Am J Physiol Regul Integr Comp Physiol 290: R139 –R144, 2006; CALL FOR PAPERS Metabolic Syndrome
Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin Fahim Abbasi,1 Sang-Ah Chang,2 James W. Chu,1 Theodore P. Ciaraldi,2 Cindy Lamendola,1
Tracey McLaughlin,1 Gerald M. Reaven,1 and Peter D. Reaven3
1Department of Medicine, Stanford University School of Medicine, Stanford; 2Medical Research Service, Veterans Affairs
San Diego Healthcare System and Division of Endocrinology and Metabolism, Department of Medicine, University
of California, San Diego, California; and
3Medical Research Service, Division of Endocrinology and Metabolism,
Department of Medicine, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona

Submitted 22 April 2005; accepted in final form 30 August 2005 Abbasi, Fahim, Sang-Ah Chang, James W. Chu, Theodore P.
and underexpression of adiponectin alters insulin sensitivity in Ciaraldi, Cindy Lamendola, Tracey McLaughlin, Gerald M.
animal models of insulin resistance (4, 29). Furthermore, in Reaven, and Peter D. Reaven. Improvements in insulin resistance
vitro and in vivo studies have demonstrated several possible with weight loss, in contrast to rosiglitazone, are not associated with mechanisms for the beneficial actions of adiponectin, including changes in plasma adiponectin or adiponectin multimeric complexes.
enhanced hepatic insulin sensitivity (4), an increase in fatty Am J Physiol Regul Integr Comp Physiol 290: R139 –R144, 2006; acid oxidation (9), and decreased inflammatory activity (20). In doi:10.1152/ajpregu.00287.2005.—It has been suggested that changes light of these observations, it has been suggested that interven- in adiponectin levels may contribute to improved insulin sensitivity ininsulin-resistant individuals both after weight loss and after treatment tions that improve insulin sensitivity may accomplish this with thiazolidinedione compounds. If this is correct, then changes in through modulation of adiponectin levels, and this notion is total circulating adiponectin and/or distribution of its multimeric consistent with evidence that plasma adiponectin concentra- complexes should coincide with improvements in insulin sensitivity tions increase when insulin-resistant individuals, either nondi- after both interventions. To address this issue, fasting adiponectin abetic or with Type 2 diabetes, are treated with thiazolidinedi- concentrations and distribution of adiponectin complexes were mea- sured in plasma samples in 24 insulin-resistant, nondiabetic subjects On the other hand, not all interventions that enhance insulin before and after 3– 4 mo of treatment with either rosiglitazone or sensitivity are associated with significant changes in plasma caloric restriction. The degree of insulin resistance in each group of 12 adiponectin concentrations. For example, plasma adiponectin subjects was equal at baseline and improved to a similar extent levels do not significantly increase in response to two thera- (ϳ30%) after each therapy. Whereas total adiponectin levels in- peutic modalities that clearly improve insulin action, namely, creased by nearly threefold and the relative amount of several higher moderate weight loss (ϳ8.0 kg) (2, 28) and increases in molecular weight adiponectin complexes increased significantly in the physical activity (14, 18, 31). There are several possible rosiglitazone treatment group, there were no discernible changes inadiponectin levels or in the distribution between high or low molec- explanations for these discrepant results. First, a functional ular weight complexes in the weight loss group. These data indicate peroxisome proliferator-activated receptor-responsive element that, although changes in total adiponectin and several specific adi- in the adiponectin promoter has recently been identified that is ponectin complexes paralleled improvements in insulin resistance in thought to play a significant role in the transcriptional activa- thiazolidinedione-treated subjects, neither circulating adiponectin tion of adiponectin gene in adipocytes (15). Thus it could be concentrations nor multimeric complexes changed in association with argued that the increase in adiponectin concentrations in TZD- enhanced insulin sensitivity after moderate weight loss in 12 insulin- treated insulin-resistant individuals was a direct effect of the drug itself, and changes in adiponectin are not responsible for thiazolidinedione; adiponectin multimers; high molecular weight improved insulin resistance resulting from all treatment mo- dalities. Second, the apparent divergent changes in plasmaadiponectin concentrations following moderate weight loss andincreased physical activity vs. TZD treatment could also be ADIPONECTIN IS A ϳ30-kDa protein produced by adipocytes, explained by differences in either the baseline degree of insulin which circulates in plasma in multimeric aggregates of differ- resistance and/or the improvement in insulin resistance after ent sizes and has been closely associated with insulin action (7, each of the interventions. Third, although adiponectin is syn- 25). Total circulating adiponectin levels have been shown to be thesized as a ϳ30-kDa monomer, it circulates as a variety of lower in insulin-resistant individuals (1, 27), and both over- multimeric forms, including homotrimers (70 –90 kDa) andlarger oligomers, and a high molecular weight (HMW) form Address for reprint requests and other correspondence: P. Reaven, Division of Endocrinology and Metabolism, Dept. of Medicine (CS-111E), Carl T.
