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Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo, and Kaleida Health, Buffalo, New York 14209
Address all correspondence and requests for reprints to: Paresh Dandona, B.Sc., M.B., B.S., D.Phil., F.R.C.P., Director, Diabetes-Endocrinology Center of Western New York, Distinguished Professor of Medicine and Pharmacology, Chief of Endocrinology, State University of New York at Buffalo, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org.
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Abstract |
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Design: Nine obese subjects underwent a 6-h infusion of TG-Hep before and after 6 wk of rosiglitazone (8 mg/d) treatment. Hyperinsulinemic euglycemic clamps were performed during 0–2 and 4–6 h of TG-Hep.
Results: After rosiglitazone for 6 wk, fasting FFA concentration fell, but not significantly (489 ± 63 at 0 wk; 397 ± 58 µmol/liter at 6 wk; P = 0.16), whereas C-reactive protein (4.26 ± 0.95 at 0 wk; 2.03 ± 0.45 µg/ml at 6 wk) and serum amyloid A (17.36 ± 4.63 at 0 wk; 8.77 ± 1.63 µg/ml at 6 wk) decreased significantly. At 0 wk, TG-Hep infusion caused a decrease in glucose infusion rate (GIR) from 4.49 ± 0.95 mg/kg·min to 3.02 ± 0.59 mg/kg·min (P = 0.018). Rosiglitazone treatment resulted in an increase in baseline GIR to 6.29 ± 0.81 mg/kg·min (P = 0.03 vs. 0 wk), which decreased to 4.52 ± 0.53 mg/kg·min (P = 0.001) after 6 h of TG-Hep infusion. The decrease in GIR induced by TG-Hep infusion was similar before and after rosiglitazone therapy [1.47 ± 0.50 vs. 1.77 0.3 mg/kg·min (28.9 ± 6.5 vs. 26.4 ± 3.7%); P = 0.51]. The rise in FFAs and triglycerides after TG-Hep infusion was significantly lower at 6 wk (P = 0.006 for FFAs; P = 0.024 for triglycerides).
Conclusions: We conclude that rosiglitazone: 1) causes a significant increase in GIR; 2) induces a decrease in inflammatory mediators, C-reactive protein, and serum amyloid A; 3) decreases the rise in FFAs and triglycerides after TG-Hep infusion; and 4) does not prevent FFA-induced IR.
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Introduction |
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and PKCßII in humans and PKC
in rats (7, 8). Acute elevation of FFAs in normal human subjects causes inflammatory and oxidative stress, which may also contribute to the pathogenesis of insulin resistance (9, 10). Thus, FFAs may have a crucial role in causing insulin resistance. It is generally believed that thiazolidinediones (TZDs) exert their insulin-sensitizing effect predominantly through a chronic lowering of FFAs after suppression of lipolysis in adipose tissue (11, 12). However, the effect of TZDs on the insulin-resistant state induced by an acute FFA load is not clear. Two animal studies examined the effect of triglyceride-heparin emulsion infusion (TG-Hep) after TZD administration (13, 14). In both these studies, the authors concluded that troglitazone was able to prevent FFA-induced insulin resistance. Troglitazone was able to prevent insulin resistance induced by high fat diet in some (15, 16, 17) but not all studies (18, 19) done in rats. To investigate whether rosiglitazone inhibits FFA-induced insulin resistance in addition to suppressing plasma FFA concentrations, we decided to study the effect of acutely raising FFAs by infusing TG-Hep in obese humans before and after 6 wk of rosiglitazone therapy. Because TZDs decrease oxidative and inflammatory stress (20, 21, 22, 23), which may impair insulin sensitivity, we also evaluated the effect of rosiglitazone on FFA-induced changes in oxidative stress and inflammatory mediators.
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Subjects and Methods |
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All subjects had normal glucose tolerance, were not on any medications, were nonsmokers, had normal blood pressure and fasting lipid profile, and were free of any chronic diseases. All female subjects were premenopausal. Liposyn-heparin infusion combined with the hyperinsulinemic euglycemic clamp studies were performed at 0 and 6 wk. Each subject received rosiglitazone (8 mg daily) for 6 wk.
