Proinsulin is an independent predictor of coronary heart disease: Report from a 27-year follow-up study.
BACKGROUND
Some, but not all, studies have reported a relationship between plasma insulin and coronary heart disease (CHD). Conventional nonspecific insulin assays are also measuring various fractions of proinsulin-like molecules due to cross-reactivity. The long-term relationship between proinsulin-like molecules and CHD is largely unknown. For this reason, the longitudinal relationships between intact proinsulin, split proinsulin, specific insulin, immunoreactive insulin, and CHD, were studied in a population-based cohort of 50-year-old men (n=874), with a follow-up of 27 years.


RESULTS
Fasting proinsulin-like molecule and specific-insulin concentrations were measured in plasma (stored frozen since baseline 1970 to 1973) by specific 2-site immunometric assays. Immunoreactive insulin concentrations were determined at baseline. The associations between proinsulin-like molecules, specific insulin, immunoreactive insulin, and CHD mortality (International Classification of Diseases [9th revision] codes 410 to 414) were analyzed using Cox's proportional hazards regression and presented as hazard ratios (HRs) with their 95% confidence intervals (CIs) for a 1-SD increase in a predictor variable. In the univariate analysis, intact proinsulin (HR, 1.69; 95% CI, 1.41 to 2.01) was the strongest predictor of death from CHD. In the multivariate analysis, smoking (HR, 1.57; 95% CI, 1.03 to 2.38), intact proinsulin (HR, 1.47; 95% CI, 1.18 to 1.82), systolic blood pressure (HR, 1.38; 95% CI, 1.14 to 1.66), and LDL/HDL cholesterol ratio (HR, 1.31; 95% CI, 1.12 to 1.53) were independent predictors of CHD mortality (adjusted for body mass index, triglycerides, and fasting glucose), whereas specific insulin and immunoreactive insulin were not (HR, 1.12; 95% CI, 0.90 to 1.40). The increased risk was restricted to the upper third of the proinsulin distribution.


CONCLUSIONS
Increased proinsulin concentrations predict death and morbidity caused by CHD over a period of 27 years, independent of other major cardiovascular risk factors.
Zethelius
Björn
B
Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Sweden. bjorn.zethelius@pubcare.uu.se
Byberg
Liisa
L
Hales
C Nicholas
CN
Lithell
Hans
H
Berne
Christian
C
D015415:Biomarkers / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000175:diagnosis / Q000401:mortality*; D005500:Follow-Up Studies; D006801:Humans; D007328:Insulin / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011384:Proinsulin / Q000097:blood* / Q000276:immunology; D011446:Prospective Studies; D011863:Radioimmunoassay; D012307:Risk Factors; D015996:Survival Rate
D015415:Biomarkers; D007328:Insulin; D011384:Proinsulin