The costs of publication of this article were defrayed in part by the payment Hayden Veterans Affairs Medical Center, 650 East Indian School Road, of page charges. The article must therefore be hereby marked “advertisement” Phoenix, Arizona 85012 (e-mail: peter.reaven@med.va.gov).
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
consisting of six trimers (21). Evidence indicates that these proximately one-third of the 490 nondiabetic subjects had SSPG multimers vary in their biologic activities, and it has been concentration values above 180 mg/dl.
suggested that the proportion of adiponectin in the HMW form To accomplish the goals of our study, we selected 24 nondiabetic is a more accurate indicator of insulin sensitivity than total insulin-resistant subjects, matched for age and gender distribution, adiponectin levels (21, 22). Therefore, there may be changes in who had similar SSPG concentrations before and after administrationof rosiglitazone (n ϭ 12) or weight loss (n ϭ 12). Rosiglitazone- the absolute or relative levels of various adiponectin multimers treated subjects received 4 mg/day for 4 wk, followed by 8 mg/day for that explain the improvement in insulin resistance accompany- 8 wk, while maintaining their usual diet. All baseline measurements ing weight loss. Finally, because moderate weight loss (unlike were repeated at the end of 12 wk of treatment. The weight loss group TZD treatment) is not associated with changes in circulating included volunteers with a BMI between 30.0 and 34.9 kg/m2. All levels of adiponectin (2, 28), other factors may contribute to subjects were instructed by a certified dietitian on calorie-restricted improvements in insulin sensitivity in this setting. The present diets calculated to lead to a weight loss of 0.5 kg/wk. The period of study was initiated to evaluate these various possibilities and weight loss was 4 mo in duration, during which time subjects were involved directly comparing the changes in total plasma adi- seen bimonthly to be weighed and receive dietary advice. At the ponectin concentrations and the distribution of adiponectin completion of the weight loss phase, subjects were instructed on a multimers that were seen in response to TZD treatment with weight-maintenance diet. After 2 wk of stable weight, all measure- those before and after weight loss in insulin-resistant subjects ments performed at baseline were repeated.
Plasma glucose and insulin levels were measured as described that were matched for both baseline insulin resistance and the previously (32). Plasma adiponectin levels were measured on blood degree to which the defect in insulin action improved with each samples drawn before the initiation of the insulin suppression test with therapeutic intervention. If variations in adiponectin are largely a radioimmunoassay established by Linco Research (St. Charles, responsible for improvements in glucose metabolism following MO). This assay has a sensitivity of 1 ng/ml, a range of 500 ng/ml to most typical therapeutic interventions, then changes in plasma 100 ␮g/ml, when samples are diluted 1/500 as per manufacturer’s adiponectin and/or distribution of its complexes should reflect instructions, and intra- and interassay coefficient of variation of Ͻ8%.