At wk 0 and 6, all patients had blood drawn for the measurement of FFAs, triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), hemoglobin, macrophage migration inhibitory factor (MIF), TNF
, soluble intercellular adhesion molecule (sICAM)-1, IL-6, serum amyloid A (SAA) and C-reactive protein (CRP). Reactive oxygen species (ROS) generation by polymorphonuclear cells (PMNs) was measured as an index of oxidative stress.
Subjects came to the clinical research center at 08.00 h, after an overnight 12-h fast. A 20-gauge catheter was inserted into the antecubital veins in each arm. After collection of the basal blood samples, triglyceride emulsion (Liposyn, 10%; Abbott Laboratories, North Chicago, IL) and heparin (0.2 U/kg·min) were infused at a rate of 1 ml/kg·h for 6 h. Insulin sensitivity was measured by performing hyperinsulinemic euglycemic clamps, using the technique of DeFronzo et al. (24) from 0 to 2 and 4 to 6 h. To shorten the experimental protocol, we used glucose infusion rate during insulin clamp at 0–2 h to calculate baseline insulin sensitivity. Thus, our experimental plan assumes that glucose infusion rate (GIR) during clamp conducted over the first 2 h of the TG-Hep infusion is not affected by FFAs. It has been shown by Boden et al. (3) that FFA-induced insulin resistance occurs only 3–4 h after the start of TG-Hep infusion. Glucose and insulin were not infused from 2 to 4 h. Insulin clamp from 4 to 6 h was used to measure the effects of TG-Hep infusion on insulin sensitivity. After a priming dose of insulin, an infusion (infusion rate 45 mU/m2) of short-acting human insulin (Humulin R; Eli Lilly & Co., Indianapolis, IN) was started and continued until 120 min. Blood samples for the measurement of blood glucose were obtained at 5-min intervals throughout the clamp. A variable glucose infusion of 20% glucose was started to maintain blood glucose concentration constant at 5.5 mmol/liter. The mean coefficient of variation of glucose during the clamps was 6.8%. The hyperinsulinemic euglycemic clamp studies were performed again from 4 to 6 h. Insulin sensitivity was calculated from the GIRs during the last 60 min of the hyperinsulinemic euglycemic clamp and expressed as glucose uptake per body mass. Blood samples for insulin levels were collected at 30-min intervals during the clamps. Mean insulin levels achieved during the clamp at 0 wk were 685.2 ± 75.3 pmol/liter at 2 h and 782.1 ± 138 pmol/liter at 6 h (P = 0.5), whereas the insulin concentrations achieved at 6 wk were 779.2 ± 121 pmol/liter at 2 h and 819.6 ± 224 pmol/liter at 6 h, respectively (P = 0.9).
TG-Hep infusion was continued from h 0 to 6. Blood samples for triglycerides and FFA concentrations were collected 0, 1, 2, 4, 5, and 6 h. As an indirect estimate of the triglyceride clearance, the total body triglyceride metabolic clearance rate (MCR) was calculated as TG-Hep infusion rate divided by the mean steady-state plasma triglyceride concentration, where the total infusion rate is expressed as milligram per kilogram per hour, and plasma triglyceride concentration is expressed as milligrams per deciliter. Assuming that all the triglycerides infused were converted to FFAs, and 1 mmol of triglyceride yielding 3 mmol of FFAs, FFA clearance rate during the clamp studies was similarly calculated. The TG-Hep infusion rate was divided by the mean FFA concentrations achieved during the clamp studies.
Insulin sensitivity data from each subject from 0 wk were compared with that at 6 wk. Thus, each subject served as his/her own control.
Plasma FFA, insulin, and glucose measurements
FFA levels were measured in plasma containing EDTA and lipoprotein lipase inhibitor Paraoxon (diethyl-p-nitrophenyl-phosphate, 0.275 mg/ml blood; Sigma, St. Louis, MO) by a colorimetric assay (Wako, Richmond, VA). Insulin levels were determined using an ELISA kit from Diagnostic Systems Laboratories Inc.(Webster, TX). Glucose values during the clamp were measured by Hemocue AB (Angelholm, Sweden). Hemocue has been used in published clamp studies and is considered a reliable, accurate, and sensitive alternative to a Beckman or YSI glucose analyzer (25, 26).
