Rachel Dankner

Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?

Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

Basal-state hyperinsulinemia in healthy normoglycemic adults is predictive of type 2 diabetes over a 24-year follow-up: a preliminary report.

OBJECTIVE We examined the predictive value of hyperinsulinemia in the basal state on the 24-year progression from normoglycemia to dysglycemia. RESEARCH DESIGN AND METHODS A sample of 515 normoglycemic men and women were studied again after 24 years for glycemic status. RESULTS Half of the participants developed dysglycemia: 11.1% progressed to impaired fasting glucose (IFG), 9.9% to impaired glucose tolerance (IGT), 4.5% to both IFG and IGT, and another 24.3% to type 2 diabetes. Elevated levels of overnight fasting (basal) insulin, triglycerides, BMI ≥27 kg/m2, fasting blood glucose, blood pressure, North African or Yemenite background, and male sex each favored conversion to dysglycemia after 24 years. In multiple ordered logistic regression analysis, the most significant predictor of progression to dysglycemia was hyperinsulinemia (upper quintile), after adjusting for BMI, ethnic origin, sex, age, smoking, physical activity, blood pressure, and triglycerides. CONCLUSIONS Basal hyperinsulinemia in normoglycemic adults constitutes an independent risk factor for developing dysglycemia over 24 years.

Cardiovascular and all-cause mortality in relation to various anthropometric measures of obesity in Europeans

BACKGROUND AND AIMS Cardiovascular and all-cause mortality in relation to various anthropometric measures of obesity is still controversial. METHODS AND RESULTS Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), A Body Shape Index (ABSI) and waist-to-hip-to-height ratio (WHHR) were measured at baseline in a cohort of 46,651 European men and women aged 24-99 years. The relationship between anthropometric measures of obesity and mortality was evaluated by the Cox proportional hazards model with age as a time-scale and with threshold detected by a piecewise regression model. Over a median follow-up of 7.9 years, 2381 men and 1055 women died, 1071 men (45.0%) and 339 women (32.1%) from cardiovascular disease (CVD). BMI had a J-shaped relationship with CVD mortality, whereas anthropometric measures of abdominal obesity had positive linear relationships. BMI, WC and WHtR showed J-shaped associations with all-cause mortality, whereas WHR, ABSI and WHHR demonstrated positive linear relationships. Accordingly, a threshold value was detected at 29.29 and 30.98 kg/m(2) for BMI, 96.4 and 93.3 cm for WC, 0.57 and 0.60 for WHtR, 0.0848 and 0.0813 m(11/6) kg(-2/3) for ABSI with CVD mortality in men and women, respectively; 29.88 and 29.50 kg/m(2) for BMI, 104.3 and 105.6 for WC, 0.61 and 0.67 for WHtR, 0.95 and 0.86 for WHR, 0.0807 and 0.0765 for ABSI in men and women, respectively, and 0.52 for WHHR in women with all-cause mortality. CONCLUSION All anthropometric measures of abdominal obesity had positive linear associations with CVD mortality, whereas some showed linear and the others J-shaped relationships with all-cause mortality. BMI had a J-shaped relationship with either CVD or all-cause mortality. Thresholds detected based on mortality may help with clinical definition of obesity in relation to mortality.

Comparison of various surrogate obesity indicators as predictors of cardiovascular mortality in four European populations

Background/Objectives:Body mass index (BMI) is the most commonly used surrogate marker for evaluating the risk of cardiovascular disease (CVD) mortality in relation to general obesity, while abdominal obesity indicators have been proposed to be more informative in risk prediction.Subject/Methods:A prospective cohort study consisting of 46 651 Europeans aged 24–99 years was conducted to investigate the relationship between CVD mortality and different obesity indicators including BMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), A Body Shape Index (ABSI) and waist-to-hip-to-height ratio (WHHR). Hazard ratio (HR) was estimated by the Cox proportional hazards model using age as timescale, and compared using paired homogeneity test.Results:During a median follow-up of 7.9 years, 3435 participants died, 1409 from CVD. All obesity indicators were positively associated with increased risk of CVD mortality, with HRs (95% confidence intervals) per standard deviation increase of 1.19 (1.12–1.27) for BMI, 1.29 (1.21–1.37) for WC, 1.28 (1.20–1.36) for WHR, 1.35 (1.27–1.44) for WSR, 1.34 (1.26–1.44) for ABSI and 1.34 (1.25–1.42) for WHHR in men and 1.37 (1.24–1.51), 1.49 (1.34–1.65), 1.45 (1.31–1.60), 1.52 (1.37–1.69), 1.32 (1.18–1.48) and 1.45 (1.31–1.61) in women, respectively. The prediction was stronger with abdominal obesity indicators than with BMI or ABSI (P<0.05 for all paired homogeneity tests). WSR appeared to be the strongest predictor among all the indicators, with a linear relationship with CVD mortality in both men and women.Conclusions:Abdominal obesity indicators such as WC, WHR, WSR and WHHR, are stronger predictors for CVD mortality than general obesity indicator of BMI.

Predictors of cardiac and noncardiac mortality among 14,697 patients with coronary heart disease.

