ArticleLiterature Review

The straight line hypothesis elaborated: Case reference obesity, an argument for acidosis, oxidative stress, and disease conglomeration?

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Abstract

Studies report on the association between obesity and oxidative stress, with and without additional diseases. Macrophages in adipocytes, and hypoxia in adipose tissue have been suggested to explain how obesity can relate to oxidative stress. The straight line hypothesis using the lactic acid trap construct has been put forward to explain how proton imbalance can relate to obesity. Proton imbalance has been also reported to associate with the production of reactive oxygen species by inhibition of mitochondrial energy production. This review brings together existing literature and concepts to explain how obesity can relate to oxidative stress via protons, uniquely for itself or, as often observed, in conglomeration of additional diseases.

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... Liver metastases of breast cancer are the most predominant group [59]. Reports on the measurement of nitric oxide, reactive oxygen species and toxic radicals [59,62,63], released by liver sinusoidal endothelial cells [59], has been proposed [59,62,63]. Measurement of TNF-α has been also suggested [61]. ...
... Liver metastases of breast cancer are the most predominant group [59]. Reports on the measurement of nitric oxide, reactive oxygen species and toxic radicals [59,62,63], released by liver sinusoidal endothelial cells [59], has been proposed [59,62,63]. Measurement of TNF-α has been also suggested [61]. ...
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Article
Background: Pomegranate juice is rich source of polyphenols and thus promising dietary antioxidant with numerous health-promoting effects. This includes beneficial impact on cardiovascular health that could be partly attributed to the polyphenols' effects on lipid metabolism. The aim of this study was to investigate whether 6-week long pomegranate juice consumption could modify lipid peroxidation and phospholipid fatty acid composition of plasma and erythrocytes in subjects with metabolic syndrome. Twenty three women, aged 40-60, were enrolled and randomly assigned into two groups: intervention group- consuming 300 ml of juice per day for 6 weeks- and the control one. Results: Statistically significant decrease in relative amount of arachidonic acid (p < 0.05) and increase in relative amount of saturated fatty acids (p < 0.05) were observed in intervention group at the end of consumption period. In addition, pomegranate juice significantly increased relative amount of total monounsaturated fatty acids (p < 0.05), and significantly decreased thiobarbituric acid reactive substances levels in erythrocytes (p < 0.05).The status of blood lipids and blood pressure' values were not changed during the study. Conclusion: The obtained results indicate positive impact of pomegranate juice consumption on lipid peroxidation and fatty acid status in metabolic syndrome subjects and suggest potential anti-inflammatory and cardio-protective effects.
... A direct association of obesity with oxidative stress was rationalised by the infiltration of macrophages into adipose tissue and their overproduction of reactive oxygen species (ROS) and cytokines. Additionally, the expansion of fat mass leads to hypoxia and the consequent apoptosis of adipocytes which serves as a trigger for macrophage infiltration [5]. A disbalance in H + levels related to hypoxia has been reported to inhibit mitochondrial production of energy and lead to an incomplete reduction of oxygen and ROS formation [6]. ...
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... This dynamic is theorized to inhibit mitochondrial energy production (MEP) through inhibition of the TCA cycle. MEP inhibition results in the diversion of electrons away from completion of the electron transport chain and toward the reduction of oxygen (O 2 ) into reactive oxygen species (ROS) such as free radical oxygen species or peroxides [34,157]. As this cycle continues, vulnerable cells develop a reduced capacity to restore homeostatic balance and are subject to increased intracellular oxidative stress. ...
