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National Institute of Diabetes and Digestive and Kidney Diseases (H.C.L., J.K., R.G.N., W.C.K., R.S.L., R.L.H.), Phoenix, Arizona 85014; Department of Internal Medicine and Molecular Science (T.F., Y.M., S.T.), Graduate School of Medicine, Osaka University, Japan 565-0871; and University of Glasgow (R.S.L.), Glasgow, United Kingdom G11 6NT
Address all correspondence and requests for reprints to: Helen C. Looker, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, Arizona 85014. E-mail: hlooker{at}mail.nih.gov.
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Abstract |
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300 mg/g), the highest adiponectin concentration was in the macroalbuminuria group (geometric mean = 9.6 µg/ml) and the lowest was in the normoalbuminuric group (geometric mean = 5.6 µg/ml). After adjustment for age, sex, body mass index, and diabetes duration, the serum adiponectin concentration in the macroalbuminuria group was significantly higher than in both other groups (P < 0.0001). Serum adiponectin is lowest in the presence of impaired glucose regulation and early diabetes. In the presence of diabetes, serum adiponectin is positively associated with abnormal renal function and diabetes duration. |
Introduction |
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Adiponectin has also been associated with complications of diabetes, being increased in the presence of end-stage renal disease (10) and lower in the presence of vascular disease (11). Whether lesser degrees of renal impairment influence adiponectin concentrations is unknown. In the present study, we have investigated the relationship of adiponectin to renal function and albuminuria in a large group of Pima Indians recruited for genetic linkage studies. Furthermore, we have examined the relationship of adiponectin to duration of diabetes, a major risk factor for diabetic nephropathy (12).
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Subjects and Methods |
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The participants come from a longitudinal study in the Pima Indians of the Gila River Indian Community in central Arizona (13). Community residents are invited to undergo examination every 2 yr regardless of health. These examinations include anthropometric measures such as weight, height, urinalysis, and blood pressure. Medicine use is recorded at each examination. Diabetes was diagnosed on the basis of a 75-g oral glucose tolerance test if the 1997 American Diabetes Association criteria [fasting plasma glucose 126 mg/dl (7.0 mmol/liter) or 2-h glucose 200 mg/dl (11.1 mmol/liter)] (14) were met at any research examination or if a documented clinical diagnosis was present. The date of diagnosis was determined from the research examinations or review of clinical records if diabetes was diagnosed in the course of routine clinical care. Subjects who were not diabetic at the time of the adiponectin measurement were categorized by glycemia as normal glucose regulation [NGR; fasting glucose < 110 mg/dl (6.1 mmol/liter) and 2-h glucose < 140 mg/dl (7.8 mmol/liter)] or impaired glucose regulation [IGR; fasting glucose of 110–125 mg/dl (6.1–6.9 mmol/liter) and/or 2-h glucose of 140–199 mg/dl (7.8–11.0 mmol/liter)].
The subjects in the present analysis were part of a genomic linkage study of diabetes, obesity, and related traits (15, 16). Subjects were included in the analyses if they had frozen serum available for adiponectin measurement and information on albumin to creatinine ratio (ACR), serum creatinine and glucose tolerance, or diabetes duration. Twelve subjects taking thiazolidinediones were excluded as thiazolidinediones raise serum adiponectin (17, 18). When a subject had multiple examinations with available sera, the serum and data from the most recent examination attended were selected for analysis. In a subset of 265 subjects with diabetes, adiponectin was also measured in the sera from their most recent examination before developing diabetes. A total of 1334 samples from 1069 individuals were included.
The longitudinal study was approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and reviewed by the Gila River Indian Community.