improvements in insulin sensitivity after both moderate weight Analysis of the multimerization status of circulating adiponectin was performed by size fractionation of plasma samples using SDS-PAGE under nonreducing, nondenaturing conditions, as described MATERIALS AND METHODS
(with minor modifications) by Waki et al. (26). Plasma was combinedwith a 4ϫ Laemmli sample buffer, prepared without ␤-mercaptoetha- The study included 24 subjects selected from a larger group of nol. Sample preparation was performed at room temperature. Sam- volunteers who had participated in studies at Stanford University’s ples, equivalent to 2 ␮l of plasma, were size fractionated on 3– 8% General Clinical Research Center examining the effect of weight loss polyacrylamide gradient gels in a Tris-acetate system. Proteins were (19) and treatment with rosiglitazone (5) on insulin resistance and transferred to nitrocellulose membranes and blocked for 3 h at room cardiovascular disease risk factors. Participants for these studies were temperature with 5% milk in Tris-buffered saline, pH 7.5. Membranes recruited from the San Francisco Bay area through advertisements in were incubated with a monoclonal antibody against human adiponec- local newspapers. Each volunteer signed a written informed consent tin (BD Biosciences, Palo Alto, CA), at a 1:500 dilution for 1 h at before admission to the General Clinical Research Center. All study room temperature. The secondary antibody was anti-mouse IgG con- participants were determined to be nondiabetic according to the jugated with horseradish peroxidase (Amersham Biosciences, Buck- criteria of the American Diabetes Association (5a) and were required inghamshire, UK). Bands were detected using SuperSignal West Pico to have normal findings on history, physical examination, and routine chemiluminescent substrate (Pierce, Rockford, IL) and captured on chemical screening battery, including hematocrit, creatinine, and ala- Hyperfilm ECL film (Amersham Biosciences). Quantitative densitom- nine transaminase levels. Degree of adiposity was assessed by body etry was performed using ChemiImager software (Alpha Innotech, mass index (BMI), and all subjects with BMI Ն35.0 kg/m2 were San Leandro, CA), and, after subtracting the background density, data excluded from the studies. Volunteers selected for the weight loss were presented as average density per band. Each subject sample was study were required to have a BMI of 30.0 –34.9 kg/m2. There were run at least two or three separate times and yielded consistent results.
no specific BMI inclusion values for the rosiglitazone-treated group, Bands were compared with HiMark Unstained HMW protein stan- and BMI ranged from 21.9 to 34.8 kg/m2. The study protocol was dards from Invitrogen (cat. no. LC5688). Manufacturer’s instructions reviewed and approved by the Institutional Review Board at Stanford were followed to visualize the bands using Coomassie blue. A single lot of standards was used for all the gels. One limitation to the Study subjects underwent an insulin suppression test to quantify SDS-PAGE is the semiquantitive nature of the results. However, the insulin-mediated glucose disposal as originally described (10) and ability to assess multiple pre- and posttherapy samples on the same validated by our research group. Briefly, after a 12-h overnight fast, gels makes this approach an excellent method to directly compare the subjects were infused for 180 min with octreotide acetate (0.27 g ⅐ mϪ2 ⅐ minϪ1), insulin (32 mIU ⅐ mϪ2 ⅐ minϪ1), and glucose (267 Summary statistics are described as means Ϯ SD. The two study mg ⅐ mϪ2 ⅐ minϪ1). Blood was drawn at 10-min intervals from 150 to groups were compared using Student’s unpaired t-test and ␹-square 180 min of the infusion to measure plasma glucose and insulin test. Within each study group, changes in clinical and metabolic concentrations, and the means of these four values were used as the variables were compared using Student’s paired t-test. Finally, Pear- steady-state plasma insulin and glucose (SSPG) concentrations for son’s correlation coefficients were calculated between the changes in each individual. Because steady-state plasma insulin concentrations SSPG and adiponectin concentrations in response to the interventions.
were similar in all subjects during these tests, the SSPG concentrationprovided a direct measure of the ability of insulin to mediate disposalof an infused glucose load; the higher the SSPG concentration, the more insulin resistant the individual. On the basis of the results of theinsulin suppression test, participants with SSPG concentrations Ͼ180 Baseline characteristics of the study population are given in mg/dl were defined as being insulin resistant and were eligible for this Table 1. The groups were similar in terms of age, gender study. This cutoff point was chosen based on the results of a previ- distribution, SSPG, and fasting plasma glucose and insulin ously reported distribution of SSPG concentrations (32) where ap- concentrations. However, based on the inclusion criteria for the AJP-Regul Integr Comp Physiol • VOL 290 • JANUARY 2006 • www.ajpregu.org Table 1. Baseline characteristics of the study subjects Values are means Ϯ SD for 12 subjects in each group. BMI, body mass index; SSPG, steady-state plasma glucose.
two different intervention arms, BMI was greater in those whoparticipated in the weight loss program.
Table 2 compares the effects of the two experimental inter- ventions on body weight, BMI, SSPG concentrations, andfasting plasma glucose and insulin concentrations. Participantsin the weight loss group lost an average of 7.4 kg (8% of initialweight, P Ͻ 0.001), whereas rosiglitazone-treated subjectsgained 1.3 kg (P ϭ 0.03). As a consequence of these changesin opposite directions, weight at the end of the study was nearlyidentical in the two groups.