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Shift of myocardial substrate preference has been observed in many chronic diseases such as diabetes and heart failure. This study was undertaken to elucidate the mechanisms underlying the chronic substrate switch in adult hearts and to determine the functional consequences of the switch. Transgenic mice with cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (TG) were used to increase intracellular glucose in cardiac myocytes. A high-fat diet was used to increase the fatty acid supply to the heart. High-fat diet induced a 40% increase in fatty acid oxidation in wild-type hearts, whereas glucose oxidation was decreased to 30% of the control. In contrast, glucose oxidation was >2-fold higher in TG hearts, and the high-fat diet failed to upregulate fatty acid oxidation in these hearts. Glucose induced changes in the expression of multiple metabolic genes, including peroxisome proliferator-activated receptor-alpha (decreased by 51%), 3-oxoacid CoA transferase (decreased by 67%), and acetyl-CoA carboxylase (increased by 4-fold), resulting in a remodeling of the metabolic network to favor a shift of substrate preference toward glucose. Although TG mice on a normal diet maintained normal cardiac energetics and function, the inability to upregulate myocardial fatty acid oxidation in TG mice fed a high-fat diet resulted in increased oxidative stress in the heart, activation of p38 mitogen-activated protein kinase, and contractile dysfunction. We have demonstrated that chronic increases in myocardial glucose uptake and oxidation reduce the metabolic flexibility and render the heart susceptible to contractile dysfunction.
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Obesity is associated with ever increasing social costs posing a general public health challenge. The most obvious reason for obesity, given healthy body functioning, is a positive calorie balance. This article delves into the lesser studied realm of the relationship of weight gain, in particular adipose tissue gain, with increased hydrogen ion concentration, taking protein and organic acids as important caveats in this discussion. The review opens the topic with the contradictory result of various studies reporting a positive relationship between chronic metabolic acidosis and weight loss. It goes to explain a process of weight gain, primarily adipose tissue gain, on acidogenic diets. Insufficient dietary protein could lead to muscle loss, and individual organic acids might indicate if there is any fatty acid oxidation or accumulation of hydrogen ion. The solution to the acid accumulation is discussed not in protein limitation but an increase in the consumption of vegetables and fruits. Finally, this review article based on studies published puts forward a physiological basis including a hypothesis to explain the possible link between hydrogen ion concentration and weight gain. This link could possibly explain the development of diseases and aging partially, and warrants research.
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Exhaled breath condensate (EBC) pH has been proposed as a biomarker of airway inflammation and oxidative stress in asthma. Cigarette smoking reduces EBC pH in mild asthma. The effects of smoking on EBC pH in more symptomatic asthmatic patients using inhaled corticosteroids (ICS) are unknown. We aimed to compare EBC pH in asthmatic smokers (AS) and non-smokers (ANS) with moderate to severe disease, who were taking ICS. We also investigated the relationship between EBC pH and biomarkers of airway inflammation and oxidative stress. AS (n = 18) and ANS (n = 17), who were using ICS, were recruited and EBC pH, sputum inflammatory cell counts and sputum supernatant 8-isoprostane concentrations were measured. Full lung function testing was performed. EBC pH was significantly lower in AS than in ANS (6.91 vs 7.41). In AS there was a significant inverse correlation between EBC pH and 8-isoprostane levels (r = -0.54, P = 0.03). There was no correlation between EBC pH and sputum neutrophil counts. EBC pH appears to be a biomarker of the level of oxidative stress in smokers with moderate to severe asthma. EBC pH may have applications for the longitudinal monitoring of the effects of smoking on the airways of asthmatic patients.
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It is not known whether there are mechanisms linking adipose tissue mass and increased oxidative stress in obesity. This study investigated associations between decreasing general and abdominal fat depots and oxidative stress during weight loss. Subjects were severely obese women who were measured serially at baseline and at 1, 6 (n = 30), and 24 months (n = 18) after bariatric surgery. Total fat mass (FAT) and volumes of visceral (VAT) and subcutaneous abdominal adipose tissue (SAT) were related to plasma concentrations of derivatives of reactive oxidative metabolites (dROMS), a measure of lipid peroxides and oxidative stress. After intervention, BMI significantly decreased, from 47.7 +/- 0.8 kg/m(2) to 43.3 +/- 0.8 kg/m(2) (1 month), 35.2 +/- 0.8 kg/m(2) (6 months), and 30.2 +/- 1.2 kg/m(2) (24 months). Plasma dROMS also significantly deceased over time. At baseline, VAT (r = 0.46), FAT (r = 0.42), and BMI (r = 0.37) correlated with 6-month decreases in dROMS. Similarly, at 1 month, VAT (r = 0.43) and FAT (r = 0.41) correlated with 6-month decreases in dROMS. Multiple regression analysis showed that relationships between VAT and dROMS were significant after adjusting for FAT mass. Increased plasma dROMS at baseline were correlated with decreased concentrations of high-density lipoprotein (HDL) at 1 and 6 months after surgery (r = -0.38 and -0.42). This study found longitudinal associations between general, and more specifically intra-abdominal adiposity, and systemic lipid peroxides, suggesting that adipose tissue mass contributes to oxidative stress.
