Risk factors for prehypertension in the community: a prospective analysis from the Western New York Health Study.

BACKGROUND AND AIM: Prehypertension is an increasingly highly prevalent condition in the general population, and is associated with an increased risk for coronary heart disease and stroke. However, evidence from population-based studies of the risk factors for prehypertension is scant. We sought to examine the predictors of progression from normotension to prehypertension in a community-based population from Western New York. METHODS AND RESULTS: A longitudinal analysis, over 6 years of follow-up, among 569 men and women (mean age 51.8 years) who were free of prehypertension, hypertension, cardiovascular disease and diabetes at the baseline examination, in the Western New York Health Study (WNYHS). Incident prehypertension at follow-up was defined as systolic blood pressure of 120-139 mm Hg and/or diastolic blood pressure of 80-89 mm Hg. The cumulative six year incidence of prehypertension was 33.5% (189/564). In bivariate analyses, there were several correlates of incident prehypertension, including age, BMI and waist circumference, impaired fasting glucose (IFG), uric acid, and baseline blood pressure levels. After multivariate adjustment, IFG at baseline [odds ratio (OR): 1.70, 95% CI: 1.07-2.69) and weight gain since age 25 (OR: 1.12, 1.04-1.21 per 10 lb increase)] were the strongest significant predictors of prehypertension at follow-up. Neither baseline waist circumference nor change in BMI were predictor variables in models when they were substituted for weight gain. CONCLUSIONS: Results from this study suggest early dysregulation of glucose metabolism and weight gain over the lifespan may represent important risk factors for prehypertension in the general population.

Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians.

BACKGROUND AND AIMS: Glycoprotein 6 (GP6) is a platelet-specific collagen receptor implicated in the thrombotic pathway to acute myocardial infarction (AMI), but a possible genetic relationship between GP6 and AMI is poorly understood. We tested for the genetic association between AMI and single nucleotide polymorphisms (SNPs) in 24 loci, including GP6. METHODS AND RESULTS: We conducted a case-control study of AMI and GP6 in a community-based population (n = 652 cases, 625 controls). We also examined men and women separately and stratified the latter by use of hormone replacement therapy (HRT). Among both sexes, the strongest association was for a protective missense polymorphism (rs1163662) in the GP6 gene (OR = 0.70; Bonferroni-adjusted p < 0.05). SNPs in GP6 were also strongly associated with AMI among women who reported ever taking HRT, but not among women who never took HRT. Haplotype analyses were consistent with the single-SNP findings. CONCLUSIONS: In this sample of white non-Hispanic men and women, several SNPs in GP6 were significantly related to risk of AMI. Development of pharmacologic therapy directed towards platelet activity and thrombosis may reduce the incidence of AMI among at-risk groups.

Impaired fasting glucose and recurrent cardiovascular disease among survivors of a first acute myocardial infarction: evidence of a sex difference? The Western New York experience.

BACKGROUND AND AIMS: There is little epidemiological evidence regarding the association of impaired glucose metabolism with recurrent cardiovascular events. We therefore examined potential sex differences in the effect of impaired fasting glucose (IFG) on recurrent cardiovascular disease (CVD) in a community-based study of survivors of a first acute myocardial infarction (MI). METHODS AND RESULTS: This report focuses on 1226 incident MI cases (28.4% women) discharged alive from area hospitals in the Western New York Acute MI Study (1996-2004). Deaths and underlying cause of death were determined via query of the National Death Index (Plus) Retrieval Program with follow-up through December 31, 2004. Outcomes reported included fatal or non-fatal coronary heart disease (CHD) or coronary revascularization surgery and total stroke. Traditional CHD risk factors and other explanatory variables were determined by clinical examination after the first acute event. Impaired fasting glucose was defined as fasting blood glucose between 100 and 125mg/dl. During a mean follow-up of 4.5 years, there were 91 recurrent events (26.1%) in women and 173 recurrent events (19.7%) in men. After multivariable adjustment, the hazard ratios for recurrent cardiovascular events were 1.96 (95% CI: 1.15-3.16) and 2.59 (1.56-4.30) in women with IFG and with diabetes, respectively, compared to normoglycemic women. Among men, neither IFG nor diabetes was independently related to risk of recurrence. CONCLUSIONS: In this study, IFG was a strong risk factor for recurrent cardiovascular events only among women. These results suggest that increased cardiovascular risk in MI survivors begins at lower glucose levels in women than men.

