Abstract
Background
Leptin is an important adipose tissue–derived hormone that has been shown to be involved in pathophysiological mechanisms related to cardiovascular disease and diabetes. However, few studies have examined the association between plasma leptin and diabetes mellitus in humans. Also, it is not clear if this association is present among women as well as in men. Therefore, we examined the association between plasma leptin levels and diabetes mellitus in a representative multiethnic sample of U.S. adults.
Methods
We examined the 1988–1994 third National Health and Nutrition Examination Survey (NHANES III) participants >20 years of age (n = 5,599, 54.7% women). Plasma leptin levels were categorized into quartiles (women, <7.68 fg/L, 7.68–13.18 fg/L, 13.19–21.70 fg/L, >21.70 fg/L; men, <2.64 fg/L, 2.64–4.36 fg/L, 4.37–7.12 fg/L, >7.12 fg/L). Diabetes mellitus was defined as fasting glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL or use of oral hypoglycemic medication or insulin (n = 395).
Results
Higher plasma leptin levels were initially found to be associated with diabetes mellitus after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, hypertension, serum cholesterol and C-reactive protein [odds ratio (OR), 3.79; confidence interval (CI), 2.05–7.00; P trend <0.0001). However, when we additionally adjusted for body mass index (BMI), the association between plasma leptin levels and diabetes mellitus disappeared in both men (OR, 1.07; CI, 0.59–1.94; P trend = 0.5004) and women (OR, 0.86; CI, 0.49–1.51; P trend = 0.2819).
Conclusion
Higher plasma leptin levels are not independently associated with diabetes mellitus after adjustment for BMI. The null association was evident both in women as well as in men.
Introduction
Leptin is an important adipose tissue–derived hormone that has been shown to be involved in pathways influencing the risk of cardiovascular disease and diabetes.1 Animal studies suggest that there is an inverse relationship between leptin levels and insulin secretion.2,3 Also, it has been suggested that the association between plasma leptin and diabetes may be a manifestation of an underlying leptin resistance mediated by obesity.4
However, relatively few studies have examined the putative association between leptin and diabetes, and their results have not been consistent. Some studies have reported that there is no association between plasma leptin levels and diabetes,5–7 whereas other studies have reported a significant positive association between plasma leptin levels and diabetes.8–11 However, two studies reported an inverse relation.12,13 Also, few studies reported that the association between plasma leptin and diabetes mellitus was observed only in men and not in women.9–11
In this context, we examined the association between plasma leptin levels and diabetes in a large nationally representative sample of U.S. adults after adjusting for major confounders. We had adequate sample size to examine this association in the whole cohort as well as separately by gender and BMI categories.
Methods
The current study is based on data from the Third National Health and Nutrition Examination Survey (NHANES III). Detailed descriptions of NHANES III study design and methods are available elsewhere.14–17 In brief, the NHANES survey included a stratified multistage probability sample representative of the civilian noninstitutionalized U.S. population. Selection was based on counties, blocks, households, and individuals within households, and included the oversampling of non-Hispanic blacks and Mexican Americans to provide stable estimates of these groups. Subjects were required to sign a consent form before their participation, and approval was obtained from the Human Subjects Committee in the U.S. Department of Health and Human Service.
The current study sample consisted of participants aged greater than 20 years who were randomly assigned to be examined in the morning after an overnight fast. Plasma leptin levels were measured in 6,415 participants who were examined in the morning after an overnight fast who had surplus sera available. We further excluded subjects with self-reported cardiovascular disease (n = 373), and also subjects with missing data (n = 443) on covariates included in the multivariable model, including systolic or diastolic blood pressure, body mass index (BMI), or cholesterol levels. This resulted in 5,599 participants (54.7% women), 395 of whom had diabetes mellitus.