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A number of systems that generate oxygen free radicals catalyze the oxidative modification of proteins. Such modifications mark enzymes for degradation by cytosolic neutral alkaline proteases. Protein oxidation contributes to the pool of damaged enzymes, which increases in size during aging and in various pathological states. The age-related increase in amounts of oxidized protein may reflect the age-dependent accumulation of unrepaired DNA damage that, in a random manner, affects the concentrations or activities of numerous factors that govern the rates of protein oxidation and the degradation of oxidized protein.
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The objective of this study was to compare the response of respiratory drive to progressive hypoxia under eucapnic and hypercapnic conditions in patients with severe COPD. Twenty-five patients with severe COPD and 13 nonsmoking young men were studied. The pressure in the occluded airway measured 0.1 second after the onset of inspiration was used as an index of respiratory drive. The occlusion pressure was measured at levels of SaO2 between 97 and 85 percent while eucapnic. The PETCO2 was then increased 10 mm Hg and the study repeated. The response of respiratory drive to hypoxia as measured by the slope of the regression line relating occlusion pressure to SaO2 was weak and variable in eucapnic hypoxia, and some subjects had no demonstrable response. When mild respiratory acidosis was created by increasing the PETCO2, the response to hypoxia was much greater and occurred in all subjects studied. Respiratory acidosis resulting from acute elevation of the PaCO2 greatly potentiates the increase in respiratory drive in response to hypoxia in normal subjects and in patients with severe COPD. Increase in occlusion pressure may occur with slight degrees of hypoxia when acute hypercapnia is present. These observations suggest that patients with acute respiratory failure complicating COPD, treated with controlled oxygen administration with only partial correction of hypoxia and continued respiratory acidosis, will have high respiratory drive.
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A syndrome of experimental chronic mountain sickness can be produced in the Hilltop strain of Sprague-Dawley rats by chronic hypobaric hypoxic exposure. This syndrome is characterized by polycythemia, plasma hemoglobinemia, pulmonary hypertension and right ventricular hypertrophy with eventual failure and death. It has generally been assumed that these changes are caused by chronic hypoxemia, not by hypobaric exposureper se. We have now confirmed this directly by showing that chronic normobaric hypoxic exposure (10.5% O2) produces similar hematologic and hemodynamic changes. Further, the addition of hypercapnic exposure to the hypoxic exposure blunted or prevented the effects of the hypoxic exposure probably by stimulating respiration, thus increasing the rate of oxygen delivery to the cells. Changes in the rate-controlling enzymes of hepatic heme metabolism, 5-aminolevulinate synthase and heme oxygenase, and in cytochrome(s) P-450, the major hepatic hemoprotein(s), were also measured in hypoxic and hypercapnic rats. Hypoxia decreased 5-aminolevulinate synthase and increased cytochrome(s) P-450, probably by increasing the size of a regulatory heme pool within hepatocytes. These changes were also prevented by the addition of hypercapnic to hypoxic exposure.
