Priya Mohanty

Metabolic Syndrome A Comprehensive Perspective Based on Interactions Between Obesity, Diabetes, and Inflammation

Received June 28, 2004; revision received August 26, 2004; accepted October 15, 2004. The original description of the metabolic syndrome by Reaven1 consisted of obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, hyperinsulinemia and dyslipidemia characterized by elevated triglyceride, and low HDL concentrations. All of the features described above are risk factors for atherosclerosis, and thus, metabolic syndrome constituted a significant risk for coronary heart disease2–5 (Table). The features of obesity/overweight and insulin resistance also provided a significant risk for developing type 2 diabetes.5,6 The risks for coronary heart disease and diabetes with metabolic syndrome are greater than those for simple obesity alone, and therefore, an understanding of the pathogenesis and through it, a rational approach to its therapy are of prime importance. View this table: Classic Biological Effects of Insulin and Classic Metabolic Syndrome Based on Resistance to the Metabolic Effects of Insulin As our understanding of the action of insulin evolves to comprehensively include the recent discoveries,7 we can better see that insulin resistance is the basis of most if not all of the features of this syndrome. The original conceptualization of this syndrome was on the basis of resistance to the metabolic actions of insulin. Thus, hyperinsulinemia, glucose intolerance, type 2 diabetes, hypertriglyceridemia, and low HDL concentrations could be accounted for by resistance to the actions of insulin on carbohydrate and lipid metabolism. Although the features described above would to some extent explain the atherogenesis, Reaven has maintained that hyperinsulinemia itself contributes to atherogenicity, and thus, insulin is atherogenic, leading to the coronary heart disease and cerebrovascular disease associated with this syndrome. Obesity probably leads to hypertension through (1) increased vascular tone created by a reduced bioavailability of NO because of increased oxidative stress,8 (2) increased asymmetric dimethylarginine (ADMA) concentrations,9 (3) increased sympathetic …

Circulating Mononuclear Cells in the Obese Are in a Proinflammatory State

Background—In view of the increase in plasma concentrations of proinflammatory mediators tumor necrosis factor-&agr; (TNF-&agr;), interleukin-6 (IL-6), and C-reactive protein (CRP) in obesity, we investigated whether peripheral blood mononuclear cells (MNC) from obese subjects are in a proinflammatory state. Methods and Results—MNC were prepared from fasting blood samples of obese (n=16; body mass index [BMI]=37.7±5.0 kg/m2) and normal-weight control (n=16; BMI=23.8±1.9 kg/m2) subjects. Nuclear factor &kgr;B (NF-&kgr;B) binding to DNA in nuclear extracts was elevated (P<0.05) and the inhibitor of NF&kgr;B-&bgr; (I&kgr;B-&bgr;) was significantly lower (P<0.001) in the obese group. Reverse transcription–polymerase chain reaction revealed elevated levels of migration inhibitor factor (MIF), IL-6, TNF-&agr;, and matrix metalloproteinase-9 (MMP-9) mRNA expression in the obese subjects (P<0.05). Plasma concentrations of MIF, IL-6, TNF-&agr;, MMP-9, and CRP were also significantly higher. Plasma glucose, insulin, and free fatty acids (FFAs) were measured, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Plasma FFA concentration related significantly to BMI, IL-6, and TNF-&agr; mRNA expression and plasma CRP levels but not to HOMA-IR. On the other hand, the inflammatory mediators were significantly related to BMI and HOMA-IR. Conclusions—These data show (1) for the first time that MNC in obesity are in a proinflammatory state with an increase in intranuclear NF-&kgr;B binding, a decrease in I&kgr;B-&bgr;, and an increase in the transcription of proinflammatory genes regulated by NF-&kgr;B; (2) that plasma FFAs are a modulator of inflammation; and (3) that insulin resistance is a function of inflammatory mediators.

Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression

BACKGROUND The intake of glucose or a high-fat, high-carbohydrate (HFHC) meal, but not orange juice, induces an increase in inflammation and oxidative stress in circulating mononuclear cells (MNCs) of normal-weight subjects. OBJECTIVE We investigated the effect of orange juice on HFHC meal-induced inflammation and oxidative stress and the expression of plasma endotoxin and Toll-like receptors (TLRs). DESIGN Three groups (10 subjects in each group) of normal, healthy subjects were asked to drink water or 300 kcal glucose or orange juice in combination with a 900-kcal HFHC meal. Blood samples were obtained before and 1, 3, and 5 h after the drinks and meal combinations were consumed. RESULTS Protein expression of the NADPH oxidase subunit p47(phox), phosphorylated and total p38 mitogen-activated protein kinase, and suppressor of cytokine signaling-3; TLR2 and TLR4 messenger RNA (mRNA) and protein expression; mRNA expression of matrix metalloproteinase (MMP)-9 in MNCs; and plasma concentrations of endotoxin and MMP-9 increased significantly after glucose or water were consumed with the meal but not when orange juice was consumed with the meal. The generation of reactive oxygen species by polymorphonuclear cells was significantly lower when orange juice was added to the meal than when water or glucose was added to the meal. CONCLUSIONS The combination of glucose or water and the HFHC meal induced oxidative and inflammatory stress and an increase in TLR expression and plasma endotoxin concentrations. In contrast, orange juice intake with the HFHC meal prevented meal-induced oxidative and inflammatory stress, including the increase in endotoxin and TLR expression. These observations may help explain the mechanisms underlying postprandial oxidative stress and inflammation, pathogenesis of insulin resistance, and atherosclerosis.