Measurements
Serum adiponectin concentrations were measured in frozen sera (samples were drawn between January 1977 and September 2001) with an ELISA using an adiponectin-specific antibody as described previously (19). Storage time was calculated as the time from when the serum was drawn to the time it was thawed for the adiponectin measurements. Samples were primarily either fasting (n = 582) or drawn during an oral glucose test at 2 h (n = 746), 1 h (n = 1), and at unspecified times (n = 5). The intra- and interassay coefficients of variation were 3.3 and 7.4%, respectively. A pilot study (n = 12) found no major difference between 2 h and fasting samples (2-h concentration was 96% of the fasting concentration; absolute difference, 0.26 ± 0.3 µg/ml; paired t test P = 0.44), so they are considered together in the analyses (16). The use of stored samples for measuring serum adiponectin raises issues concerning stability of adiponectin in frozen sera. For the 1334 samples included in these analyses, there was a positive correlation between storage time and serum adiponectin (Spearman r partialed for age and sex = 0.18; P < 0.01). However, there was a positive correlation among subjects with diabetes (Spearman r partialed for age and sex = 0.20; P < 0.01; n = 724), but not for subjects without diabetes (Spearman r partialed for age and sex = 0.04; P = 0.30; n = 610). As storage time was positively correlated in the subjects with diabetes, it was included in the multivariate analyses presented.
Albuminuria was assessed by nephelometry [Hyland nephelometer, April 1982-December 1983 (Hyland, Deerfield, IL), Baker Nephelometer, January 1984–May 1988 (Behring Nephelometer, Allentown, PA), June 1988 to present (Dade Behring, Deerfield, IL)]. With each batch of antibodies, there was a threshold beneath which albuminuria could not be detected. Subjects were classified according to ACR into those with normoalbuminuria (ACR < 30 mg/g), microalbuminuria (ACR = 30–299 mg/g), and macroalbuminuria (ACR 300 mg/g). Thirty-three individuals with values for urinary albumin less than 2 mg/liter (the highest threshold among the various assays) were classified as having normoalbuminuria and assigned the lowest ranked value for correlation analyses. Serum insulin was measured by a modification of the RIA method of Yalow and Berson (for samples drawn 1977–1986) and by Autopak Insulin RIA (Concept 4; ICN Biomedicals, Horsham, PA; for samples drawn since 1987). To allow use of all measurements, a corrected insulin value was calculated by linear regression as described previously (20).
Blood pressure was measured to the nearest 2 mm Hg with a mercury sphygmomanometer with the subject supine. Diastolic blood pressure was measured at the fourth Korotkoff sound. Mean arterial blood pressure (MAP) was calculated as one third systolic blood pressure plus two thirds diastolic blood pressure.
Statistical analysis
Spearman correlation coefficients were used to describe the association between serum adiponectin and other continuous variables of interest; the partial correlation coefficient was used to control for the effects of age and sex. Serum adiponectin concentrations for different categories of diabetes treatment, diabetes duration, and renal function were compared by ANOVA; linear regression models were used to control for potentially confounding variables. The validity of regression models was confirmed by inspection of residual plots. Nonnormally distributed variables such as serum adiponectin and fasting insulin were log-transformed to better approximate normal distributions. For presentation purposes, the geometric mean serum adiponectin concentration, adjusted for potentially confounding variables, was calculated for each category from the linear regression model; these predicted values were calculated for the mean value of all covariates. When ANOVA showed a significant (P < 0.05) difference among all categories, P values were calculated for pairwise comparisons to indicate which categories were significantly different from one another. For purposes of presentation, the overall P value from ANOVA is reported (PANOVA), along with the number of df.
To examine changes in adiponectin concentrations occurring after the onset of diabetes, serum adiponectin concentrations from examinations before and after the onset of diabetes were compared. The difference in adiponectin concentration between the two examinations was calculated, and ANOVA was used to compare the differences in adiponectin change among categories of diabetes duration at the diabetic examination.
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Results |
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. Subjects with diabetes were older and had higher blood pressure and higher ACR. There was no difference in median serum creatinine and body mass index (BMI) between the two groups. On average, samples from diabetic subjects were stored for a longer time before adiponectin assay than those from nondiabetic subjects. Serum adiponectin concentration was higher in subjects with diabetes, geometric mean 6.7 µg/ml, than in those without, geometric mean 5.6 µg/ml (P < 0.0001). However, after adjustment for age and sex, there was no significant difference between the nondiabetic and diabetic groups (adjusted geometric mean = 6.2 µg/ml and 6.3 µg/ml, respectively; P = 0.6). Further adjustment for BMI and storage time did not alter these findings.
