Circulating IL-18 and the risk of type 2 diabetes in women.

AIMS/HYPOTHESIS: The pathophysiology of type 2 diabetes involves pro-inflammatory pathways. We tested the hypothesis that IL-18 predicts future diabetes cases. METHODS: We used a nested case-control design based in the Nurses' Health Study. Baseline blood samples were collected between 1989 and 1990. Questionnaires to assess body weight, lifestyle (physical activity, diet, smoking) and diabetes diagnosis were sent out and assessed biennially (follow-up until 2002). Cases (n = 1,012) were defined as women developing type 2 diabetes at least 1 year after blood sampling. Control women (n = 1,081) were matched to cases by age, date of blood draw, fasting status and race. We calculated the RR (95% CI) of type 2 diabetes in quintiles of IL-18 using conditional logistic regression with the first quintile as referent; adjustments included matching factors, diabetes risk factors, BMI, adipokine levels (adiponectin, resistin) and inflammatory proteins (C-reactive protein, tumour necrosis factor receptor 2 (TNFalpha-R2) and IL-6). RESULTS: Higher IL-18 levels were associated with increased risk of developing diabetes, even after adjustment for matching factors and multiple diabetes risk factors: being in the highest quintile of IL-18 was associated with a RR of 1.75 (1.41-2.18) for diabetes relative to the first quintile (p < 0.0001 for trend). Significant trends in association were still observed after adjustment for BMI (RR 1.44 [1.15-1.80], p < 0.0001 for trend) and adiponectin levels (RR 1.28 [1.02-1.60], p = 0.006 for trend). Further adjustment for inflammatory markers in a sub-sample did not significantly change the results. CONCLUSIONS/INTERPRETATION: Elevated IL-18 levels are associated with higher risk of diabetes. This association is independent of usual risk factors, including BMI and adipokine levels.

Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study.

BACKGROUND: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]). METHODS: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. RESULTS: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. CONCLUSIONS: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.

The -174 IL-6 GG genotype is associated with a reduced risk of type 2 diabetes mellitus in a family sample from the National Heart, Lung and Blood Institute's Framingham Heart Study.

AIMS/HYPOTHESIS: We evaluated the -174 IL-6 gene polymorphism as a risk factor for type 2 diabetes mellitus in a family-based analysis. METHODS: We tested for associations between the -174 IL-6 G/C promoter polymorphism and fasting plasma glucose (FPG) and type 2 diabetes in a sample of 1,428 individuals from the largest 182 families in the National Heart, Lung and Blood Institute's Framingham Heart Study population. RESULTS: A significant association was found with FPG (p=0.01) and log (FPG) (p=0.005) using a modified family-based transmission disequilibrium test, the family-based association test (FBAT). The association between IL-6 genotype and FPG (p=0.035) and log (FPG) (p=0.03) was also found in the subset of families that were informative in FBAT using a mixed-effects regression model and strengthened after adjustment for potential confounders (p=0.008 for log [FPG]). The mean glucose level estimated from models with log (FPG) as the dependent variable for the GG genotype in the informative families was significantly lower (5.20+/-0.06 mmol/l) than for the GC (5.41+/-0.06 mmol/l) and CC (5.38+/-0.06 mmol/l) genotypes (p=0.03 for contrast between GG and GC genotypes). In the subset of informative families, the risk of type 2 diabetes associated with the GG genotype was lower relative to the GC and CC genotypes combined (potential confounder-adjusted, mixed-effects odds ratio 0.35, 95% CI 0.14-0.88, p=0.026, unaffected n=391, affected n=32). CONCLUSIONS/INTERPRETATION: These results are consistent with a protective role for the -174 IL-6 G allele against type 2 diabetes and warrant further analysis of this polymorphism.

Health consequences of obesity in the elderly: a review of four unresolved questions.