Plasma CRP, MIF, TNF, sICAM-1, SAA, and IL-6 measurements
Plasma sICAM-1, IL-6, MIF, and TNF were assayed with ELISA kits from R&D Systems (Minneapolis, MN). Plasma SAA and CRP levels were assayed with ELISA kits from Biosource International Inc. (Camarillo, California) and Diagnostic Systems Laboratories Inc., respectively.
ROS generation by PMNs
ROS generation by PMNs was measured as previously described (27). For PMN isolation, blood samples were collected in Na-EDTA as an anticoagulant. Then 3.5 ml of the anticoagulated blood sample were carefully layered over 3.5 ml of the PMN isolation medium (Robbins Scientific Corp., Sunnyvale, CA). Samples were centrifuged at 450 x g in a swing-out rotor for 30 min at 22 C. At the end of the centrifugation, two bands separate out at the top of the red blood cell pellet. The top band consists of mononuclear cells, whereas the bottom consists of PMNs. Respiratory burst activity of PMNs was measured by detection of superoxide radical via chemiluminescence. Five hundred microliters of PMNs were delivered into a Lumiaggregometer (Chronolog, Havertown, PA) plastic flat-bottom cuvette to which a spin bar was added. Fifteen microliters of 10 mmol/liter luminol was then added, followed by 1 µl of 10 mmol/liter formylmethionylleucinylphenylalanine. Chemiluminescence was recorded for 15 min (a protracted record after 15 min did not alter the relative amounts of chemiluminescence produced by various cell samples). Our method, developed independently, is similar to that published by Tosi and Hamedani (28). The interassay coefficient of variation for this assay is 6%. We further established that in our assay system, there is a dose-dependent inhibition of chemiluminescence by superoxide dismutase and catalase: superoxide dismutase inhibited chemiluminescence by 82% at 10 µg/ml, whereas catalase inhibited chemiluminescence by 47% at 40 µg/ml. Chemiluminescence is also inhibited by diphenyleneiodonium chloride (data not shown), a specific inhibitor of reduced nicotinamide adenine dinucleotide phosphate oxidase, the enzyme responsible for the production of superoxide radicals (29). Our assay system is exquisitely sensitive to diphenyleneiodonium chloride at nanomolar concentrations.
Other analytical procedures
Plasma hemoglobin, LDL, triglycerides, HDL, and total cholesterol were measured in our clinical laboratory using well-established essays. Homeostasis model assessment estimate of insulin resistance (HOMA-IR) was calculated as insulin concentration (microinternational units per milliliter) x glucose concentration (millimoles per liter)/22.5.
Statistical analysis
Statistical analysis was carried out using SigmaStat and SigmaPlot software (SPSS Inc., Chicago, IL). Data are presented as mean ± SE. Mann-Whitney rank sum test for nonparametric and paired t test for parametric data were used to compare values at 0 and 6 wk. ANOVA (for repeated measures where appropriate) was used to compare the data during TG-Hep infusion. Spearman’s correlation for nonparametric and Pearson correlation for parametric data were used to perform simple correlations. Data on ROS generation were normalized to a baseline of 100% in view of the interindividual variability and are expressed accordingly as percent of the baseline.
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Results |
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). Plasma CRP and SAA concentrations decreased significantly, whereas the mean fasting sICAM-1, IL-6, and TNF concentrations did not change. The mean GIRs required to maintain glucose levels at 5.5 mmol/liter are shown in Fig. 1. Before rosiglitazone therapy (0 wk), 6 h of TG-Hep infusion caused a decrease in GIR from 4.49 ± 0.95 to 3.02 ± 0.59 mg/kg·min (P = 0.018). Rosiglitazone treatment for 6 wk resulted in an increase in baseline GIR to 6.29 ± 0.81 mg/kg·min (P = 0.03 vs. 0 wk, a 40% increase), which decreased to 4.52 ± 0.53 mg/kg·min (P = 0.001 vs. pretriglyceride infusion; P = 0.03 vs. 0 wk) after 6 h of TG-Hep. The absolute or percent reduction in GIR induced by TG-Hep was not altered by rosiglitazone treatment [1.47 ± 0.50 vs. 1.77 ± 0.36 mg/kg·min (28.9 ± 6.5% vs. 26.4 ± 3.7%), P = 0.51]. The decrease in GIR after TG-Hep infusion was seen in all subjects at both 0 and 6 wk. The increase in baseline GIR after rosiglitazone was seen in eight of nine subjects. Our study included five male and four female volunteers. The results were similar in both male and females.