The decrease in mortality from ischemic heart disease during the last 25 years may partly reflect improvement in diagnosis and treatment of patients with coronary heart disease. These patients, therefore, are experiencing morbidity and mortality due to other causes. The aim of our study was to describe the incidence and causes of cardiac mortality (CM) and noncardiac mortality (NCM) and to identify predictive factors. A cohort of 14,697 patients with coronary heart disease was merged with the Central Population Registry to identify mortality records from 1990 to 1996. Among the 1,839 deaths, 1,055 (57.4%) were cardiac, 626 (34.0%) were noncardiac, and 158 deaths (8.6%) were due to unknown causes as classified in the International Classification of Diseases-Ninth Edition (ICD). The 3 most significant predictors were age for a 10-year increment (odds ratios 1.75 and 2.25 for CM and NCM, respectively), chronic obstructive pulmonary disease (odds ratios 1.67 and 1.71), and current smoking (odds ratios 1.29 and 1.66). A history of cancer was a predictor of NCM, but not of CM, whereas peripheral vascular disease predicted CM but not NCM. As the number of predictive factors increased from none to >or=5, the risk of NCM gradually increased from 1.9% to 15.5%. Similar predictors expose subjects with coronary disease to CM and NCM, but smoking plays a more pronounced role in the prediction of NCM, whereas past myocardial infarction, lower levels of high-density lipoprotein cholesterol, and peripheral vascular disease are mainly associated with CM. Because of the similarity of antecedent predictors, treatment of risk factors among patients with coronary heart disease should prove valuable for the prevention of all-cause mortality.

Waist circumference vs body mass index in association with cardiorespiratory fitness in healthy men and women: a cross sectional analysis of 403 subjects

ObjectiveBody mass index (BMI) is more commonly used than waist circumference as a measure of adiposity in clinical and research settings. The purpose of this study was to compare the associations of BMI and waist circumference with cardiorespiratory fitness.MethodsIn a cross-sectional study of 403 healthy men and women aged 50 ± 8.8 years, BMI and waist circumference were measured. Cardiorespiratory fitness was assessed from estimated maximal O2 uptake (VO2max), as calculated from a maximal fitness test.ResultsMean BMI (kg/m2) was 27.8 ± 3.7 and 25.5 ± 4.6; and mean waist circumference (cm) 94.1 ± 9.7 and 84.3 ± 10.4 for men and women, respectively. Both men and women reported an average of 2.5 hours of weekly sports related physical activity, and 18% were current smokers. Correlation coefficients between both BMI and waist circumference, and VO2max were statistically significant in men (r = −0.280 and r = −0.377, respectively, p > 0.05 for both) and in women (r = −0.514 and r = −0.491, respectively, p > 0.05 for both). In women, the contribution of BMI to the level of VO2max in a regression model was greater, while in men waist circumference contributed more to the final model. In these models, age, hours of training per week, and weekly caloric expenditure in sport activity, significantly associated with VO2max, while smoking did not.ConclusionThe differences observed between the sexes in the associations of BMI and waist circumference with VO2max support the clinical use of both obesity measures for assessment of cardiorespiratory fitness.

Time-Dependent Risk of Cancer After a Diabetes Diagnosis in a Cohort of 2.3 Million Adults

Using a time-dependent approach, we investigated all-site and site-specific cancer incidence in a large population stratified by diabetes status. The study analyzed a closed cohort comprised of Israelis aged 21-89 years, enrolled in a health fund, and followed from 2002 to 2012. Adjusting for age, ethnicity, and socioeconomic status, we calculated hazard ratios for cancer incidence using Cox regression separately for participants with prevalent and incident diabetes; the latter was further divided by time since diabetes diagnosis. Of the 2,186,196 individuals included in the analysis, 159,104 were classified as having prevalent diabetes, 408,243 as having incident diabetes, and 1,618,849 as free of diabetes. In both men and women, diabetes posed an increased risk of cancers of the liver, pancreas, gallbladder, endometrium, stomach, kidney, brain (benign), brain (malignant), colon/rectum, lung (all, adenocarcinoma, and squamous cell carcinoma), ovary, and bladder, as well as leukemia, multiple myeloma, non-Hodgkin lymphoma, and breast cancer in postmenopausal women. No excess risk was observed for breast cancer in premenopausal women or for thyroid cancer. Diabetes was associated with a reduced risk of prostate cancer. Hazard ratios for all-site and site-specific cancers were particularly elevated during the first year following diabetes diagnosis. The findings of this large study with a time-dependent approach are consistent with those of previous studies that have observed associations between diabetes and cancer incidence.

Predicting the 20-year diabetes incidence rate

The long‐range prediction from clinical variables of the onset of diabetes is important to patients and clinicians. Our objective was to evaluate the efficacy of various glucose‐related clinical measurements in predicting the 20‐year risk of developing type 2 diabetes (T2DM) in an elderly population.

One-hour post-load plasma glucose level during the OGTT predicts mortality: observations from the Israel Study of Glucose Intolerance, Obesity and Hypertension.

The relationship between 1‐ and 2‐h glucose levels following an oral glucose tolerance test (OGTT) and long‐term mortality was evaluated.