Diabetes and Heart Failure: Is it Hyperglycemia or Hyperinsulinemia?

The cardiac effects of exogenously administered insulin for the treatment of diabetes (DM) have recently attracted much attention. In particular, it has been questioned whether insulin is the appropriate treatment for patients with type 2 diabetes mellitus and heart failure. While several old and some new studies suggested that insulin treatment has beneficial effects on the heart, recent observational studies indicate associations of insulin treatment with an increased risk of developing or worsening of pre-existing heart failure and higher mortality rates. However, there is actually little evidence that the associations of insulin administration with any adverse outcomes are causal. On the other hand, insulin clearly causes weight gain and may also cause serious episodes of hypoglycemia. Moreover, excess of insulin (hyperinsulinemia), as often seen with the use of injected insulin, seems to predispose to inflammation, hypertension, dyslipidemia, atherosclerosis, heart failure, and arrhythmias. Nevertheless, it should be stressed that most of the data concerning the effects of insulin on cardiac function derive from in vitro studies with isolated animal hearts. Therefore, the relevance of the findings of such studies for humans should be considered with caution. In the present review, we summarize the existing data about the potential positive and negative effects of insulin on the heart and attempt to answer the question whether any adverse effects of insulin or the consequences of hyperglycemia are more important and may provide a better explanation of the close association of DM with heart failure.

Effect of Dietary Insulinemia on All-Cause and Cause-Specific Mortality: Results From a Cohort Study.

Background: Insulin response to diet might predict the risk of mortality; however, the evidence is limited. We prospectively evaluated the link between the dietary hyperinsulinemia index (DHI) and dietary insulin resistance index (DIRI) with all-cause and cause-specific (cardiovascular disease [CVD] and cancer) mortality.Methods: The National Health and Nutrition Examination Survey (1999-2010) database was used. Vital status through December 31, 2011, was ascertained. Stepwise linear regression models consisted of 39 macro/micronutrients applied, and fasting plasma C-peptide for the DHI and triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C) for the DIRI were used. Adjusted Cox regression (followed by propensity score matching) was performed to determine the hazard ratios (HRs) and 95% confidence interval (95% CIs).Results: Overall, 22,246 participants were included (mean age = 47.8 years; 48.9% men). There was a significant increasing risk of mortality across the quartiles of DHI, i.e., participants with a highest score of DHI (Q4) had a greater risk of all-cause (HR: 1.21, 95% CI: 1.17-1.26), CVD (HR: 1.17, 95% CI: 1.07-1.29), and cancer (HR: 1.15, 95% CI: 1.08-1.23) mortality compared with the first quartile (Q1; p < 0.001 for all comparisons). Similarly, participants in the highest DIRI quartile (Q4) had 23% and 31% higher risk of all-cause and CVD mortality, respectively, compared with Q1, while the association between cancer mortality and DIRI was non-significant (HR: 0.88, 95% CI: 0.35-2.61).Conclusions: These findings highlight, for the first time, the detrimental role (association) of insulinemia and insulin resistance potential of diet on all-cause and cause-specific mortality. Our findings support the role of C-peptide and TG/HDL-C ratio as cost-effective and practical biomarkers in clinical settings. These results need to be confirmed to establish their implications.

Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial.

BACKGROUND: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. METHODS: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. RESULTS: Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). CONCLUSION: In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.

Hyperinsulinemic Normoglycemia during Cardiac Surgery Reduces a Composite of 30-day Mortality and Serious In-hospital Complications: A Randomized Clinical Trial.