Differential Effects of Cream, Glucose and Orange Juice on Inflammation, Endotoxin and the Expression of Toll Like Receptor-4 and Suppressor of Cytokine Signaling-3

OBJECTIVE We have recently shown that a high-fat high-carbohydrate (HFHC) meal induces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the expression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated fat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and inflammation, also induce an increase in LPS, TLR-4, and SOCS3. RESEARCH DESIGN AND METHODS Fasting normal subjects were given 300-calorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Blood samples were obtained at 0, 1, 3, and 5 h for analysis. RESULTS Indexes of inflammation including nuclear factor-κB (NF-κB) binding, and the expression of SOCS3, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β in MNCs, increased significantly after glucose and cream intake, but TLR-4 expression and plasma LPS concentrations increased only after cream intake. The intake of orange juice or water did not induce any change in any of the indexes measured. CONCLUSIONS Although both glucose and cream induce NF-κB binding and an increase in the expression of SOCS3, TNF-α, and IL-1β in MNCs, only cream caused an increase in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not induce a change in any of these indexes. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance.

Troglitazone Reduces Reactive Oxygen Species Generation by Leukocytes and Lipid Peroxidation and Improves Flow-Mediated Vasodilatation in Obese Subjects

Because troglitazone has been shown to have antioxidant properties, we investigated whether troglitazone administration to obese subjects causes a reduction in (1) reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs) and mononuclear cells (MNCs) and (2) lipid peroxidation as reflected in the plasma concentrations of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE). Seven obese subjects were given 400 mg/d troglitazone for 4 weeks. Blood samples were obtained before troglitazone administration and at weekly intervals thereafter. Insulin concentrations fell significantly at week 1 and remained low at weeks 2 and 4 (P <0.001). ROS generation by PMNLs fell to 77.6±25.1% of the basal at week 1 and 47.9±41.1% at week 4 (P <0.001). ROS generation by MNCs fell to 59.8±15.7% of the basal at week 1 and 35.1±17.6% at week 4 (P <0.001). 9-HODE and 13-HODE concentrations fell significantly from 787.4±52.4 and 713.1±44.7 pg/mL to 720.4±66.7 (P <0.004) and 675.2±65.0 pg/mL (P <0.01) after 4 weeks, respectively. Postischemic dilatation of the brachial artery was measured by ultrasonography. The mean percent dilatation after forearm ischemia before and after troglitazone was 5.5±3.01% and 8.75±3.37% (P <0.02), respectively. The percent increase in diameter after nitroglycerin was 17.08±1.18% before troglitazone, whereas it was 18.9±1.91% (P <0.02) after troglitazone. We conclude that troglitazone has a potent and rapid biological inhibitory effect on ROS generation by PMNLs and MNCs and that it inhibits lipid peroxidation significantly. These changes are associated with a significant improvement in postischemic flow-mediated vasodilation in the brachial artery over a relatively short period of 4 weeks.

Insulin infusion in acute illness

The discovery of the antiinflammatory effect of insulin and the proinflammatory effect of glucose has not only provided novel insight into the mechanisms underlying several disease states but has also provided a rationale for the treatment of hyperglycemia in several acute clinical conditions. Van den Berghe et al. previously showed the benefits of intensive glycemic control with insulin in patients admitted to intensive care units. In this issue of the JCI, the same group of investigators now demonstrates that infusion of insulin to restore euglycemia in these patients results in a marked reduction in inflammatory indices such as adhesion molecules, hepatic iNOS, and plasma NO metabolites. The reduction in the mediators of inflammation may thus be responsible for the impressive improvement in clinical outcomes following insulin therapy, and the results suggest a new paradigm in which glucose and insulin are related not only through their metabolic actions but also through their opposite effects on inflammatory mechanisms.

Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin.

