Insulin sensitivity measured by the euglycaemic insulin clamp and proinsulin levels as predictors of stroke in elderly men

Abstract

Aims/hypothesis Our aim was to investigate the predictive power of a panel of variables in glucose and insulin metabolism for the incidence of stroke or transient ischaemic attacks (TIA). We hypothesised that proinsulin and insulin resistance contributes to an increase of risk for fatal and non-fatal stroke/TIA, independently of diabetes and established risk factors. Methods The study is based on the Uppsala Longitudinal Study of Adult Men cohort. The examinations were performed at age 70 years. Results In 1,151 men free from stroke at baseline, 150 developed stroke or TIA during a median follow-up of 8.8 years. In unadjusted Cox proportional hazards analyses, a 1 SD increase of a predictor variable was associated with an increased risk for stroke/TIA, e.g. plasma insulin (HR 1.19, 95% CI 1.01-1.40), fasting intact proinsulin (HR 1.28, 95% CI 1.09-1.49); whereas a 1 SD increase in insulin sensitivity measured by the euglycaemic insulin clamp method decreased the risk for stroke/TIA (HR 0.81, 95% CI 0.68-0.96). The predictive values of fasting intact proinsulin and insulin sensitivity endured but not that of plasma insulin when adjusting for diabetes. In models adjusting for diabetes, hypertension, atrial fibrillation, electrocardiographic left ventricular hypertrophy, serum cholesterol and smoking, proinsulin remained as a significant predictor of later stroke/TIA (HR 1.22, 95% CI 1.00-1.48) whereas clamp insulin sensitivity did not (HR 0.87, 95% CI 0.71-1.07). Conclusions/interpretation Fasting intact proinsulin level and insulin sensitivity at clamp predicted subsequent fatal and non-fatal stroke/TIA, independently of diabetes in elderly men whereas fasting insulin did not.

Racial Differences in the Association of Insulin Resistance With Stroke Risk

“…To our knowledge, only the Rotterdam study 13 and the Uppsala Longitudinal Study of Adult Men 11 have previously examined associations between insulin resistance and risk of ICH, finding virtually no evidence of an association (HR = 1.03; 95% CI: 0.76 – 1.39 for the Rotterdam study, HR = 0.95; 95% CI: 0.60 – 1.50 for Uppsala). The relationship of insulin resistance and stroke risk is similar to patterns observed between elevated lipids and stroke risk, where in other studies showed increased risk of CI, but lower risk of ICH with elevated lipids.…”

“…An association between insulin resistance and stroke risk was demonstrated in the Atherosclerosis Risk in Communities (ARIC) study (using fasting insulin levels), 5, 6 the Cardiovascular Health Study (CHS; using the Gutt insulin sensitivity index 7 ), 8 National Health and Nutrition Examination Survey (NHANES; using the HOMA-IR model), 9 the Northern Manhattan Study (NOMAS; using HOMA-IR, but only a marginal effect with a threshold in the highest quartile), 10 the Uppsala Longitudinal Study of Adult Men (using serum insulin, fasting pro-insulin, and insulin sensitivity by the euglycemic clamp), 11 and a study in the general Japanese population (using the HOMA-IR model). 12 In contrast, no statistically significant association was observed in the Rotterdam Study (using the HOMA-IR model) 13 or the Bezafibrate Infarction Prevention Study (BIP) study of patients in stable coronary heart disease.…”

“…Most of the studies of the association of insulin resistance and stroke risk focused on CI outcomes, and to our knowledge only two studies have assessed the association of insulin resistance and ICH risk, both failing to find an association. 1113 …”

Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip

“…In the past decades, several biomarkers, such as Lp(a) 4,5 C-reactive protein, 6 Lp-LPA2, 6 the chemokine ligand CXCL12, 7 intracellular adehesion molecule-1 (ICAM-1), 8 homocysteine, 9 brain natriuretic peptide, 10 urinary albumin, 10 and assymetric dimetylarginine (ADMA) levels, 11 have been put forward as novel risk markers for incident stroke, but to date none of these have made it to routine clinical practice.…”

Insulin Resistance and the Development of Cardiovascular Disease in a Japanese Community: the Hisayama Study

“…On the other hand, the age-and sex-adjusted HR for CVD was significantly higher in subjects in the fifth quintile of HOMA-IR than in those in the first quintile. This association also influence of directly measured insulin sensitivity on the risk of CVD are limited: only a prospective cohort study in Sweden has revealed a significant inverse association between insulin sensitivity measured by an euglycemic insulin clamp and CVD risk 27,28) . The methods used to directly measure insulin sensitivity are invasive, complex, and generally too expensive for clinical practice.…”