Discussion
In this prospective case-control study nested in a population-based cohort of middle-aged and older Chinese adults in Singapore, we did not find an association between the ELF score and T2D risk. Among the three components, TIMP1 levels were positively associated with diabetes risk; however, both PIIINP and HA were not associated with T2D risk. Therefore, elevated TIMP1 levels may contribute to the later development of incident T2D through pathways not greatly overlapping with liver fibrosis.
Our finding of the positive association between TIMP1 and T2D concur with results from several cross-sectional and case-control studies from Korea (cases n=80, controls n=80),11 Iraq (cases n=54, controls n=26),12 the UK (cases n=86, controls n=63)13 and the USA (n=1069).14 Although a case-control study in Greece (cases n=60, controls n=60) has observed lower TIMP1 levels in patients with T2D compared with controls,15 the heterogeneous results could be explained by the different characteristics of patients included in the study. Compared with all other studies, patients in the Greek study were at more advanced stage of T2D and may have received more intensive treatment15; the intensified diabetes therapy have shown to decrease TIMP1 levels significantly,13 which may explain for the lower TIMP1 levels among patients with diabetes in the Greek study. For PIIINP and HA, evidence is scarce regarding their associations with T2D risks; therefore, further studies are warranted to validate our findings.
TIMP1 is a biomarker for systemic fibrosis. Excess deposition of extracellular matrix is the hallmark of systemic fibrosis, and TIMP1 promotes fibrosis by inhibiting metalloproteinases in the breakdown of extracellular matrix.16 In support of this, epidemiological findings have reported different levels of metalloproteinases, the target enzyme of TIMP1 inhibition, between people with and without T2D.11–13 TIMP1 also enhances adipogenesis by accelerating lipid accumulation and adipocyte differentiation,17 and this process results in the rapid expansion of adipose tissues, which in turn contributes to subsequent hypoxia and inflammation in the adipose tissues, and further aggravating adipose tissue fibrosis.18 Hence, TIMP1 could be implicated in the pathogenesis of T2D by its role in adiposity, systemic fibrosis and inflammation, which have all been shown to be associated with metabolic disturbances and resulting in insulin resistance.19
To our best knowledge, this is the first prospective study investigating the association between ELF score and T2D risk. The exclusion of undiagnosed diabetes in cases at the time of blood-taking using HbA1c as diagnostic criteria is a strength of the current study in establishing temporality in the association. We also excluded possible undiagnosed diabetes among controls by using stringent HbA1c criteria at the time of blood-taking. However, several limitations merit consideration. First, residual confounding may exist since height and weight were self-reported in the current study, and some major T2D risk factors, such as family history of T2D,20 21 fasting levels of glucose and insulin and inflammatory markers (eg, IL-622), were not available in the current study due to lack of information. We did not collect the information on family history of T2D because the current cohort was initially established for cancer research. In addition, about two-thirds of the blood samples were non-fasted. However, we stratified the analysis by fasting status and observed similar TIMP1-T2D associations in both subgroups, suggesting that the fasting status is unlikely to affect the observed association. The current study was conducted among middle-aged and elderly population, and generalisability to younger population is a concern, although no significant interaction was found with age. Furthermore, the current study had a relatively short follow-up time of about 4 years; future studies with longer follow-up durations are warranted to examine the predictive performance of TIMP1 for the long-term T2D risk.
In conclusion, in this case-control study nested within a prospective cohort among Chinese living in Singapore, we found no significant association between the ELF score and T2D risk, but a positive association between TIMP1 and T2D risk. Our results suggested that elevated TIMP1 levels may contribute to the T2D development through pathways other than liver fibrosis. Future studies are warranted to validate the current finding and to elucidate the underlying mechanism to facilitate the development of drugs and therapies targeting TIMP1 levels for the prevention and management of T2D risk.