Despite significant cross-sectional correlations of adiponectin, leptin, CRP, IL-6, SAA, and the A/L ratio with metabolic measurements at baseline, only low adiponectin, high leptin, and low A/L ratio were significantly associated with incident type 2 diabetes in our multivariate models adjusted for age, sex, triglycerides, HDL cholesterol, hypertension, and IGT. With an additional adjustment for abdominal adiposity, our results provide evidence only for the association of low baseline adiponectin with incident type 2 diabetes at 10-year follow-up. Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction.
Our findings are consistent with those from the Pima Indian population, another North American Aboriginal population with the high prevalence of diabetes (4
). Using nested case-control data, Krakoff et al. (4
) reported that adiponectin predicted type 2 diabetes in a multivariate model adjusted for covariates including waist circumference (incident rate ratio 0.63 [95% CI 0.41–0.98], P
= 0.04), while CRP and IL-6 did not predict diabetes (P
= 0.88 and 0.28, respectively). Several other prospective studies from non-Aboriginal populations have also supported the association of low adiponectin at baseline with increased diabetes risk (6
). In the Health, Aging, Body Composition Study of white and black adults aged 70–79 years, however, adiponectin was not an independent predictor of incident type 2 diabetes after controlling for metabolic syndrome variables (19
). It is possible that this inconsistent finding may be related to reduced renal function in these older subjects, which has been demonstrated to result in paradoxically elevated adiponectin levels (20
Similar to our results, leptin predicted type 2 diabetes risk among Japanese men in a univariate logistic regression model (relative risk 1.78 [95% CI 1.28–2.48]), but the significance was attenuated with additional adjustment for baseline intra-abdominal fat (P
= 0.05) (10
). Previous prospective studies evaluating associations of inflammatory adipokine markers with diabetes risk have been inconsistent. Several studies supported the association of increased inflammatory marker levels with the development of type 2 diabetes, including IL-6 (8
) and CRP (9
), while others reported no associations of IL-6 (4
) and CRP (4
) with incident type 2 diabetes after adjusting for adiposity measures. Sex differences in the prediction of type 2 diabetes by inflammatory markers have been suggested (21
). However, we did not observe a significant interaction between sex and adipokines assessed in the current study population.
Recently, an interaction between CRP and leptin was proposed as a mechanism contributing to leptin resistance (11
). Evidence was presented for human CRP inhibiting the binding of leptin to its receptors in vitro and leptin stimulating expression of CRP in human primary hepatocytes (11
). Based on this report, we tested the hypothesis that combinational effects of CRP and leptin would improve prediction of diabetes risk compared with individual CRP or leptin. However, we found that the combinational effect of CRP and leptin was not significantly associated with incident diabetes. In addition, other joint effect combinations assessed by adding leptin, CRP, IL-6, and/or SAA into the full model adjusted for metabolic syndrome variables in addition to primary exposure to adiponectin did not improve diabetes prediction. The A/L ratio was identified as a sensitive and reliable marker of insulin resistance in a cross-sectional study (12
). Although we observed similar correlations in our baseline cross-sectional analysis, the A/L ratio was not significantly associated with incident diabetes in our multivariate model adjusted for metabolic syndrome variables including waist circumference.
The independent role of low adiponectin in predicting diabetes risk is likely explained by the role of this adipokine in mediating insulin sensitivity and secretion (2
). While the molecular mechanism of adiponectin is not completely understood, adiponectin has been linked with multiple signaling pathways at multiple sites (22
). Recently, evidence was provided using knockout mouse models that adiponectin receptor 1 (AdipoR1) mediated 3′ AMP-activated protein kinase activity, while adiponectin receptor 2 (AdipoR2) mediated increased peroxisome proliferator–activated receptor-α ligand activity in liver (23
). The disruption of both AdipoR1/R2 abolished adiponectin binding and action, increasing inflammation and oxidative stress, and therefore leading to insulin resistance and marked glucose intolerance (23
). In another mouse model study, decreased expression of AdipoR1 or AdipoR2 was associated with reduced insulin-sensitizing effects of adiponectin in hepatocytes and myocytes (24
). In β-cells of insulin-resistant mice, adiponectin modulated insulin secretion (22
). These proposed roles and mechanisms of multiple adiponectin-mediated pathways offer explanations for the association of low adiponectin with diabetes risk and potential for understanding the etiology of diabetes.
Limitations of our study include strategic difficulties conducting investigations in a remote Aboriginal community. We were unable to collect interim data to analyze the time to onset of diabetes. We were also unable to obtain follow-up blood samples from all subjects: diabetes outcome assessments of 109 (22.2%) subjects were by self-reported clinical diagnosis only. This 22.2% without blood samples might have caused underreporting of incident diabetes. The ratio of plasma high–molecular weight adiponectin to total adiponectin has been correlated more tightly with 2-h postload glucose than total adiponectin (r
= −0.58 for the ratio and −0.38 for total adiponectin; both P
< 0.001) (25
). However, in this prospective cohort study, high–molecular weight adiponectin analysis was not available at the time of baseline biochemical data analysis, another limitation of our study. Nonetheless, the current study was able to retain a high 10-year follow-up rate of 89.1%. In addition, investigating the association of a number of adipokines with incident type 2 diabetes in an Aboriginal Canadian population with a high prevalence of diabetes offers a unique perspective.
In summary, low adiponectin was independently associated with increased type 2 diabetes risk, while leptin, CRP, IL-6, and SAA were not associated with incident type 2 diabetes after adjustment for metabolic syndrome variables including abdominal adiposity in this Aboriginal Canadian population. Combinational effects of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using the ratio and joint effects, did not improve diabetes prediction. The strong association between adiponectin and incident type 2 diabetes, independent of obesity, suggests that adiponectin may be involved in the etiology of diabetes.