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. At 0 wk, the mean basal FFA concentration was 489 ± 63 µmol/liter before the start of infusion. At 6 wk, the mean basal FFA concentration was 397 ± 58 µmol/liter before the start of infusion. FFA levels increased significantly after TG-Hep infusion at both 0 and 6 wk (P < 0.001 for 0 wk; P = 0.019 for 6 wk). The rise in FFAs was lower at 6 wk, compared with 0 wk (P = 0.006 by two-way ANOVA). Peak FFA levels were achieved at 4 h at both 0 and 6 wk (1077 ± 101 µmol/liter at 0 wk; 707 ± 121 µmol/liter at 6 wk, P < 0.05 vs. 0 wk), and the mean change from basal to peak was 560 ± 95 µmol/liter at 0 wk and 309 ± 107 µmol/liter at 6 wk (P < 0.05). Hyperinsulinemic-euglycemic clamp from 0 to 2 and 4 to 6 h probably diminished the rise in FFA levels between 0–2 h and 4–6 h. The area under curve of circulating FFAs was lower by 34.4% at 6 wk (P = 0.02). To eliminate the possibility that this was due to decreased breakdown of triglycerides in the circulation, we measured triglyceride concentrations during TG-Hep at 0 and 6 wk. The results are shown in Fig. 3. At 0 wk, the mean basal triglyceride concentration was 1.58 ± 0.35 mmol/liter before the start of infusion. At 6 wk, the mean basal triglyceride concentration was1.69 ± 0.28 mmol/liter before the start of infusion. Triglyceride levels increased significantly after TG-Hep (P < 0.001 at 0 and 6 wk). The rise in triglycerides was lower at 6 wk, compared with 0 wk (P = 0.024 by two-way ANOVA). Peak triglyceride levels were achieved at 4 h at both 0 and 6 wk (5.209 ± 0.82 mmol/liter at 0 wk; 3.843 ± 0.51 mmol/liter at 6 wk, P = 0.05 vs. 0 wk). Area under curve of triglycerides tended to be lower by 23.5% at 6 wk but not significantly (P = 0.09). The MCR of both triglycerides and FFAs increased significantly at the end of 6 wk of rosiglitazone therapy (28.2 ± 5.2 vs. 35.2 ± 5.4 ml–1/h–1·kg–1, P = 0.01 for triglycerides; 48.7 ± 6.2 vs. 68.4 ± 7.8 ml–1/h–1·kg–1, P = 0.01 for FFAs).
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The area under curve for MIF concentrations was not significantly different at 6 wk, compared with 0 wk (P = 0.30). There was no difference between the MIF concentrations at 0 and 6 wk at any of the time points measured (0, 2, 4, or 6 h). CRP concentrations did not change over 6 h of TG-Hep infusion at 0 or 6 wk.
ROS generation (expressed as percent of baseline value) by PMNs increased significantly (P = 0.036 by ANOVA) at 0 wk (259.7 ± 54.2% at 2 h, P = 0.02 vs. 0 h; 211.4 ± 67.2% at 4 h, P = 0.13 vs. 0 h; 152.3 ± 21.9% at 6 h, P = 0.04 vs. 0 h) after TG-Hep infusion. There was a statistical trend for ROS generation to rise at 6 wk (P = 0.14 by ANOVA) after TG-Hep infusion (182.0 ± 41.4% at 2 h, P = 0.09 vs. 0 h; 243.8 ± 68.5% at 4 h, P = 0.07 vs. 0 h; 217.7 ± 75.4% at 6 h, P = 0.25 vs. 0 h).
Correlation coefficients were calculated after combining data for 0 and 6 wk. GIR correlated significantly and negatively with SAA (r = –0.461, P = 0.05), FFAs (r = –0.469, P = 0.05), and HOMA-IR (r = –0.629, P < 0.01) and showed a trend toward correlation with CRP (r = –0.393, P = 0.10). Plasma SAA correlated positively with FFAs (r = 0.464, P = 0.05), CRP (r = 0.735, P = 0.001), and sICAM-1 concentrations (r = 0.762, P < 0.001). Plasma CRP correlated positively with TNF (r = 0.739, P < 0.001) and IL-6 concentrations (r = 0.507, P = 0.032).