Is type 2 diabetes a chronic inflammatory/autoimmune disease?

The classification of diabetes mellitus into 2 main types, defined as Type 1 and 2 diabetes (T1DM, T2DM) relies mostly on the requirement of insulin therapy and on the presence of detectable immunologic abnormalities. However, this distinction is far from straightforward and there is considerable overlap between these 2 types of diabetes. Islet cell autoimmunity, which is characteristic of T1DM, appears in fact to be present in up to 10-15% of subjects diagnosed clinically with T2DM. In the UK Prospective Diabetes Study (UKPDS), it was reported that in patients diagnosed with in T2DM, the presence of autoantibodies to the enzyme glutamic acid decarboxylase (GAD) and cytoplasmic islet cell antibodies (ICA) were a predictor of insulin requirement as compared with patients not carrying these autoantibodies. These results are strikingly similar to a number of prospective studies carried out in childhood diabetes. If islet cell autoimmunity is truly present in 10-15% of subjects clinically diagnosed with T2DM, up to two million Americans might have an unidentified autoimmune form of T2DM, a prevalence similar to that of recent onset childhood diabetes. In addition, we found that in a subset of T2DM patients, a pronounced activation of the acute phase response that seems to be associated with islet cell autoimmunity. These results may in part explain the defect in insulin secretion as well as insulin resistance seen in T2DM. The identification of a subgroup of individuals at risk of developing T2DM using autoantibody as well as inflammatory markers is of public health interest, not only for the correct classification of diabetes, but also because immunomodulatory therapeutic strategies could potentially be instituted sufficiently early in a large number of patients diagnosed as having T2DM and most likely delay the onset of insulin requirement and the complications related with hyperglycemia.

Modeling preclinical cardiovascular risk for use in epidemiologic studies: Miami community health study.

To develop a method for assessing preclinical cardiovascular disease risk, models of resting cardiovascular regulation and of insulin metabolic syndrome were derived from information collected from 1991 to 1996 in a culturally heterogeneous sample of 319 healthy men and women (aged 25-44 years) from Miami-Dade County, Florida. The model of resting cardiovascular regulation used 8 noninvasive measures of autonomic and cardiovascular function. Three factors were derived: 1) parasympathetic, 2) inotropy, and 3) systemic vascular resistance. The model of insulin metabolic syndrome used 12 measures assessing body mass, insulin, glucose, and lipid metabolism. Four factors were derived: 1) body mass and fat distribution, 2) glucose level and regulation, 3) insulin level and regulation, and 4) plasma lipid levels. Analyses of the association of the two models revealed that subjects with lower cardiac contractility had greater body mass, higher fasting and postload insulin and glucose levels, and lower insulin sensitivity. Subjects with greater vascular resistance had greater body mass, higher total cholesterol and triglyceride levels, and lower high density lipoprotein cholesterol levels. These findings indicate that preclinical cardiovascular disease risk may involve pathophysiologic processes in which cardiac inotropic and vasodilatory functions are linked to specific aspects of insulin metabolic syndrome.

Insulin resistance and periodontal disease: an epidemiologic overview of research needs and future directions.

Poor periodontal health is known to be associated with Type 2 diabetes mellitus (DM). This relationship and underlying mechanisms are discussed elsewhere in this issue. Less is known concerning the link between the metabolic precursors to DM, including insulin resistance (IR), and its possible association with periodontitis. Indeed, there has been relatively little research to date in human populations concerning periodontal disease, IR, and the subsequent risk of chronic diseases, including DM. This paper will present an epidemiologist's view of how IR may link periodontal disease with DM and suggest several avenues of investigation to help clarify some of the outstanding issues.

Myelodysplastic syndrome with atypical eosinophilia in association with ring chromosome 7. A case report.

The presence of morphologically abnormal eosinophils in the bone marrow and/or peripheral blood has been rarely reported as a prominent feature in myelodysplastic syndromes (MDS). Specific chromosomal aberrations have been observed in such cases. We report a case of a 76-year-old man who presented with chronic, transfusion-dependent anemia. Peripheral blood smear analysis revealed anisocytes, mild leukopenia, and occasional hypersegmented eosinophils. A subsequent bone marrow biopsy and aspiration disclosed hypercellularity, and morphologic abnormalities within the megakaryocyte, erythroid, and myeloid series. The myeloid population was predominantly comprised of eosinophils with varying degrees of dyspoiesis. The constellation of hematologic findings were without a precise categorization according to the FAB classification of myelodysplastic syndromes. Subsequent cytogenetic techniques demonstrated a ring chromosome 7 in all 20 metaphases analyzed in cultured bone marrow cells. Eighty-five-percent of the analyzed cells showed a ring chromosome composed of both the long and short arms: r(7)(p22q36). In the remaining metaphases, the ring was composed of only the short arm: r(7)(p22q10). To our knowledge, these uncommon cytogenetic abnormalities have not been previously reported in association with MDS with morphologically atypical bone marrow or peripheral eosinophilia.