SSPG concentrations were essentially identical in the two groups before weight loss (Table 2), declined significantly andto a comparable degree after each intervention (29% vs. 30%),and were again quite similar at the end of the study. Inassociation with the improvement in insulin sensitivity, fastingplasma glucose and insulin concentrations decreased signifi-cantly (P Ͻ 0.05) and to a similar extent in both groups.
Figure 1 depicts plasma adiponectin concentrations before and after the two experimental interventions. Mean baselineadiponectin levels were not statistically different (P ϭ 0.30) Fig. 1. Effect of rosiglitazone treatment and weight loss on fasting plasmaadiponectin concentrations. Plasma adiponectin levels are presented in subjects between the rosiglitazone-treated (10.9 Ϯ 5.0 ␮g/ml) and pre- and posttreatment with rosiglitazone (A) or weight loss (B). Individual weight loss (9.0 Ϯ 3.2 ␮g/ml) groups. Plasma adiponectin data for each subject are shown, as are the mean values (bars) for each group.
concentration increased in every rosiglitazone-treated subject, Statistical comparisons are between pre- and posttreatment values for each with a tendency for the increment to be greatest in individuals with the highest baseline values. The overall increase in adi-ponectin concentration after rosiglitazone treatment (to 24.8 Ϯ ponectin concentrations at the end of the study were approxi- 11.6 ␮g/ml) was highly statistically significant (P Ͻ 0.001), mately threefold greater (24.8 Ϯ 11.6 ␮g/ml, 95% confidence and there was no relationship between the modest change in interval of 17.4 –32.1, vs. 8.9 Ϯ 3.1 ␮g/ml, 95% confidence weight seen in these subjects and the increase in adiponectin interval of 7.0 –10.8; P Ͻ 0.001) in rosiglitazone-treated sub- after administration of rosiglitazone.
jects, despite the fact that both the improvement and the final In marked contrast, plasma adiponectin concentrations re- level of insulin sensitivity were similar in the two groups.
mained unchanged in association with the enhanced insulin Furthermore, there was no correlation in the entire group sensitivity following weight loss, with values increasing between the improvement in insulin sensitivity and increases in slightly in five subjects, decreasing slightly in six others, and plasma adiponectin concentration in response to the experi- not changing in one subject. As a consequence, plasma adi- mental treatments (r ϭ 0.12, P ϭ 0.59).
Table 2. Effect of rosiglitazone treatment and weight loss on body weight and metabolic variables Values are means Ϯ SD for 12 subjects in each group. RGZ, rosiglitazone treatment. *Baseline variables compared with those after the intervention; †changes in the rosiglitazone treatment group compared with those in the weight loss group.
AJP-Regul Integr Comp Physiol • VOL 290 • JANUARY 2006 • www.ajpregu.org between the two groups were observed. First, the relativeamount or distribution of each adiponectin complex, expressedas percentage of total adiponectin for each individual, variedbetween groups at baseline. The major difference was that theweight loss group had a lower percentage of the HMW com-plex, whereas percentages of other complexes did not differbetween the two groups before the interventions. Second,whereas there were increases in the relative amounts of theHMW adiponectin band and the 200-kDa band in the rosigli-tazone group after treatment (Table 3), there was no such shiftin the distribution among adiponectin multimers from theplasma of the weight loss group. Representative examples ofthis are shown in Fig. 2. In support of this overall finding wasthe observation that the percentage of total adiponectin presentin the HMW complex increased after treatment in all 12 of thesubjects receiving rosiglitazone (with or without accompany- Fig. 2. Evaluation of complexes of adiponectin multimers. Shown in a repre- ing weight gain), whereas this only occurred in 3 of the 12 sentative image of Western blot gradient gel analysis of adiponectin multimers subjects in the weight loss group. There was also a significant from plasma of 2 subjects that were in the rosiglitazone (RGZ) treatment group decrease in the percentage of total adiponectin present in the and 2 subjects in the weight loss (WL) group. B, baseline; RGZ or WL, ϳ170-kDa band in the rosiglitazone group. There were no posttreatment. Under reducing conditions, the middle and higher molecular other consistent changes in adiponectin multimer distribution weight bands disappeared, consistent with the notion that these bands repre-sented higher-order mulitimers of adiponectin. Bands for the posttherapy in rosiglitazone subjects, and there were no consistent changes rosiglitazone group appear darker in general because there were overall in the relative amounts of any adiponectin multimers in the increases in the total amount of adiponectin. Relative distribution, as presented in Table 3, adjusts for this difference. MW, molecular weight (as measured bymolecular mass in kDa).
