Published Online
on April 15, 2002

A more recent version of this article appeared on May 7, 2002

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Submitted on December 19, 2001
Revised on February 27, 2002
Accepted on February 28, 2002

Proinsulin Is an Independent Predictor of Coronary Heart Disease. Report From a 27-Year Follow-Up Study

Björn Zethelius MD^*, Liisa Byberg MSc, C. Nicholas Hales PhD, Hans Lithell MD, and Christian Berne MD

From the Departments of Public Health and Caring Sciences/Geriatrics (B.Z., L.B., H.L.) and Medical Sciences (C.B.), Uppsala University, Sweden; and the Department of Clinical Biochemistry, Addenbrooke's Hospital (C.N.H.), Cambridge, United Kingdom.

^* To whom correspondence should be addressed. E-mail: bjorn.zethelius{at}pubcare.uu.se.

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.

Methods and 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 IRI 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.

Conclusion—Increased proinsulin concentrations predict death and morbidity caused by CHD over a period of 27 years, independent of other major cardiovascular risk factors.

Key words: insulin • risk factors • coronary heart disease • myocardial infarction • epidemiology

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