Is fasting leptin associated with insulin resistance among nondiabetic individuals? The Miami Community Health Study.

OBJECTIVE: Whether serum leptin levels are associated with insulin resistance independent of the effects of hyperinsulinemia and adiposity is an important unanswered question. We examined the relationship between the rate of insulin-mediated glucose uptake and serum leptin concentrations among nondiabetic men and women. RESEARCH DESIGN AND METHODS: A cross-sectional analysis was performed among 49 young to middle-aged men and women who participated in the Miami Community Health Study. All participants had measures of insulin resistance (euglycemic-hyperinsulinemic clamp), postchallenge insulin levels, fasting serum leptin levels, and several measures of adiposity. RESULTS: The rate of insulin-mediated glucose uptake (M in milligrams per kilogram per minute) was significantly associated with leptin concentrations in both men (r = -0.83; P < 0.001) and women (r = -0.59; P < 0.001). M was also inversely related to percent body fat and to the 2-h insulin area under the curve (AUC). After covariate adjustment for sex, percent body fat, and AUC, leptin remained a significant correlate of M (P = 0.04). CONCLUSIONS: Cross-sectionally, leptin was significantly associated with insulin resistance in this nondiabetic sample of men and women. There may be a different physiological mechanism to explain the leptin/insulin resistance association apart from the insulin/adiposity link. Confirmatory evidence awaits the results of clinical trials.

Relation of weight and rate of increase in weight during childhood and adolescence to body size, blood pressure, fasting insulin, and lipids in young adults. The Minneapolis Children's Blood Pressure Study.

BACKGROUND: Weight gain is of concern during early development because adult obesity and its cardiovascular consequences appear to have their origins during childhood. Insulin resistance is known to be related to obesity. Thus, weight gain beginning in childhood may influence the development of insulin-induced cardiovascular risk during adulthood. METHODS AND RESULTS: We monitored 679 individuals from 7.7+/-0.1 years of age with repeated measures of height, weight, and systolic blood pressure (SBP) until 23.6+/-0.2 years of age, when blood samples were obtained for measurements of insulin and lipids. Initial childhood weight, body mass index (BMI), and height were significantly correlated with young adult weight, BMI, and height and with fasting insulin, lipids, and SBP. The increases in weight and BMI but not height during childhood were significantly related to the young adult levels of insulin, lipids, and SBP. CONCLUSIONS: These data suggest that weight gain in excess of normal growth during childhood is a determinant of adult cardiovascular risk. The finding in multiple linear regression analysis that weight gain during childhood rather than the childhood weight at 7.7 years of age is significantly related to young adult risk factors suggests that a reduction in weight gain could reduce subsequent levels of cardiovascular risk.

Cigarette smoking, alcohol use, and physical activity in relation to serum leptin levels in a multiethnic population: The Miami Community Health Study.

PURPOSE: To examine the correlates of plasma leptin, including fasting insulin, adiposity, and several health habits and behaviors among a nondiabetic multiethnic population. METHODS: A cross-sectional study was conducted among 25-44 year old African-Americans (n = 126), Cuban-Americans (n = 107), and non-Hispanic whites (n = 189) randomly selected from Dade County Florida. Fasting leptin levels were correlated with fasting insulin, percent body fat, smoking, alcohol use, and physical activity within each sex. Multiple linear regression and analysis of covariance were used to estimate the independent determinants of plasma leptin concentration separately among men and women. RESULTS: Stepwise linear regression analyses revealed statistically significant associations of leptin with percent body fat, fasting insulin, cigarette smoking, and physical activity (both inversely) among men (p < 0.05 for each). Among women, percent body fat, fasting insulin (both positively), cigarette smoking, and alcohol use (inversely) were independent predictors of leptin levels explaining over 70% of the variance. Analyses of covariance revealed that women had higher adjusted mean leptin levels than men (13.1 ng/ml vs. 5.9 ng/ml; p < 0.001), whereas no separate effect of ethnicity was noted. CONCLUSIONS: Although adiposity was the strongest correlate of leptin levels, fasting insulin and several health habits and behaviors were independently associated with leptin. After adjustment for these factors, women had significantly higher mean leptin levels than men. The independent association among leptin and insulin levels is intriguing and suggests additional avenues for epidemiologic research.