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Spearman correlation coefficients of serum adiponectin with BMI, waist circumference, and fasting glucose were similar in the diabetic and nondiabetic subjects. HbA1c and fasting plasma glucose were negatively correlated with serum adiponectin in nondiabetic subjects, but the correlation with hemoglobin A1c (HbA1c) was weaker in diabetic subjects. Although age was positively correlated in both groups, the association was stronger in the diabetic than in the nondiabetic group. Both measures of renal function and duration of diabetes were strongly positively associated with serum adiponectin in the diabetic subjects. MAP was positively correlated with serum adiponectin in those with diabetes but not in those without diabetes, and there was little association in diabetic subjects (r = 0.05; P = 0.3) after excluding subjects with abnormal renal function [ACR 300 mg/g or serum creatinine 1.2 mg/dl (110 µmol/liter)]. Adjustment for age and sex made little difference in the correlation coefficients for either diabetic or nondiabetic groups.
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The nondiabetic subjects were divided into those with NGR or IGR (28% of the nondiabetic subjects) and the diabetic subjects into categories of diabetes duration. Of the 724 subjects with diabetes, 79 (11%) had newly diagnosed diabetes, 121 (17%) had diabetes of zero to less than 5-yr duration, 122 (17%) had diabetes of 5- to less than 10-yr duration, and the remaining 402 (55%) had diabetes for 10 yr or longer. Serum adiponectin concentrations were lowest in those with IGR or diabetes of less than 10-yr duration and highest in those with NGR or diabetes with at least 10-yr duration (Fig. 1).
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In analyses restricted to the 895 subjects not receiving exogenous insulin, the relationship between serum adiponectin, baseline glycemia (as assessed by HbA1c or fasting glucose), and diabetes duration persisted (PANOVA < 0.01, 5 df in both models) with higher serum adiponectin in subjects with NGR or diabetes duration of at least 10-yr duration (data not shown).
Fasting insulin measures were available for 395 subjects who were not receiving exogenous insulin; in this subgroup, adiponectin was significantly lower in those with newly diagnosed diabetes (n = 62, geometric mean = 4.8) compared with those with NGR (n = 126, geometric mean = 6.3 µg/ml) or diabetes duration of at least 10 yr (n = 69, geometric mean = 7.6 µg/ml) after adjustment for age, sex, BMI, storage time, and fasting insulin (P < 0.05 for each; PANOVA < 0.01, 5 df).
Adiponectin and renal function
Among those with diabetes, geometric mean serum adiponectin concentrations for the normoalbuminuria, microalbuminuria, and macroalbuminuria groups were 5.6, 6.2, and 9.6 µg/ml, respectively (PANOVA = <0.0001, 2 df; P < 0.0001 for macroalbuminuria vs. each of the other two groups; P = 0.08 normoalbuminuria vs. microalbuminuria). After adjustment for age, sex, BMI, storage time, and duration of diabetes, albuminuria remained a statistically significant factor (PANOVA = <0.0001, 2 df). However, there was no statistically significant difference between the normoalbuminuria and microalbuminuria groups (adjusted geometric mean = 6.2 µg/ml and 6.1 µg/ml, respectively), but the macroalbuminuria group had a higher geometric mean serum adiponectin concentration (8.2 µg/ml) than each of the other groups (P < 0.0001). To examine the role of renal insufficiency, the macroalbuminuria group was further subdivided into those with some evidence of renal insufficiency (serum creatinine 110 µmol/liter) and those with little evidence of renal insufficiency (serum creatinine < 110 mmol/liter). Those with elevated serum creatinine and macroalbuminuria had the highest adiponectin concentrations, but those with macroalbuminuria and serum creatinine concentrations less than 1.2 mg/dl (110 µmol/liter) still had a higher adiponectin concentration than either the normoalbuminuric or microalbuminuric groups (Fig. 2). Repeating the analysis among those who were not receiving exogenous insulin (n = 550) did not alter the findings, nor did further stratification by use of hypertension medication (data not shown).