OBJECTIVE To evaluate the effect of exenatide on clinical parameters in obese patients with type 2 diabetes mellitus whose hyperglycemia is not adequately controlled despite treatment with oral hypoglycemic agents and insulin. METHODS In this retrospective analysis, clinical progress of 52 obese patients with type 2 diabetes treated with exenatide, 5 mcg twice daily, in an outpatient setting was reviewed. Treatment initiation was between September and December 2005. Mean follow-up period was 26 weeks. Thirty-eight patients took exenatide regularly (Group A); 14 patients discontinued exenatide because of insurance, personal, or economic reasons (Group B). Measurements at baseline and at follow-up included body weight; blood pressure; and levels of hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (CRP), and plasma lipids. Insulin dosage requirements were assessed. RESULTS Mean body weight (+/- standard error of the mean) decreased by 6.46 +/- 0.8 kg (P<.001) in Group A and increased by 2.4 +/- 0.6 kg in Group B (P<001). In Group A, mean HbA1c decreased by 0.6 +/- 0.21% (P = .007), and the insulin dosage requirement decreased for rapid-acting and mixed insulins (P<.02). In Group A, means of the following parameters decreased: serum total cholesterol by 8.5 +/- 3.3% (P = .03), triglycerides by 26 +/- 7.6% (P = .01), systolic blood pressure by 9.2 +/- 3.3 mm Hg (P = .02), and high-sensitivity CRP by 34 +/- 14.3% (P = .05). These indices did not change in Group B. CONCLUSION Exenatide effectively treats obese patients with type 2 diabetes on insulin, leading to weight loss and reduction in levels of HbA1c, systolic blood pressure, triglycerides, and high-sensitivity CRP.

Insulin as an anti-inflammatory and antiatherogenic modulator.

Data demonstrate the anti-inflammatory effects of insulin and proinflammatory effects of glucose. These data provide a mechanistic justification for the benefits of maintaining euglycemia with insulin infusions in hospitalized patients. Regimens that infuse fixed doses of insulin with high rates of glucose are usually associated with hyperglycemia, which may neutralize the beneficial effects of insulin. Therefore, we propose that such regimens should be avoided and instead replaced by insulin infusions that normalize and maintain blood glucose at a reasonably low level and ensure that plasma insulin is maintained at levels high enough to provide clinically relevant anti-inflammatory and cardioprotective effects. Trials to test this hypothesis are in progress.

Anti-inflammatory effects of insulin.

Purpose of reviewThis review deals with the recent observations on the pro-inflammatory effects of glucose and the anti-inflammatory actions of insulin. Apart from being novel, they are central to our understanding of why hyperglycemia is a prognosticator of bad clinical outcomes including patients with acute coronary syndromes, stroke and in patients in the intensive care unit. Recent findingsThe pro-inflammatory effect of glucose as well as that of other macronutrients including fast food meals provides the basis of chronic oxidative stress and inflammation in the obese and their propensity to atherosclerotic disease. The anti-inflammatory action of insulin provides a neutralizing effect to balance macronutrient induced inflammation on the one hand and the possibility of using insulin as an anti-inflammatory drug on the other. SummaryThe actions of macronutrients and insulin described above explain why insulin resistant states like obesity and type 2 diabetes are associated with oxidative stress, inflammation and atherosclerosis. They also suggest that insulin may be antiatherogenic.

Acute Modulation of Toll-Like Receptors by Insulin

OBJECTIVE—Low-dose insulin infusion has been shown to exert a prompt and powerful anti-inflammatory effect. Toll-like receptors (TLRs) are major determinants of the inflammatory response to viral and bacterial pathogens. We have now hypothesized that low-dose insulin infusion in obese type 2 diabetic patients suppresses TLR expression. RESEARCH DESIGN AND METHODS—Ten type 2 diabetic patients were infused with a low dose of insulin (2 units/h) and dextrose to maintain normoglycemia for 4 h, while another 14 type 2 diabetic patients were infused with either dextrose or saline for 4 h and served as control subjects. Blood samples were collected before and at 2, 4, and 6 h. TLR expression was determined in mononuclear cells (MNCs). RESULTS—Insulin infusion significantly suppressed TLR1, -2, -4, -7, and -9 mRNA expression in MNCs within 2 h of the infusion, with a maximum fall at 4 h by 24 ± 9%, 21 ± 5%, 30 ± 8%, 28 ± 5%, and 27 ± 10% (P < 0.05, for all), respectively, below the baseline. TLR2 protein was suppressed by 19 ± 7% (P < 0.05) below the baseline at 4 h. The DNA binding of PU.1, a major transcription factor regulating many TLR genes, was concomitantly suppressed by 24 ± 10% (P < 0.05) by 4 h in MNCs. There was no change in TLR expression or DNA binding by PU.1 following dextrose or saline infusion in the control groups. CONCLUSIONS—Insulin suppresses the expression of several TLRs at the transcriptional level, possibly through its suppressive effect on PU.1.