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Five-week-old male obese and lean Zucker rats were made comparably diabetic by intracardiac injections of alloxan (65-72 mg/kg body wt). Lean rats were then given daily injections of protamine zinc insulin at 3 doses: 0.25, 1.25, and 4.0 U.100 g body wt-1.day-1 for 3 wk. Obese rats received identical amounts as corresponding lean controls independent of body weights. The drop of blood glucose concentration after injections of regular insulin and the percentage fall in radioactive plasma insulin after injections of 125I-insulin were comparable in lean and obese rats. Weight gain, fat gain, and protein gain over 21 days increased with increasing amounts of insulin administered. However, at the same dose of insulin, although weight gain was comparable, fat gain was higher and protein gain was lower in obese rats when compared to lean controls. These results suggest that the enhanced lipid deposition of the obese Zucker rat is not totally dependent on insulin levels, but is exaggerated by hyperinsulinemia.
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The objective of this study was to further elucidate the role of oxidative stress in the aging process by determining whether or not the rates of mitochondrial superoxide anion radical and hydrogen peroxide (H2O2) production, the activity of cytochrome c oxidase, and the concentration of protein carbonyls are correlated with the life span potential of different species. A comparison was made among five different species of dipteran flies, namely, Drosophila melanogaster (fruit fly), Musca domestica (house fly), Sarcophaga bullata (flesh fly), Calliphora vicina (blow fly) and Phaenecia sericata (a species of blow flies), which range more than 2-fold in their life span potentials. The average life span potential of these species was found to be inversely correlated with the rates of mitochondrial superoxide and H2O2 production and with the level of protein carbonyls, and to be directly related to the activity of cytochrome c oxidase. The significance of these findings in context of the validity of the oxidative stress hypothesis of aging is discussed. It is inferred that longer life span potential in these insect species is associated with relatively low levels of oxidant generation and oxidative molecular damage. These results accord with our previous findings on different mammalian species.
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The localization of vacuolar-type H(+)-ATPase and carbonic anhydrase II (CA II) in rat incisor enamel organs at maturation was examined by light and electron microscopy. The immunoreactivity for both vacuolar-type H(+)-ATPase and CA II was intense on the ruffled border of ruffle-ended ameloblasts (RA), but moderate at the distal end of smooth-ended ameloblasts (SA). Immuno-gold particles indicated that CA II was not confined to the ruffled border of RA alone, but also distributed in the cytoplasm of RA and SA. These findings suggest that RA may secrete protons produced by CA II via the ruffled border into enamel by active transport of vacuolar-type H(+)-ATPase. Secreted protons may activate hydrolytic enzymes to degrade the organic components of enamel matrix. Vacuolar-type H(+)-ATPase on vesicles of SA suggests that a specific configuration of ruffled borders in RA may be formed by the fusion of vesicle membranes in the distal end of cytoplasm of SA.
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Breast cancers have higher than normal glucose metabolism, but the mechanism of glucose entry into these tumors is not well understood. The expression of five facilitative glucose transporters, Glut-1 (erythrocyte type), Glut-2 (liver type), Glut-3 (brain type), Glut-4 (muscle/fat type), and Glut-5 (small intestine type), was studied by immunohistochemistry of paraffin sections from 12 primary human breast cancers and 8 lymph node metastases from 2 patients. Rat tissues known to express these glucose transporters were used as controls. All the primary breast cancers and the lymph node metastases were positive for Glut-1. This transporter was expressed on the cell membrane and in the cytoplasm of the tumor cells, but exhibited marked intratumoral and intertumoral variability in the proportions of positive cells and the intensity of staining. Staining of the normal mammary epithelium, if present, was much lower than observed in tumor cells from the same patient. Glut-2 was expressed in all of the tumors, but the intensity of staining was not consistently stronger than that seen in healthy breast. Clusters of Glut-4-positive granule were observed in cells in six of the tumors. None of the tumors or the healthy breast in the tissues studied expressed Glut-3 or Glut-5. Higher expression of the glucose transporter Glut-1 by breast cancer cells compared with the healthy breast tissue is common. Increased glucose transporter protein expression may contribute to the increased uptake of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) by these tumors observed by positron emission tomography (PET) imaging.
