J. (2005) · Diabetes Care · doi:10.2337/diacare.28.10.2367 · Cited by 221
Cytokines as Biomarkers in Rheumatoid Arthritis
Burska, A. N., Boissinot, M., & Ponchel, F. (2014) · Mediators of Inflammation · doi:10.1155/2014/545493 · Cited by 231
“Several methods of detection (ELISA, immunohistochemistry) identified TNF-alpha and IL-1 as major players in the network of cytokines, notably directly expressed at the disease site in joint tissue or fluid.”
Background
Prolonged Reactive Oxygen Species Generation and Nuclear Factor-κB Activation after a High-Fat, High-Carbohydrate Meal in the Obese
Patel, C., Ghanim, H., Ravishankar, S. T., Sia, C. L., Viswanathan, P., Mohanty, P., & Dandona, P. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0778 · Cited by 221
Serum Interleukin-18 Levels Are Associated With Nephropathy and Atherosclerosis in Japanese Patients With Type 2 Diabetes
Nakamura, A., Shikata, K., Hiramatsu, M., Nakatou, T., Kitamura, T., Wada, J., Itoshima, T., & Makino, H. (2005) · Diabetes Care · doi:10.2337/diacare.28.12.2890 · Cited by 218
“Activation of nuclear factor- B through oxidative stress induced by hyperglycemia increases concentrations of circulating proinflammatory cytokines (2).”
Background
Critical evaluation of the role of acarbose in the treatment of diabetes: patient considerations
Rosak, C., & Mertes (2012) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s28340 · Cited by 221
“The increased formation of adhesion molecules and increased adhesion of monocytes to endothelial cells leads to formation of thrombotic plaques.(17,18) At the same time, hyperglycemia increases the formation of cytokines and C-reactive protein.”
Guideline for management of postmeal glucose
Ceriello, A., Colagiuri, S., Gerich, J. E., & Tuomilehto, J. O. (2008) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2008.01.012 · Cited by 211
Self-citation
Prospective study of dietary patterns and chronic obstructive pulmonary disease among US women
Varraso, R., Fung, T. T., Barr, R. G., Hu, F. B., Willett, W. C., & Camargo, C. A. (2007) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/86.2.488 · Cited by 212
“[27] Furthermore, both hyperglycemia and COPD are positively related to inflammation,[28, 29] even if the causal association between COPD and the systemic inflammation remains unclear.”
Background
Obesity: Genes, brain, gut, and environment
Das, U. N. (2009) · Nutrition · doi:10.1016/j.nut.2009.09.020 · Cited by 212
Nutritionally Mediated Oxidative Stress and Inflammation
Muñoz, A. B., & Costa, M. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/610950 · Cited by 215
“Acute hyperglycemia results in elevated levels of circulating inflammatory cytokines including TNFα, IL-6, and IL-18 and more extreme responses in these parameters are observed when glucose spikes; this response is attenuated by administration of glutathione confirming the presence of an oxidative stress-related mecha…”
Background
Abdominal obesity and metabolic syndrome: exercise as medicine?
Paley, C. A., & Johnson, M. I. (2018) · BMC Sports Science Medicine and Rehabilitation · doi:10.1186/s13102-018-0097-1 · Cited by 217
“which might contribute to a chronic inflammatory state [28].”
Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis
Baker, E. H., Clark, N., Brennan, A. L., Fisher, D. A., Gyi, K. M., Hodson, M. E., Philips, B. J., Baines, D. L., & Wood, D. M. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01425.2006 · Cited by 200
“657 FEV1/FVC ratio, % 51 (12) 61 (12) 0.”

Authors: Esposito, K., Nappo, F., Marfella, R., Giugliano, G., Giugliano, F., Ciotola, M., Quagliaro, L., Ceriello, A., & Giugliano, D.
Affiliations: University of Udine (IT)
ORCID: Esposito, Katherine
Marfella, Raffaele
Ceriello, Antonio
Giugliano, Dario
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2002-10-15
Volume: 106
Issue: 16
Pages: 2067-2072
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/01.cir.0000034509.14906.ae
OpenAlex: W2123560318
Cited by: 1,961
References: 36
Citations by year: 2026: 57 · 2025: 69 · 2024: 88 · 2023: 95 · 2022: 106 · 2021: 91 · 2020: 102 · 2019: 83 · 2018: 86 · 2017: 70 · 2016: 87 · 2015: 112 · 2014: 99 · 2013: 102 · 2012: 101
FWCI: 38.18
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System (University of Udine) (submittedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords: hyperglycemia, inflammatory cytokines, interleukin-6, TNF-α, IL-18, impaired glucose tolerance, glutathione, oxidative stress, glucose clamp
MeSH terms: Adult, Antioxidants, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucose Tolerance Test, Glutathione, Humans, Inflammation, Kinetics, Male, Tumor Necrosis Factor-alpha, Interleukin-6, Cytokines, Glucose Intolerance, Oxidative Stress, Interleukin-18

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Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress

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