To assess whether changes in specific adiponectin multi- A major goal of this study was to clarify the nature of the meric complexes, rather than total plasma adiponectin concen- relationship between plasma adiponectin concentrations and tration, may have accounted for enhanced insulin sensitivity resistance to insulin-mediated glucose disposal. Perhaps the after either intervention, we compared relative levels of each of most useful way to view our results from this perspective is to the major adiponectin forms present in plasma as determined begin by identifying areas of common agreement concerning by density measurement of each band identified on the gradient this issue. In this context, several previous studies have shown gels. This analysis revealed seven or eight different bands that improved insulin sensitivity following TZD treatment is ranging in size from ϳ90 kDa, most probably the trimeric associated with increases in plasma adiponectin concentrations form, to a HMW form, Ͼ400 kDa (Fig. 2). If samples were (3, 12, 22, 23, 33). More recently, Pajvani et al. (22) have more extensively heated and denatured before addition to gels, shown, using velocity sedimentation methodology to identify the number of bands were typically reduced to the 30- and circulating adiponectin complexes, that the increase in plasma 90-kDa forms (data not shown), consistent with a reduction in adiponectin following TZD therapy in subjects with Type 2 multimerization of adiponectin as previously described (21, diabetes or insulin resistance is also associated with greater 26). The averaged results from analysis of multiple gels are amounts of larger multimeric forms of adiponectin. Similar to shown in Table 3, and it can be seen that several differences Waki et al. (26), we used a SDS-PAGE method to measure Table 3. Effect of rosiglitazone treatment and weight loss on relative amount of individual adiponectin multimers in plasma Values are means Ϯ SD and depict the amount of adiponectin multimer levels as % total adiponectin for each individual in the 12 subjects in each group.
Analysis of the multimerization status of circulating adiponectin was performed by size fractionation of plasma samples using SDS-PAGE under nonreducing,nondenaturing conditions, as described in MATERIALS AND METHODS. Bands were detected using a chemiluminescent substrate and compared with molecularweight standards. Quantitative densitometry comparisons were performed using ChemiImager software. Each gel included pre- and postsamples from individualsfrom both groups, as illustrated in Fig. 3. Although bands were relatively consistent in their distribution (and reproducible on gels run under similar conditions),some bands such as the 130-kDa band were present in very low in amounts and were only seen in some subjects. *and †, see Table 2.
AJP-Regul Integr Comp Physiol • VOL 290 • JANUARY 2006 • www.ajpregu.org adiponectin complex distribution in plasma, and our results are disposal, they account for Ͻ 40% of the variability from person quite similar to those of Pajvani et al. (22) in that we also to person when insulin-mediated glucose disposal is measured observed an increase in the very highest molecular mass band directly (32). The limitation of insulin concentrations as indi- and, to a lesser extent, in a 200-kDa band, whereas they cators of insulin action is accentuated in obese individuals described an increase in adiponectin complexes that appears to because obesity, per se, results in decreased insulin clearance include a range of HMW adiponectin complexes (22). The (8, 16). Thus large amounts of weight loss will result in lower most likely explanation for the relatively minor discrepancies insulin concentrations, in excess of any associated improve- between the results of the two studies is the difference in the ment in insulin sensitivity, and their use in this situation cannot methods used to measure adiponectin mulitimers.
