Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation.
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Animals↗
Biomedical subjects
Priya Mohanty
Publications and source records attributed to Priya Mohanty.
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.
Acute Disease↗
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-alpha (TNF-alpha), 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 kappaB (NF-kappaB) binding to DNA in nuclear extracts was elevated (P<0.05) and the inhibitor of NFkappaB-beta (IkappaB-beta) 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-alpha, and matrix metalloproteinase-9 (MMP-9) mRNA expression in the obese subjects (P<0.05). Plasma concentrations of MIF, IL-6, TNF-alpha, 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-alpha 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-kappaB binding, a decrease in IkappaB-beta, and an increase in the transcription of proinflammatory genes regulated by NF-kappaB; (2) that plasma FFAs are a modulator of inflammation; and (3) that insulin resistance is a function of inflammatory mediators.
Adult↗
Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells.
It has previously been shown that oral intake of 300 calories of glucose (75 g), lipid, or protein increases reactive oxygen species (ROS) generation by polymorphonuclear cells (PMNL) and mononuclear cells (MNCs). We investigated the effects of 75 g glucose on proinflammatory transcription factor, nuclear factor-kappaB (NFkappaB), in mononuclear cells. To further investigate whether the effects of macronutrient-induced oxidative stress are due to consumption of calories or are nutrient specific, we investigated the effects of acute oral challenge of equicaloric amounts of alcohol (300 calories) on ROS generation and NF-kappaB activation in MNCs and PMNL and compared them with those of glucose and water (control). Sixteen normal healthy adult volunteers were given either vodka (10 subjects), glucose solution (10 subjects), or 300 mL water (7 subjects). Vodka and glucose drinks were equivalent to 300 calories. We measured ROS generation and intranuclear NF-kappaB activation by PMNL cells and MNCs at 1 hour, 2 hours, and 3 hours following ingestion. ROS generation by both MNC and PMNL increased significantly (P <.05 for MNC and P <.01 for PMNL) following intake of glucose solution, but did not change significantly following alcohol or water. NF-kappaB binding activity in MNC nuclear extracts also increased (P <.001) following ingestion of glucose solution, but did not change after the administration of alcohol or water. We conclude that (1) 75 g oral glucose increases NF-kappaB binding activity in MNCs. (2) While 75 g glucose (300 calories) induces an increase in ROS generation and intranuclear NF-kappaB, equicaloric amounts of alcohol did not produce these effects.
Adult↗
Endothelial dysfunction, inflammation and diabetes.
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Acarbose↗
Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect.
BACKGROUND: In view of the stimulatory effect of glucose on reactive oxygen species (ROS) generation, we investigated the possibility that a mixed meal stimulates ROS generation and possibly induces concomitant proinflammatory changes. OBJECTIVE: The objective was to determine whether the intake of a 900-kcal mixed meal induces an increase in ROS generation by leukocytes and an inflammatory response at the cellular level. DESIGN: Nine normal-weight subjects were given a 900-kcal mixed meal, and 8 normal-weight subjects were given 300 mL water after an overnight fast. Blood samples were collected at 0, 1, 2, and 3 h. ROS generation by mononuclear cells and polymorphonuclear leukocytes and the expression of p47(phox) subunit were measured. Intranuclear nuclear factor kappaB (NF-kappaB) binding and the expression of inhibitor kappaBalpha (IkappaBalpha), IkappaB kinase alpha (IKKalpha), and IkappaB kinase beta (IKKbeta) were measured. Plasma concentrations of C-reactive protein (CRP) and soluble intercellular adhesion molecule were also measured. RESULTS: ROS generation by mononuclear cells and polymorphonuclear leukocytes and p47(phox) expression increased significantly. The expression of IKKalpha and IKKbeta and DNA-binding activity of NF-kappaB increased significantly, whereas IkappaBalpha expression decreased. Plasma CRP concentrations increased. The intake of 300 mL water did not induce a change in any of the above indexes. CONCLUSIONS: These data show that the intake of a mixed meal results in significant inflammatory changes characterized by a decrease in IkappaBalpha and an increase in NF-kappaB binding, plasma CRP, and the expression of IKKalpha, IKKbeta, and p47(phox) subunit. These proinflammatory changes are probably relevant to the state of chronic hypertension and obesity and to its association with atherosclerosis.
Adult↗
Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations.