BACKGROUND: Hyperinsulinemic normoglycemia augments myocardial glucose uptake and utilization. We tested the hypothesis that hyperinsulinemic normoglycemia reduces 30-day mortality and morbidity after cardiac surgery. METHODS: This dual-center, parallel-group, superiority trial randomized cardiac surgical patients between August 2007 and March 2015 at the Cleveland Clinic, Cleveland, Ohio, and Royal Victoria Hospital, Montreal, Canada, to intraoperative glycemic management with (1) hyperinsulinemic normoglycemia, a fixed high-dose insulin and concomitant variable glucose infusion titrated to glucose concentrations of 80 to 110 mg · dl; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl. The primary outcome was a composite of 30-day mortality, mechanical circulatory support, infection, renal or neurologic morbidity. Interim analyses were planned at each 12.5% enrollment of a maximum 2,790 patients. RESULTS: At the third interim analysis (n = 1,439; hyperinsulinemic normoglycemia, 709, standard glycemic management, 730; 52% of planned maximum), the efficacy boundary was crossed and study stopped per protocol. Time-weighted average glucose concentration (means ± SDs) with hyperinsulinemic normoglycemia was 108 ± 20 versus 150 ± 33 mg · dl with standard glycemic management, P < 0.001. At least one component of the composite outcome occurred in 49 (6.9%) patients receiving hyperinsulinemic normoglycemia versus 82 (11.2%) receiving standard glucose management (P < efficacy boundary 0.0085); estimated relative risk (95% interim-adjusted CI) 0.62 (0.39 to 0.97), P = 0.0043. There was a treatment-by-site interaction (P = 0.063); relative risk for the composite outcome was 0.49 (0.26 to 0.91, P = 0.0007, n = 921) at Royal Victoria Hospital, but 0.96 (0.41 to 2.24, P = 0.89, n = 518) at the Cleveland Clinic. Severe hypoglycemia (less than 40 mg · dl) occurred in 6 (0.9%) patients. CONCLUSIONS: Intraoperative hyperinsulinemic normoglycemia reduced mortality and morbidity after cardiac surgery. Providing exogenous glucose while targeting normoglycemia may be preferable to simply normalizing glucose concentrations.

Association between hyperinsulinemia and increased risk of cancer death in nonobese and obese people: A population-based observational study.

Obesity, metabolic syndrome and type 2 diabetes are associated with cancer-related mortality. We assessed whether hyperinsulinemia is a risk factor for cancer death in nonobese people without diabetes. We conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey 1999-2010 and followed up the participants until December 31, 2011. For the primary analysis of cancer mortality, we used Cox proportional hazard models to estimate hazard ratios (HRs) in the participants with hyperinsulinemia and those without. Hyperinsulinemia was defined as a fasting insulin level of ≥10 µU/mL. To identify causes of deaths, the International Classification of Diseases, Tenth Revision codes were used. This study included 9,778 participants aged 20 years or older without diabetes or a history of cancer: 6,718 nonobese participants (2,057 with hyperinsulinemia [30.6%]) and 3,060 obese participants (2,303 with hyperinsulinemia [75.3%]). A total of 99.9% completed follow-up. Among all study participants, cancer mortality was significantly higher in those with hyperinsulinemia than in those without hyperinsulinemia (adjusted HR 2.04, 95% CI 1.24-3.34, p = 0.005). Similarly, among nonobese participants, multivariable analysis showed that cancer mortality was significantly higher in those with hyperinsulinemia than in those without (adjusted HR 1.89, 95% CI 1.07-3.35, p = 0.02). Considering that nonobese people with hyperinsulinemia were at higher risk of cancer mortality than those without hyperinsulinemia, improvement of hyperinsulinemia may be an important approach for preventing cancer regardless of the presence or absence of obesity.

Disorders of carbohydrate metabolism in experimental brain injury.

In experimental heavy closed brain injury (mortality infive days - 86%) it is shown that from the first hours the violations of carbohydrate metabolism in the form of triad were formed: the marked hyperglycemia (3.3-3.6 times), hyperinsulinemia (2.4-3.2 times) and insulin resistance (HOMA-indexes increased to 8.0-11.7 times). These changes were caused by a decrease in tissue sensitivity to insulin and were accompanied by decrease in functional activity of the pancreatic ß-cells. In total it is possible to consider these changes as a pentad of the typical disorders of carbohydrate metabolism at brain injury.

Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up.

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P < 0.0022) and 161% higher risk of gastrointestinal cancer mortality (HR = 2.61 95% CI: 1.73-3.94; P < 0.0001). Age- and sex-adjusted analysis showed that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and the metabolic syndrome.

Increased EpCAM expression in malignant insulinoma: potential clinical implications.

OBJECTIVE: EpCAM (CD326) is overexpressed in progenitor cells of endocrine pancreatic islands of Langerhans during fetal development and was suggested to act as a morphoregulatory molecule in pancreatic island ontogeny. We tested whether EpCAM overexpression is reactivated in insulinomas, endocrine tumors arising in the pancreas. DESIGN/METHOD: We used monoclonal anti-EpCAM antibody Ber-Ep4 for immunohistochemistry on formalin-fixed and paraffin-embedded tumor material. We analyzed 53 insulinomas: 40 benign (disease stage

Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly.

AIMS: To study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death. METHODS: This study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (>or=55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis. RESULTS: Overall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin >or=100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (-33.7 ms (-48.8; -18.6) and -44.4 ms (-58.7; -30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02-4.06); HR 3.05 (1.99-4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34-0.80)). CONCLUSION: In this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.

[Association between metabolic syndrome and the 10 years mortality of cerebro-cardiovascular diseases in the senile population].

OBJECTIVE: To assess the prevalence of metabolic syndrome (MS) and its association with mortality of cerebro-cardiovascular diseases in senile population. METHODS: Data were collected from 1926 people aged 60 and over, who took part in routine health examination in our hospital from 1996 to 1997. All subjects were followed up for 10 years. MS was diagnosed by using the definition recommended by Chinese Diabetic Society in 2004. Cox-proportional hazards models were used in survival analyses and to calculate the relative risk (RR) of cerebro-cardiovascular diseases mortality. RESULTS: The prevalence of MS was 25.03% (n = 482, Group 2) in this population. The 10 year mortality of cerebro-cardiovascular diseases was significantly higher (6.82/1000-person year vs. 2.55/1000-person year, P < 0.05) and the cumulative survival rate was significantly lower (92.46%vs. 97.14%, P < 0.05) in group 2 compared that in group 1 (non-MS, n = 1444). Compared with group 1, RR of cerebro-cardiovascular diseases mortality was 2.52 (95% CI 1.367 - 4.661, P < 0.05) in group 2. CONCLUSION: There was a high prevalence of MS in the senile population and MS was associated with higher 10 years mortality of cerebro-cardiovascular diseases.

Endogenous hyperinsulinemic hypoglycemia: diagnostic strategies, predictive features of malignancy and long-term survival.

Diagnostic strategies, malignancy predictors and long-term survival were retrospectively evaluated in patients with hyperinsulinemic hypoglycemia (64 insulinomas). Lower median glycemia was 30 (range 20-53) mg/dl [1.6 (1.1-2.9) mmol/l] with concurrent insulin of 48 (13.2-217) microU/ml and 15 (2-46) microU/ml measured by radioimmunoassay (RIA) and immunofluorimetric assay (IFMA), respectively. All patients with insulinomas had a positive prolonged fast within 48 h. Sensitivity of localization methods was: ultrasonography (US) 23%, computed tomography (CT) 28%, magnetic resonance imaging (MRI) 65%, endoscopic US 75%, arteriography 38%, portal venous sampling 67%, selective arterial calcium stimulation 67%, intraoperative US 94% and palpation 92%. Nine patients (14%) had malignant insulinomas. Age at diagnosis (mean+/-SD, 53.8+/-19 vs 39.4+/-16.3 yr; p=0.03), insulin (1372+/-730 vs 785+/-659% (percentage of the method's diagnostic cut-off; 6 and 3 microU/ml for RIA and IFMA, respectively; p=0.007) and C-peptide levels (9.8+/-2.9 vs 3.9+/-2.8 ng/ml (3.2+/-0.9 vs 1.3+/-0.9 nmol/l; p=0.006), and tumor size (6.2+/-4.1 vs 1.5+/-0.6 cm; p=0.0002) were increased in malignant insulinomas. C-peptide level above 6.1 ng/ml (2.0 nmol/l) had a 100% sensitivity and 96% specificity, and tumor size above 2.6 cm yielded a sensitivity of 88% and specificity of 100% in predicting malignancy. Survival of patients with malignant insulinomas was significantly impaired (16 vs 100% at 5 yr; p=0.0000001). The diagnosis of insulinoma can be made within 48 h of fasting. The association between intraoperative US and palpation evidenced the tumor in 95% of the patients. C-peptide and tumor size were reliable malignancy predictors.