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The macrophage plays an important role in host development and physiology, and in pathogenesis of many infectious, immunologic and degenerative disease processes. It displays marked heterogeneity of phenotype in different tissues, reflecting local interactions with other cell types, and contributes to host homeostasis through a varied repertoire of plasma membrane and secretory molecules. Upon isolation from the body it continues to express special, as well as general, features of cellular organisation and function, which make it a delight to study in cell culture.
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To determine the clinical conditions associated with systemic oxidative stress in a community-based cohort. Information regarding cardiovascular risk factors associated with systemic oxidative stress has largely been derived from highly selected samples with advanced stages of vascular disease. Thus, it has been difficult to evaluate the relative contribution of each cardiovascular risk factor to systemic oxidative stress and to determine whether such risk factors act independently and are applicable to the general population. We examined 2828 subjects from the Framingham Heart Study and measured urinary creatinine-indexed levels of 8-epi-PGF2alpha as a marker of systemic oxidative stress. Age- and sex-adjusted multivariable regression models were used to assess clinical correlates of oxidative stress. In age- and sex-adjusted models, increased urinary creatinine-indexed 8-epi-PGF2alpha levels were positively associated with female sex, hypertension treatment, smoking, diabetes, blood glucose, body mass index, and a history of cardiovascular disease. In contrast, age and total cholesterol were negatively correlated with urinary creatinine-indexed 8-epi-PGF2alpha levels. After adjustment for several covariates, decreasing age and total/HDL cholesterol ratio, sex, smoking, body mass index, blood glucose, and cardiovascular disease remained associated with urinary 8-epi-PGF2alpha levels. Smoking, diabetes, and body mass index were highly associated with systemic oxidative stress as determined by creatinine-indexed urinary 8-epi-PGF2alpha levels. The effect of body mass index was minimally affected by blood glucose, and diabetes and may suggest an important role of oxidative stress in the deleterious impact of obesity on cardiovascular disease.
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There is substantial evidence that oxidative stress participates in the pathophysiology of cardiovascular disease. Biochemical, molecular and pharmacological studies further implicate xanthine oxidoreductase (XOR) as a source of reactive oxygen species in the cardiovascular system. XOR is a member of the molybdoenzyme family and is best known for its catalytic role in purine degradation, metabolizing hypoxanthine and xanthine to uric acid with concomitant generation of superoxide. Gene expression of XOR is regulated by oxygen tension, cytokines and glucocorticoids. XOR requires molybdopterin, iron-sulphur centres, and FAD as cofactors and has two interconvertible forms, xanthine oxidase and xanthine dehydrogenase, which transfer electrons from xanthine to oxygen and NAD(+), respectively, yielding superoxide, hydrogen peroxide and NADH. Additionally, XOR can generate superoxide via NADH oxidase activity and can produce nitric oxide via nitrate and nitrite reductase activities. While a role for XOR beyond purine metabolism was first suggested in ischaemia-reperfusion injury, there is growing awareness that it also participates in endothelial dysfunction, hypertension and heart failure. Importantly, the XOR inhibitors allopurinol and oxypurinol attenuate dysfunction caused by XOR in these disease states. Attention to the broader range of XOR bioactivity in the cardiovascular system has prompted initiation of several randomised clinical outcome trials, particularly for congestive heart failure. Here we review XOR gene structure and regulation, protein structure, enzymology, tissue distribution and pathophysiological role in cardiovascular disease with an emphasis on heart failure.
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Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two-thirds of all deaths in the U.S. and about US dollars 700 billion in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity-the major risk factors for these diseases-and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the American Cancer Society, American Diabetes Association, and American Heart Association review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment.
Article
Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two-thirds of all deaths in the United States and about 700 billion US dollars in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity-the major risk factors for these diseases-and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the American Cancer Society, the American Diabetes Association, and the American Heart Association review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment.
Article
Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two thirds of all deaths in the United States and about 700 billion dollars in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity-the major risk factors for these diseases-and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the ACS, ADA, and AHA review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment.
Article
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-alpha, interleukin [IL]-6, IL1-beta, 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.