BACKGROUND: Glucose intake has been shown to cause an increase in intranuclear nuclear factor-kappa B and a decrease in inhibitor kappa B that are consistent with a proinflammatory effect. We investigated the effect of glucose intake on 2 other proinflammatory transcription factors, activator protein 1 (AP-1) and early growth response 1 (Egr-1), and on the genes regulated by them, ie, the genes for matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and tissue factor (TF), respectively. OBJECTIVE: The objective of the study was to ascertain whether the intake of 75 g glucose induces an increase in AP-1, Egr-1, and the genes regulated by them. DESIGN: Eight healthy subjects were given 75 g glucose dissolved in 300 mL water to drink. Blood samples were collected before and 1, 2, and 3 h after glucose intake. Four weeks later, the same subjects were given 300 mL water sweetened with saccharine, and blood samples were collected at the same time points. Mononuclear cells (MNCs) were separated, and nuclear fractions were isolated. RESULTS: AP-1 and Egr-1 binding activities were significantly higher 1 and 2 h after glucose intake and then decreased toward the baseline by 3 h. The expression of MMP-2 and TF in MNC homogenates also was significantly higher at 2 and 3 h. Plasma concentrations of MMP-2 were significantly higher at 3 h, whereas those of MMP-9 were significantly higher at 1, 2, and 3 h. In addition, TF was significantly higher at 2 and 3 h. Intake of saccharine-sweetened water had no significant effect on the inflammatory mediators measured in this study. CONCLUSION: Glucose induces proinflammatory changes, including increases in AP-1, Egr-1, MMPs, and TF, the factors that regulate processes that are potentially relevant to atherosclerotic plaque rupture and thrombosis.
Adult↗
Evidence for a potent antiinflammatory effect of rosiglitazone.
We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and a partial agonist of PPARalpha in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPARgamma agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor kappaB (NFkappaB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured. Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFkappaB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-alpha and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFkappaB-binding activity and plasma MCP-1, CRP, SAA, and TNF-alpha did not change in the obese and obese diabetic control groups. We conclude that rosiglitazone, a selective PPARgamma agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.
Adult↗
Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin.
The objective of the study was to determine whether plasma migration inhibitor factor (MIF) concentration and mononuclear cell (MNC) mRNA are elevated in obesity and whether treatment with metformin reduces plasma MIF concentration. Forty obese subjects [body mass index (BMI), 37.5 +/- 4.9 kg/m(2)] and 40 nonobese healthy subjects (BMI, 22.6 +/- 3.4 kg/m(2)) had their plasma MIF, glucose, insulin, free fatty acids (FFAs) and C-reactive protein (CRP) concentrations measured. Sixteen obese patients and 16 nonobese healthy subjects had RNA prepared from MNCs. Eight obese subjects with normal glucose concentration were treated with metformin 1 g (Glucophage XR; 1000 mg twice daily) twice daily for 6 wk. Eight obese subjects were used as controls. Plasma concentration of glucose, insulin, FFAs, and MIF was measured by appropriate assays. mRNA for MIF was measured by real-time PCR. Forty obese subjects had a fasting concentration of MIF of 2.8 +/- 2.0 ng/ml, whereas 40 nonobese subjects had a fasting MIF concentration of 1.2 +/- 0.6 ng/ml (P < 0.001). Plasma MIF concentrations were significantly related to BMI (r = 0.52; P < 0.001). mRNA for MIF was correlated to plasma FFAs (r = 0.40; P < 0.05) and plasma CRP (r = 0.42; P < 0.05) concentrations. Eight obese subjects had their fasting blood samples taken before and after taking a slow-release preparation of metformin at 1, 2, 4, and 6 wk. The mean plasma concentration fell from 2.3 +/- 1.4 to 1.6 +/- 1.2 ng/ml at 6 wk (P < 0.05). Obese subjects not on treatment with metformin showed no change. During the period of treatment with metformin, the body weight did not change and the plasma concentration of glucose, insulin, and FFAs did not alter. We conclude that: 1) plasma MIF concentrations and MIF mRNA expression in the MNCs are elevated in the obese, consistent with a proinflammatory state in obesity; 2) these increases in MIF are related to BMI, FFA concentrations, and CRP; 3) metformin suppresses plasma MIF concentrations in the obese, suggestive of an antiinflammatory effect of this drug; and 4) this action of metformin may contribute to a potential antiatherogenic effect, which may have implications for the reduced cardiovascular mortality observed with metformin therapy in type 2 diabetes mellitus.
