Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions
We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker–incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes.
The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these.
E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]).
These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.
KeywordsAdiponectin Biomarkers C-reactive protein Diabetes prevention E-selectin Interleukin 6 Leptin Lifestyle change Metformin Tissue plasminogen activator
Diabetes risk factor
Diabetes Prevention Program
Inverse of fasting insulin
Intensive lifestyle modification
Monocyte chemoattractive protein 1
Plasminogen activator inhibitor 1
Soluble intercellular adhesion molecule 1
Tissue plasminogen activator
This manuscript is dedicated to the late Abbas Kitabchi MD, in recognition of his many contributions to the field of diabetes.
The Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and Diabetes Prevention Program Outcomes Study (DPPOS). A complete list of centres, investigators and staff can be found in the ESM.
MT and RG wrote the manuscript, SM performed the assays, MT did the major analyses and RG, MT, GB, SM, TO, LP and KM, who comprised the Writing Group, all made substantial contributions to study design, analysis and interpretation of data, and revised the manuscript critically for intellectual content and gave final approval of the version to be published. MT is the guarantor of the work.
During the DPP and DPPOS, the NIDDK of the National Institutes of Health provided funding to the clinical centres and the coordinating centre for the design and conduct of the study and collection, management, analysis and interpretation of the data (U01 DK048489). Funding for measurement of biomarkers was provided by an NIDDK grant (1R01DK078907-01A1). The Southwestern American Indian centres were supported directly by the NIDDK, including its intramural research programme, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources and the Department of Veterans Affairs supported data collection at many of the clinical centres. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication and LifeScan donated materials during the DPP and DPPOS. This research was also supported, in part, by the intramural research programme of the NIDDK. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, SlimFast Foods and Quaker Oats donated materials, equipment or medicines for concomitant conditions. McKesson BioServices, Matthews Media Group and the Henry M. Jackson Foundation provided support services under subcontract with the coordinating centre. The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done and publication. The funding agency was not represented on the writing group, although all members of the Steering Committee had input into the report’s contents. All authors in the writing group had access to all data. The opinions expressed are those of the investigators and do not necessarily reflect the views of the funding agencies. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Duality of interest
KM received an investigator-initiated project grant from Novo and has also received donations of medications or supplies with aggregate value >$10,000 for other research studies from Novo Nordisk, Sanofi, Merck and Abbott. MT received honoraria for speaking at symposium from Merck. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.
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