provide reliable estimates of insulin action. It is also worth Thus there is general agreement that TZD treatment is noting that the increment in adiponectin concentration follow- associated with enhanced insulin sensitivity, higher plasma ing massive weight loss was substantially less than that de- adiponectin concentrations, and an increase in HMW forms of scribed following TZD administration (13, 17, 33). Thus, adiponectin. Although there is accumulating evidence that although changes in plasma adiponectin concentration may TZD-associated changes in adiponectin concentration and/or vary as a function of the amount of weight lost, insulin multimer distribution may mediate improved insulin sensitiv- sensitivity can improve after moderate weight loss in the ity, it remains possible that the changes in insulin action and absence of any change in plasma adiponectin, and the increase adiponectin concentration and size distribution represent sep- in adiponectin concentration with even massive weight loss is arate and unrelated TZD effects. Consistent with this possibil- attenuated compared with the changes seen after TZD treat- ity was our inability to discern a significant relationship following TZD administration between the enhanced insulin In contrast to previous studies, ours was explicitly designed sensitivity and the changes in plasma adiponectin concentra- to elucidate the relationship between adiponectin and treat- tion. The results of the recent report by Hammarstedt et al. (12) ment-induced changes in insulin sensitivity. Furthermore, ours also show that insulin sensitivity improves, associated with is the only study that directly compared the effects of rosigli- increases in plasma adiponectin concentration and a shift to a tazone administration vs. those of moderate weight loss on HMW form, subsequent to pioglitazone administration in in- both insulin action and adiponectin concentration and its mul- sulin-resistant, nondiabetic individuals. However, as was the timeric complex distribution. Finally, the impact of the two case with our study, there was no relationship between the treatments was compared in insulin-resistant, nondiabetic sub- enhanced insulin sensitivity and the changes in adiponectin jects, well matched at baseline for age, gender, and degree of amount or multimer distribution. It is possible that the lack of insulin resistance. The similarity of the two groups before a relationship between changes in insulin action and adiponec- treatment permits us to more confidently compare the impact of tin concentration is due to the relatively few number of patients the two interventions on the relationship between treatment- in both studies and/or the fact that they were all insulin induced changes in insulin action and plasma adiponectin resistant. In any event, there appears to be relative unanimity concentrations. The results presented clearly demonstrate that concerning the fact that administration of TZD compounds to the relationship between these variables varied dramatically as insulin-resistant individuals leads to enhanced insulin sensitiv- a function of the intervention. Despite essentially identical ity, increases in total adiponectin concentration, and a shift to improvement in insulin sensitivity, the changes in plasma HMW forms. What is not so clear is the nature and strength of adiponectin concentrations were quite disparate. Whereas in- the relationship between these metabolic changes.
creases in total adiponectin and several higher molecular There is less agreement concerning the effect of weight loss weight complexes paralleled improvements in insulin resis- on plasma adiponectin concentrations. The results of the tance in TZD-treated subjects, we report the novel finding that present study, as well as previous findings of our research no changes in adiponectin concentrations or molecular weight group (2) and those of Xydakis et al. (28), indicate that insulin complexes were observed when insulin sensitivity improved to sensitivity improves after relatively moderate weight loss in the a similar degree after weight loss. As indicated above, exer- absence of any change in plasma adiponectin concentration. In cise-mediated improvements in insulin sensitivity also appear contrast, evidence has also been published that the improve- independent of changes in total adiponectin levels (14, 18, 31).
ment in insulin action associated with weight loss is accompa- Thus it is possible to dissociate improvements in insulin nied by higher plasma adiponectin concentrations (6, 11, 30).
sensitivity from increases in adiponectin concentration, sup- However, these studies differed from ours in two important porting the notion that changes in adiponectin may not be ways. First, the magnitude of obesity at baseline in these latter instrumental in improving insulin resistance in all therapeutic studies was much greater; bariatric surgery was used to induce settings. As a corollary, it appears that other factors (e.g., other weight loss, resulting in relatively massive amounts of weight adipokines or cytokines produced in adipose tissue or else- loss, i.e., 23 kg to almost 57 kg (6, 11, 30). This approach is where) may play a role in the improvement in insulin-mediated quite different from ours in which moderate calorie restriction glucose disposal that occurs when insulin-resistant individuals was instituted to bring about weight loss of 8 –9 kg. Further- more, we directly measured the improvement in insulin sensi-tivity after moderate weight loss, whereas surrogate measures, based on changes in plasma insulin concentration, were used toassess insulin action in those studies in which massive weight This work was, in part, supported by the office of Research and Develop- ment, Medical Research Service, Department of Veterans Affairs, and by loss was associated with increases in plasma adiponectin con- research grants from the Department of Veterans Affairs, the National Insti- centration. Although these estimates of insulin action are tutes of Health Grants RR-00070 and HL-067690, and the American Diabetes correlated with specific measures of insulin-meditated glucose AJP-Regul Integr Comp Physiol • VOL 290 • JANUARY 2006 • www.ajpregu.org REFERENCES
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