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Description
Aim: To identify if proinsulin and C-peptide, as compared to non-fasting and fasting insulin, are better predictors of both all-cause and cause-specific mortality from cardiovascular disease and cancer. Background: Over the next quarter-century, the diabetes mellitus epidemic is anticipated to worsen considerably and further burden the public health system. Thus, much research in the field of chronic disease epidemiology is turning to earlier identification of pre-diabetes and diabetic conditions in order to prevent and risk stratify individuals at risk for poor outcomes from morbidity and mortality from this insidious disease. Serum insulin levels rise even prior to the development of full-blown diabetes and have been proposed as potential biomarkers for all-cause and cardiovascular mortality. However, the results have been mixed due to the instability of the insulin molecule. Thus the precursor molecule, proinsulin and the cleavage product, C-peptide, have been proposed to be more favorable biomarkers to predict all-cause and cause-specific mortality. Methods: Community-dwelling older adults participated in this prospective cohort study and gave laboratory measurements of non-fasting insulin, fasting insulin, proinsulin, and C-peptide at Visit 7, between 1992-1996. Participants with these laboratory measurements were followed prospectively for mortality outcomes through 2009. Bivariate Cox models were used to assess the relationship between the predictor molecules and the mortality outcomes to assess significance for inclusion in the multivariable models. Separate Cox proportional hazard models were used to estimate hazard ratios and 95% C.I. for the association between the insulin molecules and the three mortality outcomes of all-cause mortality, cardiovascular mortality, and cancer mortality. Results: Of the 1,183 subjects, 378 or 32% of the population had died by the end of the study period in 2009. On bivariate analysis none of the predictor molecules were significantly associated with any cancer mortality outcome so cancer mortality was not further analyzed. The hazard ratio for death from all causes for subjects categorized as having an elevated proinsulin level, prior to adjustment was 1.39 (95% C.I. 1.14-1.71). The hazard ratio for death from all causes for subjects categorized as having an elevated C-peptide level as compared to those with a normal C-peptide level, prior to any adjustment was 1.35 (95% C.I. 1.10-1.67). The hazard ratio for death from a cardiovascular cause for subjects categorized as having an elevated C-peptide level, prior to adjustment was 1.50 (95% C.I. 1.08-2.08). Conclusions: Neither fasting insulin nor non-fasting insulin were associated with any mortality outcome. Proinsulin had a modest association with all-cause mortality. C-peptide also had a modest association with all-cause mortality and a stronger association with cardiovascular mortality. Thus, it seems that the precursor insulin molecule, proinsulin, and the cleavage product C-peptide, may be better predictors for all-cause mortality than intact insulin, and C-peptide may be useful for cardiovascular mortality.