Hyperinsulinaemia is associated with increased long-term mortality following acute myocardial infarction in non-diabetic patients.

AIMS: To study the impact of disturbances in glucose metabolism on total mortality in non-diabetic patients with acute myocardial infarction. METHODS AND RESULTS: Four hundred and ninety four patients with a verified myocardial infarction and no history of diabetes were studied. The study population comprised a subgroup of patients screened for participation in the Trandolapril Cardiac Evaluation (TRACE) study. At baseline, fasting insulin, fasting glucose, glycosylated haemoglobin (HbA1c), and urinary albumin excretion were measured. Survival status was determined after 6-8 years. Patients with hyperinsulinaemia were more obese and more frequently suffered from hypertension, previous myocardial infarction and congestive heart failure. In a univariate regression analysis, values in the upper quartile of insulin, glucose, HbA1c, and urinary albumin were associated with an excess mortality risk (RR=1.8 (1.2-2.7), p=0.002; RR=1.6 (1.2-2.1), p=0.001; RR= 1.9 (1.3-2.9), p=0.001; RR=1.6 (1.2-2.1), p=0.02 respectively). However, only a high insulin level remained significant in a multivariable analysis (RR=1.54 (1.03-2.31), p=0.04) including baseline variables, left ventricular systolic function and in-hospital complications. CONCLUSIONS: High fasting plasma insulin is an independent risk factor of all-cause mortality in non-diabetic patients with acute myocardial infarction. This justifies future intervention studies aiming at reducing insulin resistance and using fasting insulin as the target variable.

Amniotic fluid insulin levels and fetal abdominal circumference at time of amniocentesis in pregnancies with diabetes.

AIMS: Fetal hyperinsulinism is a strong predictor for excessive growth and fetopathy in pregnancies complicated by diabetes. We examined (i). the relationship between measurements of amniotic fluid insulin (AF insulin) and fetal abdominal circumference (AC) at the time of amniocentesis, and (ii). whether there is a threshold for fetal AC percentiles which can identify low vs. high-risk levels of AF insulin without performing an amniocentesis. METHODS: In a retrospective study, AF insulin from 121 pregnant diabetic women (32 pregestational; 89 gestational) was measured during the 3rd trimester as part of a diabetes management protocol. AC measurements were transformed into a continuous variable of percentile growth for gestational age (Hadlock). Division of the cohort according to deciles or quartiles of AC percentiles was performed to identify a threshold AC with a significant increase in elevated AF insulin, previously defined as AF insulin >or= 7 microU/ml. A receiver operator characteristic (ROC) curve was created and the negative predictive value (NPV) of the determined threshold was calculated. RESULTS: AF insulin levels were significantly correlated with the AC percentiles (r = 0.3, P = 0.0005) by linear regression. No AC threshold could reliably identify a moderate elevated AF insulin >or= 7 microU/ml (NPV 77.2%), but an AC threshold >or= 75th percentile could identify with fetal hyperinsulinism with an AF insulin >or= 16 microU/ml. All 10 cases of AF insulin >or= 16 microU/ml were identified with a NPV of 100% (74/74). CONCLUSIONS: Our data indicate that an AC >or= 75th percentile determined by a 3rd trimester ultrasound examination may discriminate between pregnancies at low vs. high risk for AF insulin >or= 16 microU/ml. This AF insulin concentration corresponds to a level of hyperinsulinism reported to be associated with considerable neonatal and long term morbidity.

Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction.

Mortality and morbidity were examined in 117 laboratory-maintained rhesus monkeys studied over approximately 25 years (8 dietary-restricted [DR] and 109 ad libitum-fed [AL] monkeys). During the study, 49 AL monkeys and 3 DR monkeys died. Compared with the DR monkeys, the AL monkeys had a 2.6-fold increased risk of death. Hyperinsulinemia led to a 3.7-fold increased risk of death (p <.05); concordantly, the risk of death decreased by 7%, per unit increase in insulin sensitivity (M). There was significant organ pathology in the AL at death. The age at median survival in the AL was approximately 25 years compared with 32 years in the DR. The oldest monkey was a diabetic female (AL) that lived to be 40 years of age. These results suggest that dietary restriction leads to an increased average age of death in primates, associated with the prevention of hyperinsulinemia and the mitigation of age-related disease.

Hyperinsulinaemia as long-term predictor of death and ischaemic heart disease in nondiabetic men: The Malmö Preventive Project.

OBJECTIVES: Prospective studies have indicated that hyperinsulinaemia/insulin resistance is a risk factor for ischaemic heart disease (IHD), the risk decreasing with time of follow-up. Few studies have so far investigated the role of hyperinsulinaemia in the prediction of long-term total mortality. SETTING: Section of Preventive Medicine, Department of Medicine, University Hospital, Malmö, Sweden. SUBJECTS: A total of 6074 nondiabetic, middle-aged, healthy Swedish males. SCREENING EXAMINATION: We determined IHD risk factors including blood glucose and plasma insulin before and 2 h after an oral glucose tolerance test (OGTT). Total follow-up time was 19 years. Hyperinsulinaemia was defined as values above the 10th decentile of fasting or 2 h insulin concentration. MAIN OUTCOME MEASURES: Total mortality and cardiac event (CE) rate for IHD. RESULTS: Unadjusted relative risks (RRs) for both death and CE were J-shaped with the highest relative risk (RR: 1.4-1.6) in the hyperinsulinaemic group compared with all other men. The RRs for death and CE were significant for fasting insulin but became nonsignificant after adjustment for other risk factors and also with a longer follow-up. The risk of death in hyperinsulinaemic men, defined on the basis of 2-h insulin level, increased with time of follow-up and was still significantly increased after 19 years [RR: 1.32 (95% CI: 1.05-1.65], even after adjustment for other risk factors. CONCLUSIONS: Fasting hyperinsulinaemia was a predictor of total mortality and IHD in nondiabetic men, although not more significantly after adjustment for other risk factors and with lengthening of follow-up time. The 2-h postglucose hyperinsulinaemia appeared to be a stronger and independent predictor of mortality over long-term follow-up. These findings support the view that insulin resistance with associated cluster of risk factors predicts increased long-term risk of mortality and IHD.

[Ischemic heart disease and metabolic syndrome X (family study)]. / Ishemicheskaia bolezn' serdtsa i komponenty metabolicheskogo sindroma X.