Main outcome of interest
Serum glucose was measured using the modified hexokinase method at the University of Missouri Diabetes Diagnostic Laboratory. Diabetes was defined based on the guidelines of the American Diabetes Association as a serum glucose ≥126 mg/dL after fasting for a minimum of 8 h, a serum glucose ≥200 mg/dL for those who fasted <8 h before their NHANES visit, or a self-reported current use of oral hypoglycemic medication or insulin.18
Exposure measurements
Age, gender, race/ethnicity, smoking status, alcohol intake (g/day), level of education, history of diabetes and oral hypoglycemic intake or insulin administration, and antihypertensive medication use were assessed using a questionnaire. Individuals who had not smoked ≥100 cigarettes in their lifetimes were considered never smokers; those who had smoked ≥100 cigarettes in their lifetimes were considered former smokers if they answered negatively to the question “Do you smoke now?” and current smokers if they answered affirmatively. BMI was calculated as weight in kilograms divided by height in meters squared. Serum total cholesterol was measured enzymatically.19
Rigorous procedures with quality control checks were used in blood collection and details about these procedures are provided in the NHANES Laboratory/Medical Technologists Procedures Manual.15,17 Measurement of plasma leptin was performed by Linco Research, Inc. (St. Louis, MO). The assay was a radioimmunoassay (RIA) with a polyclonal antibody raised in rabbits against highly purified recombinant human leptin. The minimum detectable concentration of the assay was 0.5 fg/L leptin and the limit of linearity was 100 fg/L. Recovery of leptin added to serum is 99–104% over the linear range of the assay. The RIA agrees reasonably well with rough quantification by western blotting. Within- and between-assay CVs ranged from 3.4% to 8.3% and from 3.6% to 6.2%, respectively.17
Statistical analysis
Plasma leptin was analyzed as a categorical variable. Because physiologically normal leptin levels vary in men and women, we categorized plasma leptin level as quartiles by gender (women, <7.68 fg/L, 7.68–13.18 fg/L, 13.19–21.70 fg/L, >21.70 fg/L; men, <2.64 fg/L, 2.64–4.36 fg/L, 4.37–7.12 fg/L, >7.12 fg/L).
The odds ratio [(OR) (95% confidence interval (CI)] of diabetes mellitus for each higher leptin quartile was calculated by taking the lowest quartile as the referent, using multivariable logistic regression models. We used three models: The age and sex-adjusted model, the multivariable model, additionally adjusting for race/ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), education categories (below high school, high school, above high school), smoking (never smoker, former smoker, current smoker), alcohol intake (g/day), hypertension (absent, present), total serum cholesterol (mg/dl), and C-reactive protein (CRP; mg/dL), and the multivariable model further adjusting for BMI (kg/m2).20 Trends in the OR of diabetes mellitus across the increasing plasma leptin category were determined by modeling leptin categories as an ordinal variable. Sample weights16 that account for the unequal probabilities of selection, oversampling, and nonresponse were applied for all analyses using SUDAAN (version 8.0; Research Triangle Institute, Research Triangle Park, NC) and SAS (version 9.2; SAS Institute, Cary, NC) software; standard errors (SEs) were estimated using the Taylor series linearization method.
Results
Table 1 presents the baseline characteristics of the study sample by increasing quartiles of plasma leptin level. Individuals in the higher plasma leptin quartiles were: More likely to be older, woman, non-Hispanic black, never or former smoker; more likely to have a higher BMI and a higher total cholesterol level; and less likely to be a non-Hispanic white, current smoker, and current drinker. The average plasma leptin level was found to be over three times higher among women compared to men (17.6 fg/L vs. 5.9 fg/L). The proportion of subjects with diabetes mellitus increased with increasing quartiles of plasma leptin.
Table 1.