The change in SAA concentration correlated positively with change in CRP (r = 0.683, P = 0.036), TNF (r = 0.750, P = 0.016), and IL-6 (r = 0.728, P = 0.02) concentrations. As expected, the change in GIR correlated negatively with change in HOMA-IR (r = –0.869, P = 0.005).
The change in GIR after TG-Hep did not correlate with the change in FFA or MIF levels at 0 or 6 wk.
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Discussion |
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We also demonstrate for the first time in humans that the triglyceride and FFA levels achieved after TG-Hep were lower after rosiglitazone therapy. This has previously been shown in animal studies in which the rise in FFAs was diminished by 30–40% after treatment with troglitazone (13, 14). The fact that the rise of both triglyceride and FFA concentrations was significantly diminished after rosiglitazone in our study suggests that the clearance of both is increased. Consistent with this is the fact that MCR of triglycerides and FFAs was significantly increased after rosiglitazone treatment. However, our study is limited by the fact that the metabolic clearance of FFAs and triglycerides was calculated and not measured directly at the tissue level by using a tracer approach. It is relevant that rosiglitazone treatment decreases the postprandial rise in triglyceride and FFA levels after a mixed meal containing (1,1,1-13C) tripalmitin in type 2 diabetic subjects (30). The rate of appearance of (13C) palmitic acid in the FFA fraction decreased after treatment with rosiglitazone in this study. TZDs can enhance protein-mediated as well as direct diffusion-dependent FFA uptake into cells by enhancing plasma triglyceride lipolysis, transendothelial FFA transport, and conversion to intracellular triglycerides by also enhancing glyceroneogenesis in the adipocyte (12, 31, 32, 33, 34). Troglitazone has been shown to induce the expression of peroxisomal proliferator-activated receptor-, a receptor that mediates increased lipid oxidation and use (35). The results of our study are consistent with the increased capacity of adipose tissue to act as a buffer for lipid flux after treatment with TZDs (36).
In skeletal muscle cells, TZDs can enhance the uptake and ß-oxidation of FFAs (37). Despite the lower triglyceride and FFA concentrations after rosiglitazone, the magnitude of the fall in GIR was unchanged after TG-Hep infusion. These data suggest that whereas TZDs enhance uptake of FFAs and channel it effectively into storage or oxidation in a fasting state, the capacity of skeletal muscles to do so may be overwhelmed in the presence of an acute FFA load, leading to the accumulation of intracellular FFA/FFA metabolites (diacylglycerol, ceramide) in the skeletal muscle, thus inducing insulin resistance. The measurement of intramyocellular lipid content in a similar protocol as used in our study would give us a more specific insight into the mechanisms at play. In our study, TG-Hep infusion was given from 0 to 6 h. Baseline insulin sensitivity was calculated by measuring GIR during 1–2 h, and FFA-induced insulin resistance was calculated from GIR during 5–6 h. It can be argued that TG-Hep infusion may have induced some insulin resistance at 1–2 h. However, this makes the results of our study even more significant because FFA-induced decrease in GIR was manifested in all subjects and the magnitude was unchanged after 6 wk of rosiglitazone therapy. However, the induction of insulin resistance at 1–2 h is unlikely because it has previously been shown that FFA-induced insulin resistance does not occur for 3–4 h after the start of infusion (3).
Another limitation of our study is that we did not measure hepatic glucose output (HGO). It is possible that HGO may not be completely suppressed in obese individuals after TG-Hep infusion, and therefore after triglyceride infusion, GIR value at 0 wk may underestimate true glucose use. However, most studies in humans have shown that despite FFA-induced increase in gluconeogenesis, the net effect of FFAs on HGO is minimal because of intact hepatic autoregulatory mechanisms, particularly in nondiabetic subjects (38, 39). Therefore, even if we account for the possible increase in endogenous glucose production or impaired suppression of endogenous glucose production after the Liposyn infusion, it is unlikely to influence the difference in the two groups in the whole-body glucose uptake rates. Also, because TZDs enhance insulin-mediated suppression of HGO (40), it is possible that the posttriglyceride infusion GIR value at 6 wk will be affected less than that at 0 wk. This only strengthens the conclusion of our study: that rosiglitazone was not able to prevent FFA-induced insulin resistance.