Obesity prevalence is growing progressively even among older age groups. Controversy exists about the potential harms of obesity in the elderly. Debate persists about the relation between obesity in old age and total or disease-specific mortality, the definition of obesity in the elderly, its clinical relevance, and about the need for its treatment. Knowledge of age-related body composition and fat distribution changes will help us to better understand the relationships between obesity, morbidity and mortality in the elderly. Review of the literature supports that central fat and relative loss of fat-free mass may become relatively more important than BMI in determining the health risk associated with obesity in older ages. Weight gain or fat redistribution in older age may still confer adverse health risks (for earlier mortality, comorbidities conferring independent adverse health risks, or for functional decline). Evaluation of comorbidity and weight history should be performed in the elderly in order to generate a comprehensive assessment of the potential adverse health effects of overweight or obesity. The risks of obesity in the elderly have been underestimated by a number of confounders such as survival effect, competing mortalities, relatively shortened life expectancy in older persons, smoking, weight change and unintentional weight loss. Identification of elderly subjects with sarcopenic obesity is probably clinically relevant, but the definition of sarcopenic obesity, the benefits of its clinical identification, as well as its relation to clinical consequences require further study. Studies on the effect of voluntary weight loss in the elderly are scarce, but they suggest that even small amounts of weight loss (between 5-10% of initial body weight) may be beneficial. In older as well as in younger adults, voluntary weight loss may help to prevent the adverse health consequences of obesity.

Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men.

We defined risk factors for a clinical diagnosis of benign prostatic hyperplasia (BPH) among subjects of the population-based Massachusetts Male Aging Study. In 1987-89 1709 men aged 40-70 provided baseline risk factor data and were followed for a mean of 9 years; 1019 men without prostate cancer provided follow-up data. We classified men with clinical BPH at follow-up if they reported (1) frequent or difficulty urinating and were told by a health professional that they had an enlarged or swollen prostate or (2) if they reported having surgery for BPH. At follow-up the prevalence of clinical BPH was 19.4%, increasing from 8.4% of men aged 38-49 years to 33.5% of men aged 60-70 years (P < 0.001 for trend). Elevated free PSA levels (age- and total PSA-adjusted OR, top vs. bottom quartile ng/mL 4.4, 95% CI 1.9-10.5), heart disease (age-adjusted OR 2.1, CI 1.3-3.3), and use of beta-blocker medications (OR 1.8, CI 1.1-3.0) increased odds for BPH, while current cigarette smoking (OR 0.5, CI 0.3-0.8) and high levels of physical activity (top vs. bottom quartile kcals/day OR 0.5, CI 0.3-0.9) decreased odds of BPH. All but the medication effects persisted in fully adjusted multivariable models. Total or fat calorie intake, sexual activity level, alcohol intake, body mass index, waist-hip ratio, diastolic blood pressure, a history of diabetes, hypertension, vasectomy, or serum levels of androgens or estrogens did not individually predict clinical BPH. We conclude that physical exercise and cigarette smoking appear to protect against development of clinical BPH. Elevated free PSA levels predict clinical BPH independent of total PSA levels. Risk associated with heart disease does not appear to be due solely to detection bias or to effects of heart disease medications. A wide variety of other characteristics appear to have no influence on risk for clinical BPH.

Association of the Ala54-Thr polymorphism in the intestinal fatty acid-binding protein with 2-h postchallenge insulin levels in the Framingham Offspring Study.

OBJECTIVE: To investigate the association of variants of the intestinal fatty acid-binding protein gene (FABP2) with fasting and postchallenge glucose and insulin levels, HbA(1c), and prevalence of type 2 diabetes in a separate sample of men and women. RESEARCH DESIGN AND METHODS: Subjects were participants in the Framingham Offspring Study, a long-term community-based prospective observational study of risk factors for cardiovascular disease. The study sample consisted of 762 men and 922 women. RESULTS: In women, carriers of the Thr54 allele had significantly higher 2-h postchallenge insulin levels than noncarriers (104.4 +/- 73.0 vs. 93.4 +/- 61.5 microU/ml; P = 0.0139). This relationship remained significant after adjustment for familial relationship, age, BMI, triglycerides, APOE genotype, smoking, alcohol intake, the use of beta-blockers, menopausal status, and estrogen therapy. No such significant association was observed in men. In both men and women, there were no statistical associations between the FABP2 polymorphism and BMI, fasting glucose, fasting insulin, 2-h postchallenge glucose levels, HbA(1c), and prevalence of type 2 diabetes. CONCLUSIONS: These results suggest that the FABP2 Thr54 allele may have a minor contribution to the insulin resistance syndrome in a white general population.

Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance.

Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients (age 43 +/- 1 yr, BMI 26.1 +/- 0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin >15 microU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500 mg twice daily. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1 +/- 4 vs 18.9 +/- 0.9 microg/L PAI-1, 16.6 +/- 0.8 vs. 8.0 +/- 0.3 microg/L tPA, P = 0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9 +/- 1.4 vs +1.4 +/- 1.0 microg/L in the placebo-treated group P = 0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7 +/- 2.3 vs +1.7 +/- 2.9 microg/L, P = 0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r = 0.43, P = 0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk.

Cardiovascular disease prevention practices by U.S. Physicians for patients with diabetes.

OBJECTIVE: Cardiovascular diseases account for the majority of morbidity and mortality in patients with type 2 diabetes mellitus. We describe patterns of cardiovascular disease primary prevention practices used for patients with diabetes by U.S. office-based physicians. MEASUREMENTS AND MAIN RESULTS: We analyzed a representative sample of 14,038 visits from the 1995 and 1996 National Ambulatory Medical Care Surveys (NAMCS), including 1,489 visits by patients with diabetes. Physicians completed visit forms describing diagnoses, demographics, services provided, and current medications. Diabetes was defined by diagnostic codes; patients with ischemic heart disease or younger than 30 years were excluded. We estimated national visit volumes by extrapolation using NAMCS sampling weights. Independent determinants of prevention practices were evaluated using multiple logistic regression. Actual visits sampled translated into an estimated 407 million office visits in 1995 and 1996, of which 44.8 million (11%) were by patients with diabetes. Overall, patients with diabetes received more cardiovascular disease prevention services than patients without diabetes, including cholesterol reduction (8% vs 5%, P <.001) and exercise counseling (22% vs 13%, P <.001), blood pressure measurement (82% vs 72%, P <.001), and aspirin prescription (5% vs 2%, P <.001). Patients with diabetes and hyperlipidemia were more likely to receive lipid-lowering medications than patients without these diagnoses (67% vs 51%, P =.007), but those who had diabetes and hypertension or who smoked were no more likely than those without to receive antihypertensive medications or smoking cessation counseling, respectively. These effects persisted in multiple logistic regression analyses controlling for potential confounders. CONCLUSIONS: Patients with diabetes visiting U.S. physicians in 1995 and 1996 received somewhat more cardiovascular disease prevention services than patients without diabetes. Absolute rates of services, however, remained lower than desired based on national recommendations. Current evidence suggests that wider implementation of these recommendations can be expected to reduce the burden of cardiovascular disease in patients with diabetes.

Incidence rates and risk factors for acute urinary retention: the health professionals followup study.

PURPOSE: We define incidence rates and risk factors for acute urinary retention. MATERIALS AND METHODS: In 1992, 41,276 United States male health professionals 45 to 83 years old self-reported baseline health data and American Urological Association symptom index scores. In 1995 a subset reported the year of any episode of acute urinary retention requiring catheterization. Of 8,418 respondents 6,100 without a history of prostate cancer, prostatectomy or acute urinary retention before 1992 provided data. Incidence rates from 1992 to 1995 were calculated and risk factors were assessed using logistic regression. RESULTS: During 15,851 person-years of followup 82 men reported an episode of acute urinary retention (sampling weighted incidence 4.5/1,000 person-years, 95% confidence intervals 3.1 to 6.2). Rates increased with age and baseline symptom severity. In men with symptom score 0 to 7 (none or mild lower urinary tract symptoms) the incidence of acute urinary retention increased from 0.4/1,000 person-years for those 45 to 49 years old to 7.9/1,000 person-years for those 70 to 83 years old. In men with symptom score 8 to 35 (moderate or severe lower urinary tract symptoms) rates increased from 3.3/1,000 person-years for those 45 to 49 years old to 11.3/1,000 person-years for those 70 to 83 years old. Men with a clinical diagnosis of benign prostatic hyperplasia and a symptom score 8 or greater had the highest rates (age adjusted incidence 13.7/1,000 person-years). All 7 lower urinary tract symptoms comprising the American Urological Association symptom index individually predicted acute urinary retention (age adjusted odds ratio 1.8 to 2.9 for symptoms occurring more than 25% of the time during the last month). The sensation of incomplete bladder emptying, having to void again after less than 2 hours and a weak urinary stream were the best independent symptom predictors. Use of medications with adrenergic or anticholinergic side effects also predicted acute urinary retention. CONCLUSIONS: Acute urinary retention occurred relatively infrequently but older age, moderate or severe lower urinary tract symptoms, a diagnosis of benign prostatic hyperplasia and specific drug therapies significantly increased the risk of occurrence.