Adult↗
Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action.
In view of the pro-oxidant and proinflammatory effects of angiotensin II, we have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappa B) in mononuclear cells. Four groups of eight normal subjects were given 1) 160 mg daily of valsartan, 2) 80 mg daily of simvastatin, 3) 40 mg quinapril, or 4) no treatment. Fasting blood samples were obtained before treatment and at d 1, 8, and 14 (7 d after the cessation of the drug). After valsartan, ROS generation by polymorphonuclear cells and mononuclear cells fell significantly by more than 40% (P < 0.01). NF-kappa B binding activity and the expression of total cellular p65, a protein component of NF-kappa B, fell significantly (P < 0.01). The expression of inhibitor kappa B (I kappa B) increased significantly (P < 0.05). Plasma C-reactive protein (CRP) concentration fell significantly (P < 0.01). All indices, except I kappa B, reverted toward baseline, 7 d after the cessation of the drug. I kappa B persisted in an elevated state. Neither quinapril nor simvastatin given for 7 d produced a suppression of ROS generation, intranuclear NF-kappa B, p65, or CRP, and these two agents did not alter cellular I kappa B either. The untreated controls also did not demonstrate a change in their ROS generation or NF-kappa B binding activity or plasma CRP concentration. We conclude that valsartan at a modest dose exerts a profound and rapid ROS and inflammation-suppressive effect that may be relevant to its potential beneficial effects in atherosclerosis, diabetes, and congestive cardiac failure. In contrast, quinapril and simvastatin produced no similar effect over the period of 1 wk. Our observations may also have implications to clinical situations in which a rapid antiinflammatory effect is required.
Adult↗
Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects.
To test the possible acute proinflammatory effects of fatty acids, we induced an increase in plasma free fatty acid (FFA) concentrations after a lipid and heparin infusion for 4 h in 10 healthy subjects. We determined the nuclear factor-kappaB (NF-kappaB) binding activity in mononuclear cells (MNCs), the p65 subunit of NF-kappaB, reactive oxygen species (ROS) generation by MNC, and polymorphonuclear leukocytes (PMN). Brachial artery reactivity, using postischemic flow-mediated dilation, was also measured. NF-kappaB binding activity in the MNC nuclear extracts increased to 163 +/- 17% and 144 +/- 14% as compared with basal levels at 2 and 4 h (P < 0.005) and remained elevated (P < 0.05) at 6 h (2 h after cessation of lipid infusion). NF-kappaB p65 subunit protein expression in MNC homogenates also increased at 2, 4, and 6 h (P < 0.05). ROS generation by PMNs increased significantly at 2 and 4 h (P < 0.005), whereas that by MNCs increased at 4 h (P < 0.05). Plasma macrophage migration inhibitory factor increased at 2 (P < 0.05) and 4 h (P < 0.005), respectively, and declined to baseline at 6 h. The postischemic flow-mediated dilation of brachial artery decreased from 6.3 +/- 1.1% at baseline to 4.3 +/- 1.9% and 2.7 +/- 2.1% (P < 0.01) at 2, 4, and 6 h, respectively. We conclude that an increase in FFA concentration induces oxidative stress and has a proinflammatory effect; it also impairs postischemic flow-mediated vasodilation of the brachial artery.
Adult↗
Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9.