Detection of mosaicism in amniotic fluid cultures: a CYTO2000 collaborative study.

PURPOSE: To evaluate the assumptions on which the American College of Medical Genetics (ACMG) Standards and Guidelines for detecting mosaicism in amniotic fluid cultures are based. METHODS: Data from 653 cases of amniotic fluid mosaicism were collected from 26 laboratories. A chi-square goodness-of-fit test was used to compare the observed number of mosaic cases with the expected number based on binomial distribution theory. RESULTS: Comparison of observed data from the in situ colony cases with the expected distribution of cases detected based on the binomial distribution did not reveal a significant difference (P = 0.525). CONCLUSIONS: The empirical data fit the binomial distribution. Therefore, binomial theory can be used as an initial discussion point for determining whether ACMG Standards and Guidelines are adequate for detecting mosaicism.

The relation of fasting insulin to blood pressure in a multiethnic population: the Miami Community Health Study.

PURPOSE: The aim of this study was to examine the associations among fasting insulin, adiposity, waist girth, and blood pressure among a nondiabetic multiethnic population. METHODS: A cross-sectional study was performed among 25-44-year-old African-Americans (n = 159), Cuban-Americans (n = 128), and non-Hispanic whites (n = 207) selected from Dade County, Florida. Fasting insulin levels were correlated with resting blood pressure level within each ethnic group. The separate effects of percentage body fat and waist girth on the association between blood pressure and insulin were analyzed in multiple linear regression and analysis of covariance. RESULTS: Fasting insulin was positively associated with systolic (r = 0.26-0.39; P < 0.01) and diastolic blood pressure (r = 0.19-0.30; P = 0.10 to P < 0.001) among women of all ethnic groups and among non-Hispanic white men (r = 0.27; P < 0.05). Stepwise linear regression analyses revealed statistically significant associations between systolic and diastolic blood pressure and fasting insulin level in non-Hispanic whites independent of other covariates, including sex and percentage body fat (P < 0.001). Fasting insulin was also independently and significantly related to systolic blood pressure among African-Americans (P = 0.02). Among Cuban-Americans, sex and percentage body fat were the main correlates of blood pressure level. Analysis of covariance revealed a relationship between insulin and blood pressure that was independent of waist girth among men and women. CONCLUSIONS: Fasting insulin level and blood pressure were positively associated among African-Americans and non-Hispanic whites. This association was not entirely due to the common association with percentage body fat or waist girth.

Does insulin resistance unite the separate components of the insulin resistance syndrome? Evidence from the Miami Community Health Study.

A number of coronary heart disease risk factors have been identified that often cluster together to increase the risk of macrovascular disease. This cluster is referred to as the insulin resistance syndrome, and the risk factors commonly include dyslipidemia, elevated blood pressure, an android pattern of body fat distribution, and glucose intolerance. Whether hyperinsulinemia or insulin resistance per se provides a common pathway for these metabolic abnormalities is unclear. The authors studied 50 nondiabetic persons who had completed a euglycemic hyperinsulinemic clamp protocol in addition to a 75-g oral glucose tolerance test and other measures of the coronary risk profile. Using principal-component analysis, we reduced nine coronary risk factors to two uncorrelated factors that explained 54.5% of the variance. Factor 1 consisted of positive loadings for uric acid, systolic and diastolic blood pressure, triglyceride concentration, and waist girth and negative loadings for HDL cholesterol and the rate of insulin-mediated glucose disposal (M, in milligrams per kilogram of body weight per minute). M also loaded on factor 2, along with fasting insulin and glucose concentrations, diastolic blood pressure, and waist girth. The observation that M loaded on both factors suggests that a resistance to insulin action may provide the mechanism uniting the features of the insulin resistance syndrome. Hyperinsulinemia with concomitant insulin resistance may be necessary to produce this metabolic derangement, as well as the increased risk of macrovascular complications.

Insulin response in a triethnic population: effects of sex, ethnic origin, and body fat. Miami Community Health Study.