Characteristics of the NHANES III (1988–1994) Study Population by Categories of Plasma Leptin Level
| Characteristics | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P value |
|---|---|---|---|---|---|
| Number at risk | 1,186 | 1,345 | 1,533 | 1,535 | |
| Age, years | 40.4 ± 0.5 | 45.1 ± 0.5 | 46.4 ± 0.5 | 47.8 ± 0.5 | <0.0001 |
| Women, % | 589 (49.7) | 726 (54.0) | 880 (57.4) | 866 (56.4) | 0.0002 |
| Race-ethnicity, % | 0.0012 | ||||
| Non-Hispanic whites | 527 (44.4) | 573 (42.6) | 612 (39.9) | 596 (38.8) | |
| Non-Hispanic blacks | 328 (27.7) | 331 (24.6) | 393 (25.6) | 501 (32.6) | |
| Mexican Americans | 277 (23.4) | 380 (28.3) | 468 (30.5) | 383 (25.0) | |
| Others | 54 (4.6) | 61 (4.5) | 60 (3.9) | 55 (3.6) | |
| Education categories, % | 0.2926 | ||||
| Below high school | 417 (35.2) | 485 (36.1) | 582 (38.0) | 563 (36.7) | |
| High school | 368 (31.0) | 431 (32.0) | 492 (32.1) | 519 (33.8) | |
| Above high school | 401 (33.8) | 429 (31.9) | 459 (39.9) | 453 (29.5) | |
| Smoking, % | 0.0261 | ||||
| Never smoker | 588 (49.6) | 703 (52.3) | 834 (54.4) | 822 (53.6) | |
| Former smoker | 178 (15.0) | 287 (21.3) | 365 (23.8) | 420 (27.4) | |
| Current smoker | 420 (35.4) | 355 (26.4) | 334 (21.8) | 293 (19.1) | |
| Alcohol intake, % | <0.0001 | ||||
| Current drinker | 648 (54.6) | 694 (51.6) | 713 (46.5) | 610 (39.7) | |
| Body mass index, kg/m2 | 22.3 ± 0.1 | 24.7 ± 0.1 | 27.6 ± 0.1 | 32.7 ± 0.1 | <0.0001 |
| Total cholesterol, mg/dL | 189.3 ± 1.2 | 201.8 ± 1.2 | 207.5 ± 1.1 | 212.3 ± 1.1 | <0.0001 |
| C-reactive protein, mg/L | 1.8 ± 1.2 | 2.1 ± 1.2 | 2.8 ± 1.8 | 3.1 ± 1.9 | 0.002 |
| Diabetes mellitus, % | 35 (3.0) | 83 (6.2) | 115 (7.5) | 162 (10.6) | <0.0001 |
Data presented are row percentages or mean values ± standard error (SE).
Plasma leptin quartiles in women: quartile 1 (<7.68 fg/L), quartile 2 (7.68–13.18 fg/L), quartile 3 (13.19–21.70 fg/L), quartile 4 (>21.70 fg/L); in men: quartile 1 (<2.64 fg/L), quartile 2 (2.64–4.36 fg/L), quartile 3 (4.37–7.12 fg/L), quartile 4 (>7.12 fg/L).
NHANES III, Third National Health and Nutrition Examination Survey.
Table 2 presents the association between increasing plasma leptin levels and diabetes mellitus in the whole cohort and separately by gender. Initially, we observed a positive association between plasma leptin levels and diabetes mellitus in both the age- and sex-adjusted (P trend <0.0001) and the multivariable-adjusted model (P trend <0.0001). However, when additionally adjusted for BMI, the association between increasing plasma leptin levels and diabetes mellitus disappeared entirely (P = 0.7863). This finding of a null association after additional BMI adjustment was consistently observed in separate analyses among men (P trend = 0.5004) as well as women (P = 0.2819).
Table 2.