AIM: To evaluate prevalence of metabolic syndrome "X" (MS) components in the families of probands and their wives regarding the presence of hyperinsulinemia and in probands' children of both sexes regarding their having vegetovascular dystonia. MATERIAL AND METHODS: 92 families were selected by the proband who survived acute myocardial infarction (MI) at the age under 50: 92 probands (mean age 47 +/- 1.1 years), 57 probands' wives (mean age 47 +/- 0.7 years), 20 sons (mean age 18.3 +/- 0.8 years), 24 daughters (mean age 19.1 +/- 1.0 years). Two groups were formed: group 1 of 48 probands and 25 wives (the presence of hyperinsulinemia in the proband); group 2 of 44 probands and 32 their wives (controls with normal insulin levels). Anthropometric, arterial pressure and lipid-hormonal measurements were made by standard techniques. Nutrition was studied by random reproduction of 24-h diet. RESULTS: More factors of risk to develop atherosclerosis and MS"X" components in probands and their wives were found in group 1. More frequent in the parents were the following MS components: hypoalphacholesterolemia, overweight, arterial hypertension, hyperapolipoprotein-B-emia. Vegetovascular asthenia in the probands' children predisposed to cardiovascular diseases is closely linked with the presence of hypoalphacholesterolemia, hypertriglyceridemia, overweight and arterial hypertension. CONCLUSION: MS "X" for probands and their wives is a "malignant" risk factor for cardiovascular diseases; in the presence of IHD in father, vegetovascular asthenia in children is a risk factor of cardiovascular disease.

Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with Type II diabetes.

AIMS/HYPOTHESIS: Information on the association of hyperinsulinaemia with coronary heart disease (CHD) in patients with Type II (non-insulin-dependent) diabetes is limited and controversial. Therefore, we carried out a prospective study to examine the predictive value of fasting plasma insulin and "hyperinsulinaemia cluster" with regard to the risk of CHD mortality. METHODS: At baseline risk factors for CHD were determined in 902 patients aged 45 to 64 years with Type II diabetes not treated by insulin (499 men and 403 women). These patients were followed up to 7 years for CHD mortality. RESULTS: Coronary heart disease mortality (16.2% in men, 9.2% in women) increased significantly in men with increasing plasma insulin tertiles (p = 0.006) and in both sexes combined (p = 0.010) but not in women (p = 0.090). The predictive value of hyperinsulinaemia with regard to death from CHD was independent of conventional cardiovascular risk factors but not of risk factors clustering with hyperinsulinaemia. By applying factor analysis and principal component analysis we showed that "hyperinsulinaemia cluster" (a factor having high positive loadings for body mass index, triglycerides and insulin; and a high negative loading for high-density lipoprotein cholesterol) was predictive of death from CHD in patients with Type II diabetes (hazard ratio with 95% confidence intervals 1.43 (1.18, 1.73), p < 0.001). CONCLUSION/INTERPRETATION: Our results support the notion that cardiovascular risk factors clustering with endogenous hyperinsulinaemia increase the risk of death from CHD in patients with Type II diabetes not treated with insulin.

Hyperinsulinemia and the risk of stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study.

BACKGROUND AND PURPOSE: Several studies have shown that hyperinsulinemia is associated with the risk of coronary heart disease, but information on the association of hyperinsulinemia with the risk of stroke is limited. We investigated the association of hyperinsulinemia with the risk of stroke during a 22-year follow-up of the Helsinki Policemen Study population. METHODS: The study was based on a cohort of 970 men aged 34 to 64 years who were free of cerebrovascular disease, other cardiovascular disease, or diabetes. Risk factor measurements at baseline examination included an oral glucose tolerance test with blood glucose and plasma insulin measurements at 0, 1, and 2 hours. Area under the insulin response curve during oral glucose tolerance test was used as a composite variable reflecting plasma insulin levels. RESULTS: During the 22-year follow-up, 70 men had a fatal or nonfatal stroke. Hyperinsulinemia (highest area under the insulin response curve quintile compared with the combined 4 lower quintiles) was associated with the risk of stroke (age-adjusted hazard ratio, 2.12; 95% CI, 1.28 to 3.49), but not independently of other risk factors (multiple-adjusted hazard ratio, 1.54; 95% CI, 0.90 to 2.62), which was mainly due to the impact of obesity, particularly upper body obesity, with subscapular skinfold thickness used as an index. Of other risk factors, upper body obesity, blood pressure, and smoking were independent predictors of the risk of stroke. CONCLUSIONS: Hyperinsulinemia was associated with the risk of stroke in Helsinki policemen during the 22-year follow-up, but not independently of other risk factors, particularly upper body obesity.