OBJECTIVE: To assess sex and ethnic differences in hyperinsulinemia/insulin resistance and to examine the impact of percent body fat on such differences. RESEARCH DESIGN AND METHODS: A cross-sectional epidemiological study was performed in a normoglycemic population of African-Americans (n = 159), Cuban Americans (n = 128), and non-Hispanic whites (n = 207) who resided in Dade County, Florida, from 1990 to 1995. The insulin area under the curve (AUC) in response to a standard 75-g oral glucose tolerance test (OGTT) was used as an indicator of hyperinsulinemia/insulin resistance. Analysis of covariance was performed to compare sex and ethnic differences in the insulin AUC. Multiple linear regression was used to evaluate the independent correlates of the insulin AUC. RESULTS: After covariate adjustment for percent body fat, men displayed a significantly higher insulin AUC than did women (P < 0.001). African-Americans and Cuban-Americans each had a significantly higher insulin AUC than did non-Hispanic white participants (P = 0.01). Alcohol consumption was inversely related to AUC (P = 0.04). CONCLUSIONS: Despite the greater percentage of body fat in women, the insulin AUC was similar in women and men. After adjustment for the sex difference in percent body fat, women displayed a lower insulin AUC than did men, indicating enhanced insulin sensitivity. These differences by sex and ethnicity in insulin resistance are consistent with established differences in heart-disease risk (i.e., higher in men and African-Americans) and suggest that hyperinsulinemia/insulin resistance may partly underlie such differences.

Insulin sensitivity and blood pressure in a biethnic sample: the Miami Community Health Study.

An association between blood pressure and insulin sensitivity among normotensive African-Americans has not been demonstrated consistently in epidemiologic studies. Part of the discrepancy may be due to studying persons with profound obesity-an insulin-resistant state itself. The association between insulin-mediated glucose uptake (i.e., insulin sensitivity) and blood pressure was examined among 25 nondiabetic African-American and 28 white non-Hispanic persons aged 25-44 years who ranged from normal weight to obese, using the hyperinsulinemic euglycemic clamp technique. In bivariate analyses, insulin sensitivity was inversely related to systolic (p < 0.01) and diastolic blood pressure (p = 0.08) among African-American persons and to diastolic blood pressure among white non-Hispanic subjects (p < 0.05). Covariate adjustment for age and sex had only a marginal effect on these results. When the data were pooled and further adjusted for ethnicity, insulin sensitivity remained significantly associated with both systolic and diastolic blood pressure (p < 0.01 for each). To consider the effect of obesity, body mass index (BMI) was divided at the sample median (26.5 kg/m2) and the analyses were repeated within each stratum. Among those whose BMI was below the median value, each increment in insulin sensitivity was associated with a 2-mmHg decrease in systolic blood pressure (p = 0.02). These results suggest that ethnicity was not a strong effect modifier in this sample and indicated that insulin sensitivity was inversely related to blood pressure level in these normotensive African-American and white, non-Hispanic participants.

The female 'insulin advantage' in a biracial cohort: results from the Miami Community Health Study.

OBJECTIVE: To determine the extent to which gender differences in the rate of insulin-mediated glucose disposal are influenced by differences in body fatness. DESIGN: A cross-sectional study of a biracial sample of men and women drawn from a population-based study. SUBJECTS: Twenty-five 25-44 year old residents of Dade County, FL. Twenty-five African-Americans (14 men and 11 women) and 28 white, nonHispanics (15 men and 13 women). All participants were free of diabetes mellitus (WHO Criteria). MEASUREMENTS: All persons volunteered to undergo a hyperinsulinemic euglycemic clamp procedure to determine the rate of insulin-mediated glucose disposal (insulin sensitivity, M). Several measures of body fatness were quantified and the percentage body fat determined according to published equations. RESULTS: Men and women had similar unadjusted M values. Within each gender and ethnic group M was inversely related to percentage body fat (r = -0.55 to -0.84; p < 0.05). After adjustment for percentage body fat, women were more insulin sensitive than men (10.1 vs 5.1 mg/kg/min among African-Americans and 10.1 vs 6.9 mg/kg/min among white, nonHispanics; p < 0.05 for each). When M was expressed per unit of fat free mass, women were still significantly more insulin sensitive than men (p < 0.05 for each ethnic group). In multivariate analyses, gender and percentage body fat were independently related to M in both ethnic groups accounting for 70% of the variance among African-American participants and 34% of the variance among white nonHispanic participants. CONCLUSION: The similar M values between men and women despite the higher percent body fat among women indicate that women are more insulin sensitive in muscle tissue than men. This was substantiated when M was normalized for fat free mass. This 'insulin advantage' may be related to the lower risk of coronary disease experienced by women and the loss of this advantage may in part underlie the stronger deleterious effects of diabetes that women suffer.