Association Between Plasma Leptin Level and Diabetes Mellitus in NHANES III (1988–1994)
| Plasma leptin levela | Number at risk (diabetes cases) | Age, sex-adjusted odds ratio (95% confidence interval) | Multivariable-adjusted odds ratio 1 (95% confidence interval)b | Multivariable-adjusted odds ratio 2 (95% confidence interval)c |
|---|---|---|---|---|
| Whole cohort | ||||
| Quartile 1 | 1,186 (35) | 1 (referent) | 1 (referent) | 1 (referent) |
| Quartile 2 | 1,345 (83) | 1.37 (0.74–2.53) | 1.36 (0.71–2.59) | 0.96 (0.49–1.89) |
| Quartile 3 | 1,533 (115) | 2.00 (1.12–3.54) | 1.90 (1.04–3.47) | 0.81 (0.38–1.70) |
| Quartile 4 | 1,535 (162) | 4.12 (2.32–7.30) | 3.79 (2.05–7.00) | 0.98 (0.56–1.72) |
| p-trend | <0.0001 | <0.0001 | 0.7863 | |
| Women | ||||
| Quartile 1 | 589 (16) | 1 (referent) | 1 (referent) | 1 (referent) |
| Quartile 2 | 726 (46) | 1.28 (0.51–3.23) | 1.29 (0.50–3.35) | 0.90 (0.39–2.08) |
| Quartile 3 | 880 (62) | 1.89 (0.86–4.14) | 1.69 (0.78–3.65) | 0.50 (0.21–1.19) |
| Quartile 4 | 866 (74) | 3.32 (1.47–7.48) | 2.76 (1.32–5.77) | 0.86 (0.49–1.51) |
| p-trend | <0.0001 | 0.0009 | 0.2819 | |
| Men | ||||
| Quartile 1 | 597 (19) | 1 (referent) | 1 (referent) | 1 (referent) |
| Quartile 2 | 619 (37) | 1.47 (0.65–3.32) | 1.37 (0.62–3.03) | 1.06 (0.45–2.55) |
| Quartile 3 | 653 (53) | 2.11 (1.05–4.27) | 1.88 (0.91–3.90) | 1.03 (0.41–2.59) |
| Quartile 4 | 669 (88) | 4.89 (2.58–9.28) | 4.36 (2.15–8.85) | 1.07 (0.59–1.94) |
| p-trend | <0.0001 | <0.0001 | 0.5004 | |
Plasma leptin quartiles in women: quartile 1 (<7.68 fg/L), quartile 2 (7.68–13.18 fg/L), quartile 3 (13.19–21.70 fg/L), quartile 4 (>21.70 fg/L); in men: quartile 1 (<2.64 fg/L), quartile 2 (2.64–4.36 fg/L), quartile 3 (4.37–7.12 fg/L), quartile 4 (>7.12 fg/L).
Adjusted for age (years), sex (men, women), race-ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), education categories (<high school, high school, >high school), smoking (never, former, current), alcohol intake (never, former, current), hypertension (absent, present), serum total cholesterol (mg/dL), and high sensitivity C-reactive protein (mg/L).
Additionally adjusted for body mass index.
NHANES III, Third National Health and Nutrition Examination Survey.
Table 3 presents the association between increasing plasma leptin levels and diabetes mellitus by BMI categories. Consistent with the findings in Table 2, there was no association between the increasing plasma leptin levels and diabetes mellitus in normal-weight subjects (P trend = 0.8071), overweight subjects (P trend = 0.2143), or obese subjects (P trend = 0.7776).
Table 3.
Association Between Plasma Leptin Level and Diabetes Mellitus, by Body Mass Index in NHANES III (1988–1994)
| Plasma leptin levela | Number at risk | Diabetes cases | Multivariable-adjusted odds ratio (95% confidence interval)b |
|---|---|---|---|
| Normal weight (BMI <25 kg/m2) | |||
| Quartile 1 | 994 | 21 | 1 (referent) |
| Quartile 2 | 776 | 25 | 0.97 (0.40–2.35) |
| Quartile 3 | 348 | 12 | 1.09 (0.48–2.49) |
| Quartile 4 | 69 | 3 | 1.06 (0.34–3.30) |
| P trend | 0.8071 | ||
| Overweight (BMI 25–29 kg/m2) | |||
| Quartile 1 | 168 | 11 | 1 (referent) |
| Quartile 2 | 499 | 45 | 0.95 (0.31–2.91) |
| Quartile 3 | 848 | 58 | 0.61 (0.19–1.98) |
| Quartile 4 | 463 | 40 | 0.59 (0.18–1.96) |
| P trend | 0.2143 | ||
| Overweight/obese (BMI ≥30 kg/m2) | |||
| Quartile 1 | 24 | 3 | 1 (referent) |
| Quartile 2 | 70 | 13 | 0.74 (0.10–5.45) |
| Quartile 3 | 337 | 45 | 0.790 (0.18–3.52) |
| Quartile 4 | 1,003 | 119 | 0.96 (0.39–0.36) |
| P trend | 0.7776 | ||
Plasma leptin quartiles in women: quartile 1 (<7.68 fg/L), quartile 2 (7.68–13.18 fg/L), quartile 3 (13.19–21.70 fg/L), quartile 4 (>21.70 fg/L). In men: quartile 1 (<2.64 fg/L), quartile 2 (2.64–4.36 fg/L), quartile 3 (4.37–7.12 fg/L), quartile 4 (>7.12 fg/L).