OBJECTIVE: We recently demonstrated a potent anti-inflammatory and thus a potential antiatherogenic effect of insulin in human aortic endothelial cells and mononuclear cells at physiologically relevant concentrations. We have now further investigated the anti-inflammatory suppressive action of insulin on vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. VEGF and MMP-9 play a central regulatory role in angiogenesis, contribute to the pathogenesis of proliferative retinopathy, and have also been found to accelerate atherosclerosis. RESEARCH DESIGN AND METHODS: Insulin was infused (2 IU/h) in 5% dextrose (100 ml/h) and KCl (8 mmol/h) into 10 fasting, obese, nondiabetic subjects for 4 h. Subjects were also infused with 5% dextrose without insulin and with saline on two separate occasions. Blood samples were obtained at 0, 2, 4, and 6 h. RESULTS: Plasma insulin concentrations increased from a basal level of 12.5 +/- 2.2 to 28.2 +/- 3.3 micro U/ml at 2 h and 24.4 +/- 3.7 micro U/ml at 4 h after insulin infusion. VEGF concentration decreased from 307.2 +/- 163.8 pg/ml (100%) at 0 h to 73.5 +/- 20.9% of the basal level at 2 h and 67.1 +/- 23.2% at 4h. Plasma MMP-9 concentrations decreased from 375 +/- 196.3 ng/ml (100%) at 0 h to 83 +/- 22% of the basal level at 2 h and to 82 +/- 21% of the basal level at 4 h (P < 0.05). Dextrose infusion alone did not change plasma VEGF concentration. However, plasma MMP-9 concentration increased significantly at 4 h following dextrose infusion alone (P < 0.05). Saline infusions without insulin caused no alteration in glucose, insulin, VEGF, or MMP-9. CONCLUSIONS: These observations may have implications for a potential antiretinopathic and antiatherosclerotic effect of insulin in the long term.
Adult↗
Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells.
BACKGROUND: It was recently shown that glucose challenge leads to increased generation of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs). OBJECTIVE: To further elucidate the relation between nutrition and ROS generation, we investigated the effect of lipid and protein challenges on ROS generation by leukocytes. DESIGN: After having fasted overnight, one group of healthy subjects consumed a carbohydrate- and protein-free cream preparation (1257 kJ) and another group of healthy subjects consumed an equienergetic pure preparation of casein. Sequential blood samples were obtained after the intake of cream and casein. ROS were measured by chemiluminescence after stimulation by N-formyl-methionyl-leucinyl-phenylalanine. Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) and alpha-tocopherol was measured by HPLC. RESULTS: ROS generation by MNCs and PMNs increased significantly 1, 2, and 3 h after cream intake and 1 h after protein intake. Cholesterol concentrations did not change significantly, whereas triacylglycerol concentrations increased significantly 2 h after cream intake. Total TBARS concentrations increased 1 h after cream intake and remained elevated 3 h after intake, but the increase was not significant when corrected for changes in triacylglycerol. After casein intake, total cholesterol, triacylglycerol, and TBARS concentrations did not change significantly. alpha-Tocopherol concentrations did not change significantly after either cream or casein intake. CONCLUSIONS: Both fat and protein intakes stimulate ROS generation. The increase in ROS generation lasted 3 h after cream intake and 1 h after protein intake. Cream intake also caused a significant and prolonged increase in lipid peroxidation. These data are important because increased ROS generation and lipid peroxidation are key events in atherogenesis.
Aged↗
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.
We have recently demonstrated that an infusion of a low dose of insulin reduces the intranuclear NF-kappa B (a pro-inflammatory transcription factor) content in MNC while also reducing the plasma concentration of NF-kappa B dependent pro-inflammatory cytokines and adhesion molecules. We have now tested the effect of insulin on the pro-inflammatory transcription factor, early growth response-1 (Egr-1) and plasma concentration of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), two major proteins whose expression is modulated by Egr-1. Insulin was infused at the rate of 2 IU/h in 5% dextrose (100 mL/h) and KCI (8 mmol/h) for 4 h in the fasting state in ten obese subjects. Blood samples were obtained at 0, 2, 4 and 6 h. MNC were isolated and their total homogenates and nuclear fractions were prepared and Egr-1 was measured by electrophoretic mobility shift assay (EMSA). Plasma TF and PAI-1 were assayed by ELISA. There was a significant fall in Egr-1 at 2 (66 +/- 14% of basal level) and 4 h (47 +/- 17% of the basal level; P<0.01). PAI-1 levels (basal = 100%) decreased significantly after insulin infusion at 2 h (57 +/- 6.7% of the basal level) and at 4 h (58 +/- 8.3% of the basal level; P<0.001). Plasma TF levels (basal = 100%) decreased to 76 +/- 7.7% of the basal level at 2 h and to 85 +/- 10.4% of the basal level at 4 h (P<0.05). Thus, insulin reduces intranuclear Egr-1 and the expression of TF and PAI-1. These data provide further evidence that insulin has an anti-inflammatory effect including the inhibition of TF and PAI-1 expression. These effects suggest a potential beneficial effect of insulin in thrombin formation and fibrinolysis in atherothrombosis.
Adult↗