Tracking of elevated systolic blood pressure among lean and overweight adolescents: the Minneapolis Children's Blood Pressure Study.

OBJECTIVE: To determine whether elevated blood pressure tracks to a greater degree in overweight than in lean children. DESIGN: Prospective cohort study. METHODS: We examined 758 adolescents (mean age 13.4 years) who participated in a longitudinal study of blood pressure. The degree of tracking was examined by cross-classification of sex-specific tertiles of systolic blood pressure (SBP) and body mass index determined at baseline and 5 years later. Those children that were in the highest tertile of SBP and body mass index were considered to be 'overweight with elevated blood pressure'. Those that were in the highest tertile of SBP but lowest tertile of body mean index were considered to be 'lean with elevated blood pressure'. RESULTS: Of those boys that were initially classified as lean with elevated blood pressure, 38% remained so classified compared with 54.6% of those that were initially classified as overweight with elevated blood pressure. Among the girls the respective proportions were 48 and 44.2%. The subjects of each sex who were lean with elevated blood pressure were significantly shorter at baseline than their overweight counterparts, and over the follow-up period experienced a greater mean increase in SBP than their overweight peers. This difference was almost totally explained for the boys once the difference in height change was taken into account. For the girls a difference of 5.9 mmHg remained after covariate adjustment for the change in height. CONCLUSION: These results fail to support the hypothesis that blood pressure tracks differently in obese and in lean adolescents, particularly once differences in sexual maturation are considered.

Isolation and characterization of conditionally immortalized astrocyte cell lines derived from adult human spinal cord.

As an approach to develop both oligodendrocytic and astrocytic cell lines from adult human spinal cord, a cellular preparation of highly enriched oligodendrocytes and their precursors was infected with a replication-deficient retrovirus containing DNA sequences encoding the temperature-sensitive mutant of SV40 large T antigen. Six immortal cell lines were obtained. At both permissive (33 degrees C) and non-permissive (38.5 degrees C) temperatures, all cell lines were positive for vimentin, two demonstrated glial fibrillary acidic protein (GFAP) immunoreactivity, and none expressed oligodendrocyte or microglial markers. The 2 GFAP-positive cell lines [human spinal cord (HSC)2 and HSC6] were further characterized. Karyotype analysis revealed that both HSC2 and HSC6 cells showed gain of chromosomal material and structural chromosomal abnormalities. However, at non-permissive temperature both cell lines were indistinguishable from primary human astrocytes by a number of criteria. These properties included glutamine synthetase activity, Na(+)-dependent glutamate uptake, K+ flux, purine-evoked Ca2+ mobilization and entry, and the ability to support neurite outgrowth from embryonic rat retinal explants. The HSC2 and HSC6 cell lines may prove to be valuable models for studying the physiological properties of adult human astrocytes.

The influence of sex and diabetes mellitus on survival following acute myocardial infarction: a community-wide perspective.

The objective of this report was to examine the effects of sex and diabetic status on in-hospital mortality and 12 year survival following hospital discharge among 4109 patients hospitalized between 1974 and 1986 with acute myocardial infarction. Sixteen general hospitals in the Worcester, MA, standard metropolitan statistical area were included. The age-adjusted in-hospital case-fatality rate was significantly higher in diabetic women (23.3%) than in non-diabetic women (18.9%) (p < 0.05) while no significant difference was noted among men. Over a 12 year follow-up period, the relative risk of dying among diabetic men was 1.56 times that for non-diabetic men (95% CI, 1.43, 1.68). Diabetic women were 1.57 times as likely to die as non-diabetic women (95% CI, 1.45, 1.73). Among non-diabetic subjects, men had a 17% excess risk of death compared to women (95% CI, 1.09, 1.25). No significant difference in long-term mortality was noted among diabetic persons. Thus, the "female advantage" observed in the non-diabetic population was eliminated among the diabetic patients. Randomized clinical trials are needed in the diabetic population to identify specific therapies to reduce their increased risk of death.