High rates of prostate-specific antigen testing in men with evidence of benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia is common among men who may be candidates for prostate cancer screening using prostate-specific antigen (PSA) testing. Patterns of PSA testing among men with evidence of benign prostatic hyperplasia have not been studied. METHODS: We examined the prevalence and correlates of a self-reported history of PSA testing. In 1994, 33,028 US health professionals without prostate cancer aged 47 to 85 years provided information on prior PSA testing, lower urinary tract symptoms characteristic of benign prostatic hyperplasia, history of prostatectomy, and prostate cancer risk factors. In 1995, a subset of 7,070 men provided additional information on diagnosis and treatment of benign prostatic hyperplasia. RESULTS: From 39% of men in their 50s to 53% of men in their 80s reported PSA testing in the prior year (P <0.0001 for trend with age). Men were more likely to report PSA testing if they had lower urinary tract symptoms characteristic of benign prostatic hyperplasia (age-adjusted odds ratio for severe symptoms 2.2, 95% confidence interval 1.8 to 2.6), a prior history of prostatectomy (age-adjusted odds ratio 1.1, 95% confidence interval 1.02 to 1.2), or a physician diagnosis of benign prostatic hyperplasia (odds ratio 1.9, 95% confidence interval 1.7 to 2.2; adjusted for age, signs or symptoms of benign prostatic hyperplasia, and prostate cancer risk factors). CONCLUSIONS: These US health professionals reported preferential use of PSA testing among men least likely to benefit from early cancer detection (older men) and among men most likely to have a false-positive PSA result (men with benign prostatic hyperplasia). Physician and patient education are needed to promote more rational and selective use of this screening test.

Metabolic control and prevalent cardiovascular disease in non-insulin-dependent diabetes mellitus (NIDDM): The NIDDM Patient Outcome Research Team.

PURPOSE: Cardiovascular disease is a major cause of morbidity and death in non-insulin-dependent diabetes mellitus (NIDDM). While hyperglycemia is clearly related to diabetic microvascular complications, it contribution to large-vessel atherosclerosis is controversial. PATIENTS AND METHODS: We performed an analysis of the association between glycemic control and prevalent cardiovascular disease in 1,539 participants in the NIDDM Patient Outcomes Research Team study who were under usual care in a health maintenance organization. Prevalent cardiovascular disease and its risk factors were identified by self-administered questionnaire. Cardiovascular disease was defined by the presence of coronary heart disease, peripheral vascular disease, and/or cerebrovascular disease. Glycohemoglobin and lipid levels were obtained from a computerized laboratory database. RESULTS: The mean age of participants was 63 years (range 31 to 91); 51% were women. The mean duration of NIDDM was 9 years (range < 1 to 50), 35% took insulin, and 48% took sulfonylureas. Mean glycohemoglobin was 10.6%. Sixty percent had hypertension, 16% currently smoked cigarettes, and the mean total high-density lipoprotein (HDL) cholesterol ratio was 5.7. Fifty-one percent had cardiovascular disease. Cardiovascular disease prevalence remained constant across increasing quartiles of glycohemoglobin for both men and women. In contrast, prevalent cardiovascular disease was associated with established cardiovascular disease risk factors including age (67 versus 59 years, P < 0.0001), hypertension (66% versus 54%, P < 0.0001), current cigarette smoking (17% versus 13%, P < 0.005), and total/HDL cholesterol ratio (5.9 versus 5.6, P < 0.005). Cardiovascular disease was also associated with duration of NIDDM (11 versus 8 years, P < 0.0001). In multiple logistic regression analysis controlling for established cardiovascular disease risk factors and diabetes duration and therapy, glycohemoglobin remained unassociated with cardiovascular disease. CONCLUSIONS: Glycemic control is not associated with prevalent cardiovascular disease in this large population of individuals with NIDDM. Conventional cardiovascular disease risk factors are independently associated with cardiovascular disease and be a more promising focus for clinical intervention to reduce atherosclerotic complications in NIDDM.

