In this study, plasma concentrations of POPs, especially PCBs and organochlorine pesticides, strongly predicted incident type 2 diabetes during a 5-year follow-up. Although there were some differences in terms of the strengths of the associations, most POPs measured in the current study showed positive associations. Although PCBs with differing biological characteristics were included in this study, dioxin-like PCBs (PCB105, PCB118, PCB156, PCB157, and PCB189) and nondioxin-like PCBs showed similar associations. It is important to note that prediction using the summary measure of PCBs improved risk classification compared with traditional risk factors for diabetes. Although the cross-sectional associations also showed significant results, the strengths of associations in this study of elderly subjects, in whom selective survivorship could play an important role, were weaker than those of prospective analyses.
Although obesity is critical in the pathogenesis of type 2 diabetes, one recent prospective study (11
) reported that the association between adiposity and type 2 diabetes was weaker in elderly subjects. When the pathogenesis of type 2 diabetes is classified into two stages, insulin resistance and insulin secretory defects, the latter part seems to be more important among elderly people (10
). Indeed, it is well known that many chemicals, including streptozotocin, alloxan, and vacor, can induce β-cell destruction (19
). Although there has been no experimental study on the effects of POPs on pancreatic β-cells, one experimental study (9
) observed alterations in mitochondrial function and oxidative capacity in the liver of rats exposed to a mixture of POPs. Similar mitochondrial defects may happen in the pancreatic β-cell after long-term exposure to low-dose POPs in humans, possibly more severely in elderly people because of the general decrease of antioxidant capacity with aging (20
). Mitochondrial function has been implicated as a key for pancreatic β-cells to secrete insulin (21
Aside from studies performed among people with high exposure to several selected POPs in the occupational or accidental setting, there have been three prospective studies that examined associations of type 2 diabetes with organochlorine pesticides and PCBs in general populations (6
). Compared with occupational or accidental exposures, the background exposure in the general population is characterized by low-dose and long-term exposure to a mixture of various POPs. Consistent with the current findings, all three prospective studies have reported that some organochlorine pesticides and PCBs predicted the future risk of type 2 diabetes, but the details differed among the studies.
A prospective study in a cohort of Great Lakes sport fish consumers in Michigan in the U.S. demonstrated a strong association of incident diabetes with p,p’
-DDE but not PCBs (7
). Likewise, in a nested case-control study among a cohort of Swedish women, p,p’
-DDE was also a risk factor for developing type 2 diabetes later in life but not PCB153 (8
). In these two studies, no other organochlorine pesticides, except p,p’
-DDE, were measured. In a nested case-control study performed in young adults within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, trans
-nonachlor and highly chlorinated PCBs predicted type 2 diabetes, whereas p,p’
-DDE did not (6
). In the current study, the association between p,p’
-DDE and type 2 diabetes was not as strong as that seen in the Michigan study. Unlike the CARDIA study, both moderately and highly chlorinated PCBs predicted future risk of type 2 diabetes. However, trans
-nonachlor came out as the most significant among the organochlorine pesticides, similar to the CARDIA study.
The shapes of dose-response relations also differed among the studies. The current study and the Michigan study showed similar dose-response curves (7
). The risk of future diabetes was substantially increased with only a slight increase of concentrations of POPs. However, after that, only a slight increase in risk was seen when the concentrations of POPs became higher. Although the CARDIA study also observed the increased risk at the low dose of some POPs, after that the risk even decreased as concentrations of POPs increased (6
). Considering all these findings, the bottom line may be that the biological effects of POPs already are induced at very low concentrations of certain POPs.
At present, we do not have any clear explanation for why different POPs predicting type 2 diabetes and/or shapes of dose-response relations were different among epidemiological studies. The inconsistency may be related to the idea that POPs are involved in the pathogenesis of type 2 diabetes by interfering with endocrine signaling pathways (22
). First, low-dose effects have been proposed as possible biological responses of endocrine disruptors (23
). Also, endocrine function generally declines with age because hormone receptors become less sensitive and levels of most hormones change with age (24
). Therefore, the different age distribution among the study populations may have led to different results even when comparing similar concentrations of POPs. In addition, endocrine-disturbing effects of one specific POP may differ depending on concentrations of other related endocrine disruptors. Humans are exposed to a mixture of various POPs with unique exposure patterns depending on the study population. For example, concentrations of p,p
´-DDE in the CARDIA study was higher than in those of the current study and the Michigan study. However, concentrations of PCBs with six or seven chlorine atoms were much higher in the current study than in the CARDIA study, whereas those with four or five chlorine atoms were similar between these two studies. Although concentration of any particular POP might be similar between two populations, the strength of association between this POP and diabetes can differ depending on concentrations of other POPs.
There are several study limitations. First, there were only 36 incident type 2 diabetes cases. Therefore, the CIs were wide, and some associations may be chance findings despite strong statistical significance. In addition, although our general hypothesis of associations between POPs and incident diabetes were made a priori, we did perform many statistical tests, and caution should be exercised in interpreting the findings. Second, some diabetes cases would be misclassified as noncases because we did not perform an oral glucose tolerance test. Isolated postprandial hyperglycemia with normal fasting glucose is common among the elderly (25
). Third, because concentrations of POPs tend to be highly correlated in the general population, any POP that is strongly correlated with other biologically important POPs may come out statistically significant in epidemiological studies. Although the measured POPs in the current study are a selection of the POPs referred to in the Stockholm Convention and are representative markers for the group of compounds, the real exposure of the subject is, of course, more complex.
In conclusion, the current study observed that PCBs and some organochlorine pesticides predicted the future risk of type 2 diabetes. Although careful interpretation may be needed because of the small number of incident type 2 diabetes cases, the association between PCBs and incident type 2 diabetes seemed to be at least as strong as the association of adiposity with incident diabetes in this elderly population. The environmental exposure to PCBs and some organochlorine pesticides may play a role in the development of type 2 diabetes.