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The geometric mean of serum adiponectin according to categories of diabetes duration and albuminuria or treatment for diabetes is shown in Fig. 3. Those with macroalbuminuria had higher adiponectin concentrations in most duration categories, and this relationship remained statistically significant after control for age, sex, BMI, and duration (Fig. 3A). In contrast, there was no consistent relationship between treatment group and adiponectin concentration across duration categories (Fig. 3B). Duration of diabetes, log serum creatinine, and macroalbuminuria were all significantly positively associated with serum adiponectin concentration (P < 0.01 for all) even after additional adjustment for age, sex, MAP, storage time, and insulin treatment.
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Longitudinal data
Among the 265 diabetic subjects in whom serum adiponectin was measured from an examination before diabetes onset, 104 individuals had NGR and the remaining 161 had IGR at the prediabetic examination. Those with NGR had a higher serum adiponectin concentration (geometric mean adjusted for age sex, BMI, and storage time = 5.0 µg/ml) than those with IGR (geometric mean adjusted for age sex, BMI, and storage time = 4.4 µg/ml; P = 0.03). Overall, BMI was not significantly different between the nondiabetic and subsequent diabetic examinations (mean change ± SEM = 1.4 ± 0.3 kg/m2; P = 0.9), whereas adiponectin increased (mean change, 1.1 ± 0.2 µg/ml; P < 0.0001) over a median time interval of 9.4 yr. The subjects who had their second measurement in the 10 yr or greater diabetes duration period had a greater rise in serum adiponectin concentration (mean change = 2.4 ± 0.4 µg/ml) than those who had their second measurement at diabetes durations 0–5 yr (mean change in adiponectin = 0.7 ± 0.3 µg/ml) or 5–10 yr (mean change in adiponectin = 0.6 ± 0.3 µg/ml) (Fig. 4). In general, BMI increased for subjects seen within 5 yr of the diagnosis of diabetes (mean change in BMI = 0.8 ± 0.4 kg/m2). However, for longer durations BMI tended to decrease (mean change in BMI = –0.6 ± 0.5 kg/m2 and –0.9 ± 0.7 kg/m2 at 5–10 yr and 10 yr durations, respectively; P = 0.7). There was a mean rise in serum adiponectin in subjects seen within 5 yr of diagnosis whether they had NGR or IGR at their initial examination (mean change in adiponectin = 0.5 ± 0.3 µg/ml and 0.8 ± 0.2 µg/ml for the NGR and IGR subjects, respectively). The subjects with the greatest rise in serum adiponectin were the ones with IGR at baseline and a diabetic examination at 10 yr or longer duration (n = 43; mean change in serum adiponectin = 3.2 ± 0.6 µg/ml). The change in serum adiponectin was positively correlated with change in serum creatinine (r = 0.14; P = 0.02) and when change in creatinine was included in a model with age, sex, storage time, change in BMI, baseline glycemia, and time between examinations, those with at least 10 yr duration still had the greatest increase in serum adiponectin (mean change = 1.8 ± 0.5 µg/ml compared with 0.9 ± 0.3 µg/ml for 0–<5 yr and 0.9 ± 0.3 µg/ml for 5–10 yr). The differences among the groups, however, were modestly attenuated and not statistically significant (PANOVA = 0.2, 2 df); this suggests that change in renal function may partially account for the differences observed in adiponectin among duration categories.
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Discussion |
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Duration of diabetes has not been explicitly reported in previous studies regarding diabetes and adiponectin. Previous studies in Pima Indians with diabetes included only those with newly diagnosed diabetes (P. A. Tataranni, personal communication), so their findings are in keeping with those reported here (1). Hotta et al. (6) do not report duration of diabetes in their study of Japanese subjects. However, in comparison with the diabetic subjects of the present report, those in the report by Hotta et al. (6) have lower fasting glucose concentrations and fewer microvascular complications, suggesting that their diabetes may be of short duration. Our study indicates that diabetes duration has a strong association with serum adiponectin concentrations, and thus duration needs to be included in any analysis of adiponectin in diabetic individuals. In the present study, the majority of subjects with diabetes had diabetes duration of at least 10 yr; this explains why there was no significant difference in adiponectin concentrations between the diabetic and nondiabetic subjects.