Interpreting results of prostate-specific antigen testing for early detection of prostate cancer.

OBJECTIVE: Calculation of likelihood ratios for serum prostate-specific antigen (PSA) levels to discriminate potentially curable prostate cancer in men selected for having benign prostatic hyperplasia (BPH) or in randomly selected men. DESIGN: Retrospective analysis of prospectively measured PSA levels. SETTING: A tertiary referral center, a multicenter randomized controlled trial, and a community-based study, all providing PSA data. PATIENTS: We used PSA measurements from four groups of men aged 50 to 79 years: 276 men with organ-confined prostate cancer treated with radical prostatectomy, 305 randomly selected men without clinical evidence of prostate cancer or a history of surgery for BPH recruited for a community study, 173 men without cancer but with BPH coming to prostatectomy, and 770 men without cancer and with symptoms of BPH enrolled in the North American finasteride clinical trial. MEASUREMENTS AND MAIN RESULTS: Age-standardized, stratum-specific likelihood ratios for organ-confined prostate cancer were calculated separately for unselected men in the community sample and for selected men with BPH (pooling both BPH populations). Likelihood ratios ranged from 0.2 for PSA between 0.0 and 2.0 ng/mL to 54.8 for a PSA level of 10.1 ng/mL or higher in unselected men, but rose to only 2.9 for PSA values of 10.1 ng/mL or higher in men with BPH. Forty percent of the men in the community study had moderate to severe lower urinary tract symptoms. In these men, likelihood ratios ranged from 0.2 for PSA values between 0.0 and 2.0 ng/mL to 17.2 for PSA values of 6.1 ng/mL or higher, while in men with no or mild symptoms, likelihood ratios rose to 26.9 for PSA values of 6.1 ng/mL or higher. CONCLUSIONS: Likelihood ratios for PSA test results allow stratification of men along a continuum of risk for prostate cancer. Likelihood ratios demonstrate that the ability of the PSA test to discriminate potentially curable prostate cancer from BPH is dramatically lower in men selected with lower urinary tract symptoms than in randomly selected men.

Tracking of glycated hemoglobin in the original cohort of the Framingham Heart Study.

Glycated hemoglobin measures average blood glucose over the preceding 2 to 3 months. The authors examined the tracking of the major glycated hemoglobin A1c (HbA1c), over a period of 4 to 6 years. Two HbA1c measurements were obtained between 1986 and 1993 from 639 elderly, presumptively nondiabetic members of the original cohort of the Framingham Heart Study, Framingham, Massachusetts. Mean +/- standard deviation (SD) baseline and follow-up HbA1c were 5.43% +/- 0.7 and 5.71% +/- 0.9, respectively. Intraclass correlation of 0.59 between baseline and follow-up measurements indicated good reliability of a single HbA1c measurement. Ninety-one percent of follow-up measurements were within +/- 20% of baseline value; HbA1c values tended to move 15% closer to the baseline mean over time. There was a modest tendency for HbA1c values to increase with time; the mean difference between measurements was 0.28% +/- 0.7 SD (p < 0.0001). Change in HbA1c was positively associated with age and body mass index at baseline examination, and negatively associated with cigarette smoking, even after controlling for age and body mass index. These effects were very small, however. We conclude that glycated hemoglobin reliably categorizes the glucose control of nondiabetic subjects over a period of 4 to 6 years, confirming its value as an epidemiological measure.