TZDs decrease circulating FFA levels in some (11, 32) but not all studies (30, 41, 42, 43, 44). This may be due to the variability that is commonly observed in fasting FFA levels. In our study, FFA concentrations showed a trend toward a decrease (P = 0.16) after treatment with rosiglitazone. It has been suggested that inflammatory mechanisms may interfere with insulin signal transduction and thus may contribute to insulin resistance (10, 45). Indeed, the administration of the classical antiinflammatory drug, aspirin, has been shown to cause a reduction in insulin resistance through a suppression of inhibitory-
B kinase-ß, a known serine kinase and an activator of the inflammatory cascade that phosphorylates inhibitory-B to induce the nuclear translocation of nuclear factor-B (NF-B) and the transcription of proinflammatory genes (46). It is therefore of significance that TZDs, known to restore insulin sensitivity, have profound, comprehensive and rapid antiinflammatory effects (20, 21, 22, 23, 47, 48). These effects may contribute to their beneficial action on insulin sensitivity. Fasting levels of both SAA and FFA concentrations correlated to a similar extent with GIR (r = –0.461 for SAA and r = –0.469 for FFAs) in our study. Therefore, it is possible that a part of the insulin-sensitizing effect of rosiglitazone may be due to the decrease in inflammatory mediators. This area clearly needs further investigation to determine which FFA derivative and/or inflammatory mediator in the skeletal muscle correlates best with insulin resistance.
Acute elevation of FFAs in humans causes inflammatory and oxidative stress, as reflected in increased ROS generation, NF-B binding, p65(RelA) expression, and an increase in plasma MIF but no change in CRP, monocyte chemotactic protein-1, sICAM-1, or TNF concentrations (9). We have also shown in the past that insulin has a profound antiinflammatory effect (49, 50). Insulin infusion over 4 h decreases NF-B binding, ROS generation, and serum sICAM-1 and monocyte chemotactic protein-1 concentrations in obese humans. Because we have infused insulin (during clamps) for the major duration of the study, we did not measure NF-B binding in mononuclear cells. MIF concentrations in the serum and ROS generation by PMNs increased significantly after TG-Hep at 0 but not 6 wk. Thus, rosiglitazone was able to diminish the FFA-induced increase of oxidative stress and MIF.
In conclusion, we have demonstrated that rosiglitazone treatment for 6 wk in obese humans results in insulin sensitization and a decrease in inflammatory mediators (CRP and SAA); it reduces the magnitude of increase in FFAs, triglycerides, and MIF after TG-Hep infusion but does not prevent FFA-induced insulin resistance.
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Footnotes |
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First Published Online June 28, 2005
1 S.D. and D.T. contributed equally to this work. 
Abbreviations: BMI, Body mass index; CRP, C-reactive protein; FFA, free fatty acid; GIR, glucose infusion rate; HDL, high-density lipoprotein; HGO, hepatic glucose output; HOMA-IR, homeostasis model assessment estimate of insulin resistance; LDL, low-density lipoprotein; MCR, metabolic clearance rate; MIF, migration inhibitory factor; NF-B, nuclear factor-B; PKC, protein kinase C; PMN, polymorphonuclear cell; ROS, reactive oxygen species; SAA, serum amyloid A; sICAM, soluble intercellular adhesion molecule; TG-Hep, triglyceride-heparin; TZD, thiazolidinedione.
Received February 2, 2005.
Accepted June 16, 2005.
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B-. Diabetes 51:2005–2011 and alterations in the insulin signaling cascade. Diabetes 48:1270–1274[Abstract]
B suppressive and inhibitor-B stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab 86:3250–3256B and stimulation of inhibitor B by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab 86:1306–1312
while stimulating that of PPAR in mononuclear cells in obese subjects. J Clin Endocrinol Metab 86:3130–3133B and stimulates IB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265This article has been cited by other articles:
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