The finding that adiponectin concentration increases after the onset of diabetes may be somewhat surprising, because many metabolic characteristics such as hyperglycemia and hyperlipidemia tend to worsen with longer duration of diabetes. It also contrasts with the cross-sectional findings of lower adiponectin in subjects with diabetes of short duration. On the other hand, individuals in this population tend to lose weight after the onset of diabetes (21). However, as the findings persisted with adjustment for BMI, this weight loss does not entirely explain the changes in adiponectin concentration. The tendency for adiponectin to increase could be due to changes in body composition that are not fully measured by changes in body weight, the development of adiponectin resistance, or reduced clearance of adiponectin. It should be noted that the rise in serum adiponectin between prediabetic and postdiabetic examinations is not what would be expected if this were purely related to storage time effects, because the older samples would be expected to be higher. We therefore do not believe that the longitudinal findings are confounded by storage time of samples. As individuals progress from IGR to diabetes, there is a decline in insulin sensitivity and a decline in insulin secretory function (22), although it is not clear which is the major contributor to deterioration in glucose tolerance. If hypoadiponectinemia causes the decline in insulin sensitivity, one might expect a decline in adiponectin concentrations to accompany this transition, but in the present study, increased adiponectin was observed (even in those whose diabetes was of 0–5 yr duration). This is consistent with the hypothesis that insulin secretory dysfunction is a major contributor to the transition from IGR to diabetes (23) or to the progression of hyperglycemia once diabetes has developed. This longitudinal analysis represents the largest such study of adiponectin before and after development of diabetes as yet published.
At present, the mechanism by which adiponectin is metabolized and excreted is unknown, but the kidney could be involved. There have been few studies of serum adiponectin and diabetic renal disease. In dialysis patients, most of whom were nondiabetic, plasma adiponectin concentrations were approximately double those found in subjects without renal disease (10). Serum adiponectin and glomerular filtration rate (GFR) were inversely associated in subjects with chronic hypertension (24). A study of patients before and after renal transplantation found a fall in adiponectin after successful renal transplantation, although concentrations remained higher 1 month after transplantation than in healthy subjects (25). All of this suggests that the kidney is involved in the degradation and/or elimination of adiponectin, although it is unlikely to be the sole mechanism. In patients with nephrotic syndrome, adiponectin and proteinuria were positively correlated even after accounting for serum creatinine (26). This is consistent with our finding of a strong relationship between serum adiponectin and albuminuria, even when serum creatinine concentrations were normal. In the present study, even in the absence of renal insufficiency (creatinine < 110 mmol/liter), there was a significantly higher concentration of serum adiponectin in individuals with macroalbuminuria, although concentrations were highest in subjects with both macroalbuminuria and renal insufficiency (creatinine 110 mmol/liter). However, Hotta et al. (6) found no difference in plasma adiponectin between Japanese diabetic subjects with or without a urinary albumin concentration of more than 20 mg/g creatinine (similar to the cutoff used here for microalbuminuria). In the present study, there was little difference in serum adiponectin between subjects with normoalbuminuria and microalbuminuria, and because most of the subjects in the report by Hotta et al. had microalbuminuria, their findings are consistent with those in the present study. There was no association between renal function measures and serum adiponectin in the nondiabetic subjects. This could imply that the relationship with renal function is only important in the presence of diabetes but more likely reflects the limited number of nondiabetic subjects with abnormal renal function.
We did not measure GFR, but our findings are in keeping with the observation of a negative association between GFR and serum adiponectin concentrations, because GFR is highest during the early stages of diabetes, and hyperfiltration is also present in IGR (27). As type 2 diabetes progresses, GFR falls; this is most marked as macroalbuminuria develops (12).
Insulin concentrations are inversely associated with adiponectin (1). Changes in insulin concentrations with increasing duration of diabetes could be one mechanism by which serum adiponectin is influenced by diabetes duration. In a smaller group of Pima Indians, differences in serum adiponectin among subjects with normal glucose tolerance, impaired glucose tolerance, and diabetes were not significant after adjustment for fasting plasma insulin (1). In the present larger study, among those not receiving exogenous insulin, the difference between the newly diagnosed diabetic subjects and those with NGR or at least 10 yr of diabetes persisted with control for fasting plasma insulin, implying that the differences reported may not be entirely explained by differences in insulin concentration.
