Proinsulin Is an Independent Predictor of Coronary Heart Disease

Abstract

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 (nϭ874), 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 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. Conclusion-Increased proinsulin concentrations predict death and morbidity caused by CHD over a period of 27 years, independent of other major cardiovascular risk factors.

Supplementation with trans10cis12-conjugated linoleic acid induces hyperproinsulinaemia in obese men: close association with impaired insulin sensitivity

“…As hyperproinsulinaemia predicts Type 2 diabetes [1,9] and cardiovascular death [2], our results are clinically relevant, especially as t10c12CLA is a constituent of commercial weight-loss supplements. Supporting previous data [6,10], our results suggest that CLA supplementation might increase cardiovascular risk.…”

“…Hyperproinsulinaemia independently predicts Type 2 diabetes [1] and cardiovascular disease [2]. Crosssectionally, hyperproinsulinaemia is associated with insulin resistance [3,4], and beta cell dysfunction [5].…”

Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease

“…Also, some data on the long storage of peptides, e.g. proinsulin, in this same cohort demonstrate that no significant degradation occurred over 25 years of storage time [3]. Even if a minor degradation cannot be ruled out, it should have proceeded at the same rate in all samples and so its impact on the outcome and interpretation of the data can be assumed to be minor.…”

“…Study population Random plasma samples from 509 men, obtained from the previously described ULSAM cohort study (www.pubcare.uu.se/ULSAM, accessed 2 September 2009) [3], were stored at −70°C and analysed in 2007. In the prospective analyses, 62 men were excluded due to prior myocardial infarction or angina pectoris (ICD-9 codes 410-414, ICD-10 codes I20-25 [www.who.int/classifica tions/icd/en/, accessed 1 October 2007]).…”

“…Insulin sensitivity index (M/I) was determined with the euglycaemic-hyperinsulinaemic clamp technique [3,7]. Plasma glucose was analysed by a device using glucose dehydrogenase method (Gluc-DH; Merck, Darmstadt, Germany).…”