Adjusted for age (years), sex (men, women), race-ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), education categories (<high school, high school, >high school), smoking (never, former, current), alcohol intake (never, former, current), hypertension (absent, present), serum total cholesterol (mg/dL), and high sensitivity C-reactive protein (mg/L).
NHANES III, Third National Health and Nutrition Examination Survey; BMI, body mass index.
In a supplementary analysis, we examined the association between plasma leptin levels and high-sensitivity CRP levels after adjusting for age (years), sex (men, women), race-ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), education categories (<high school, high school, >high school), smoking (never, former, current), alcohol intake (never, former, current), BMI (kg/m2), hypertension (absent, present), and serum total cholesterol (mg/dL). We found that plasma leptin levels were significantly positively related to CRP levels (beta [standard error] = 2.8 [1.9]; P = 0.001).
Discussion
In a large, contemporary, multiethnic sample of U.S. adults, we found that higher plasma leptin levels were not independently associated with diabetes mellitus, after adjustment for BMI. In separate analysis by gender, there was no independent association between plasma leptin levels and diabetes mellitus either in women or men. Also in subgroup analysis by BMI categories, we found that the observed null association was consistently present in normal weight, overweight, and obese BMI categories.
Previous studies examining the association between serum leptin levels and diabetes mellitus were restricted to specific racial/ethnic groups and were not consistent in their findings. Some studies reported that there is no association between plasma leptin levels and diabetes,5–7 whereas some other studies reported significant positive associations between plasma leptin levels and diabetes only in men8–11; however, two studies reported an inverse relation.12,13 It is possible that these differences in previous study results may be due to differences in the inclusion or exclusion of one or two important confounding variables in the multivariable model.
To clarify the independent relation between plasma leptin levels and diabetes mellitus, we decided to adjust for confounders in an incremental fashion. We found that in the current study, in initial statistical models, a positive association was observed between leptin and diabetes mellitus even after adjusting for age, sex, race-ethnicity, education, smoking, alcohol intake, hypertension, serum total cholesterol, and high-sensitivity CRP. However, after adjusting for BMI, the association entirely disappeared. This suggests that the leptin–diabetes mellitus association may be explained by confounding due to BMI. The large sample size that is available for the current analyses, our ability to adjust for all potential confounders, and the consistency of these results after subgroup analysis by gender and BMI categories suggests that our findings are less likely due to chance.
Experimental animal and human studies suggest that leptin levels are closely related to body fatness.21–23 It is reported that plasma leptin may be a good biomarker of obesity.24 Therefore, an association between plasma leptin and diabetes mellitus may be mediated by body fat.24,25 Higher leptin levels, conjunct with obesity and weight gain are probably involved in the subsequent development of diabetes.1,24,26 Also, consistent with previous studies,27,28 we have found that plasma leptin levels are positively related to CRP levels independent of BMI.
The main strengths of our study include its population-based nature, inclusion of a representative multiethnic sample, and the availability of data on confounders for multivariable adjustment. We had a large sample size that enabled us to perform separate analysis by gender. Furthermore, all data were collected following rigorous methodology, including a study protocol with standardized quality control checks. The main limitation of our study is the cross-sectional nature of NHANES, which precludes conclusions regarding the temporal nature of the association between plasma leptin and diabetes mellitus.
In summary, in a multiethnic sample of U.S. adults, we found that higher plasma leptin levels are not associated with diabetes mellitus, independent of BMI. Plasma leptin was not associated with diabetes either in men or in women.
Acknowledgments
A.S. was funded by a Research Funding Development Grant from the West Virginia University School of Medicine and a National Clinical Research Program grant from the American Heart Association. “The guarantor, A.S., accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.” All the authors contributed to the intellectual development of this paper. P.B. wrote the first draft of the paper. A.S. had the original idea for the study, supervised statistical analysis, and was involved in drafting and revising the paper.
Author Disclosure Statement
There are no conflicts of interest related to this manuscript.
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