The majority of those with diabetes in the present study were taking medicine for their diabetes, and those medicines may have influenced serum adiponectin concentrations. Individuals taking thiazolidinediones, which are known to increase serum adiponectin (17, 18), were excluded. Relatively few of the present participants were taking metformin, but other studies suggest that metformin has no effect on adiponectin concentrations (18). The present observational study showed little difference in adiponectin concentrations between those taking sulfonylureas and those taking no antidiabetic medicines. Participants taking insulin had higher serum adiponectin concentrations than those taking no antidiabetic medicines, but this association was largely explained by longer duration of diabetes. The role of exogenous insulin on adiponectin concentrations has been studied in vitro where conflicting results have been reported, with insulin infusions both stimulating transcription of the adiponectin gene and secretion of adiponectin in some studies while suppressing of adiponectin gene transcription in others. In vivo data concerning exogenous insulin have yet to be reported. Whatever the role of insulin treatment in influencing adiponectin concentrations, it does not appear to influence the results, as similar findings were obtained after exclusion of those subjects receiving exogenous insulin.
Adiponectin and age are positively associated in both diabetic (9) and nondiabetic persons (28). There was no association between adiponectin and MAP in the nondiabetic subjects or in diabetic subjects with normal renal function. The positive correlation between adiponectin and MAP in diabetic subjects was unexpected and seemed related to the association of renal impairment with hypertension. In a small study of subjects with essential hypertension, a negative correlation was reported between MAP and adiponectin (29). Animal studies have also found that raising adiponectin concentrations by increasing dietary linoleic acid intake was associated with lowering blood pressure, although it is not clear that this was mediated via the change in adiponectin (30).
Serum adiponectin was measured in stored sera. Longer storage time was associated with higher serum adiponectin concentrations in the diabetic but not in the nondiabetic subjects. Some evaporation of the older samples may have occurred, causing an artifactual rise in serum adiponectin, although it is unclear why that would be the case only for the diabetic subjects. Although the laboratory’s experience suggests that adiponectin is stable in stored specimens (Funahashi, T., unpublished data), there are few data on the stability of adiponectin over long periods of time, i.e. more than 5 yr. We have adjusted all analyses for the length of time samples were stored before analysis to minimize error due to sample storage but cannot be certain that storage time has not influenced some of the findings reported here. To further minimize the influence of storage time, the analyses were repeated, including only those samples collected within 5 yr of adiponectin measurement, and essentially the same results as reported above were found (data not shown). There have also been secular changes in the Pima population with a rise in BMI, which may in part explain the association with serum adiponectin and storage time, although the correlation of adiponectin and storage time persisted after adjustment for BMI. Over the course of the study, there have also been alterations in methodology for measurements of insulin, which may also have an effect on the results reported, although the two insulin assays were standardized from data on subjects where both assays were used.
Adiponectin concentrations are in part heritable. Genome-wide linkage analysis found suggestive linkage of adiponectin adjusted for age and sex on chromosome 9 (16). Analysis, including many of the participants of this present study, found a single nucleotide polymorphism within the adiponectin gene that was associated with serum adiponectin concentrations but only accounted for 2% of its variance (Vozarova, B., R. L. Hansen, T. Funahashi, R. S. Lindsay, Y. Matsuzawa, S. Tanaka, F. Thameem, J. D. Gruber, P. Froguel, J. K. Wolford, unpublished data). As the present population is part of a family study, some of the associations described may reflect confounding by family membership. To account for this, the multivariate models were repeated using generalized estimating equations to allow for the correlations of serum adiponectin among family members. This did not alter any of the findings as to which factors were related to serum adiponectin concentrations (data not shown).
In summary, serum adiponectin concentration was positively associated with duration of diabetes and was higher in those with diabetes of longer duration after adjustment for potential confounders such as age, sex, and BMI. In the presence of diabetes, impaired renal function assessed by either ACR or serum creatinine was associated with higher serum adiponectin concentration, independent of duration of diabetes. It is important to consider these associations in assessing the relationship between serum adiponectin and health outcomes in diabetic individuals. Elucidation of the mechanisms underlying these associations will require longitudinal studies and studies of the metabolism and excretion of adiponectin.
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Acknowledgments |
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Footnotes |
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Received November 6, 2003.
Accepted April 21, 2004.
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