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Introduction: Diabetic nephropathy (DN) is a form of progressive kidney disease that often leads to end-stage renal disease (ESRD). It is initiated by microvascular complications due to diabetes. Although microalbuminuria (MA) is the earliest clinical indication of DN among patients with type 1 diabetes (T1D), it lacks the sensitivity and specificity to detect the early onset of DN. Recently, microRNAs (miRNAs) have emerged as critical regulators in diabetes as well as various forms of kidney disease, including renal fibrosis, acute kidney injury, and progressive kidney disease. Additionally, circulating extracellular miRNAs, especially miRNAs packaged in extracellular vesicles (EVs), have garnered significant attention as potential noninvasive biomarkers for various diseases and health conditions., Methods: As part of the University of Pittsburgh Epidemiology of Diabetes Complications (EDC) study, urine was collected from individuals with T1D with various grades of DN or MA (normal, overt, intermittent, and persistent) over a decade at prespecified intervals. We isolated EVs from urine and analyzed the small-RNA using NextGen sequencing., Results: We identified a set of miRNAs that are enriched in urinary EVs compared with EV-depleted samples, and identified a number of miRNAs showing concentration changes associated with DN occurrence, MA status, and other variables, such as hemoglobin A1c levels., Conclusion: Many of the miRNAs associated with DN occurrence or MA status directly target pathways associated with renal fibrosis (including transforming growth factor-β and phosphatase and tensin homolog), which is one of the major contributors to the pathology of DN. These miRNAs are potential biomarkers for DN and MA.

Introduction: CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration rate (eGFR) to <60 ml/min per 1.73 m 2 ., Methods: In analyses of 2087 individuals from 6 cohorts (46.4% women; 73.5% with diabetes; mean age, 46.1 years; eGFR ≥ 60 ml/min per 1.73 m 2 , 100%; urinary albumin excretion rate [UAE] ≥20 μg/min, 6.2%), we accounted for cohort, sex, age, mean arterial pressure, diabetes, and eGFR at baseline and expressed associations per 1-SD increment in urinary biomarkers., Results: Over 5 (median) follow-up visits, eGFR decreased more with higher baseline CKD273 than UAE (1.64 vs. 0.82 ml/min per 1.73 m 2 ; P  < 0.0001). Over 4.6 years (median), 390 participants experienced a first renal endpoint (eGFR decrease by ≥10 to <60 ml/min per 1.73 m 2 ), and 172 experienced an endpoint sustained over follow-up. The risk of a first and sustained renal endpoint increased with UAE (hazard ratio ≥ 1.23; P  ≤ 0.043) and CKD273 (≥ 1.20; P  ≤ 0.031). UAE (≥20 μg/min) and CKD273 (≥0.154) thresholds yielded sensitivities of 30% and 33% and specificities of 82% and 83% ( P  ≤ 0.0001 for difference between UAE and CKD273 in proportion of correctly classified individuals). As continuous markers, CKD273 ( P  = 0.039), but not UAE ( P  = 0.065), increased the integrated discrimination improvement, while both UAE and CKD273 improved the net reclassification index ( P  ≤ 0.0003), except for UAE per threshold ( P  = 0.086)., Discussion: In conclusion, while accounting for baseline eGFR, albuminuria, and covariables, CKD273 adds to the prediction of stage 3 chronic kidney disease, at which point intervention remains an achievable therapeutic target.

Background: Although studies to date have confirmed the association between nutrition and frailty, the impact of dietary intake and dietary patterns on survivorship in those with frailty is yet to be examined in a well-powered cohort with validated frailty status. Moreover, previous studies were limited by measurement error from dietary self-reports. Objective: We derived biomarker-calibrated dietary energy and protein intakes to address dietary self-report error. Using these data, we then evaluated the association of mortality in older women with frailty and dietary intake and healthy diet indexes, such as the alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII). Design: The analytic sample included 10,034 women aged 65-84 y with frailty and complete dietary data from the Women's Health Initiative Observational Study. Frailty was assessed with modified Fried's criteria. Dietary data were collected by food-frequency questionnaire. Results: Over a mean follow-up period of 12.4 y, 3259 (31%) deaths occurred. The HRs showed progressively decreased rates of mortality in women with higher calibrated dietary energy intakes ( P- trend = 0.003), higher calibrated dietary protein intakes ( P- trend = 0.03), higher aMED scores ( P- trend = 0.006), and higher DASH scores ( P- trend = 0.02). Although the adjusted point estimates of HRs (95% CIs) for frail women scoring in the second, third, and fourth quartiles on DII measures were 1.15 (1.03, 1.27), 1.28 (1.15, 1.42), and 1.24 (1.12, 1.38), respectively, compared with women in the first quartile, no overall effect was observed across quartiles ( P- trend = 0.35). Subgroup analyses by chronic morbidity or smoking status or by excluding women with early death did not substantially change these findings. Conclusions: The current study highlights the importance of nutrition in older, frail women. Diet quality and quantity should be considered in managing persons with frailty., (© 2017 American Society for Nutrition.)

Background: Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes., Methods: Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1., Findings: 1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18-55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups., Interpretation: Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.

Background: Diabetic retinopathy remains a leading cause of visual loss in people of working age. We examined whether candesartan treatment could slow the progression and, secondly, induce regression of retinopathy in people with type 2 diabetes., Methods: We did a randomised, double-blind, parallel-group, placebo-controlled trial in 309 centres worldwide. We recruited normoalbuminuric, normotensive, or treated hypertensive people with type 2 diabetes with mild to moderately severe retinopathy and assigned them to candesartan 16 mg once a day or placebo. After a month, the dose was doubled to 32 mg once per day. Investigators and patients were unaware of the treatment allocation status. Progression of retinopathy was the primary endpoint, and regression was a secondary endpoint. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00252694., Findings: 1905 participants (aged 37-75 years) were randomised to candesartan (n=951) or placebo (n=954). 161 (17%) patients in the candesartan group and 182 (19%) in the placebo group had progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale. The risk of progression of retinopathy was non-significantly reduced by 13% in patients on candesartan compared with those on placebo (hazard ratio [HR] 0.87, 95% CI 0.70-1.08, p=0.20). Regression on active treatment was increased by 34% (1.34, 1.08-1.68, p=0.009). HRs were not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial. An overall change towards less severe retinopathy by the end of the trial was observed in the candesartan group (odds 1.17, 95% CI 1.05-1.30, p=0.003). Adverse events did not differ between the treatment groups., Interpretation: Treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy.

Purpose: Anemia tends to be more severe and occur earlier in individuals with diabetic nephropathy. We thus examined whether hemoglobin (HGB) relates to end-stage renal disease (ESRD), coronary artery disease (CAD), and all cause mortality in type 1 diabetes (T1D) subjects with overt nephropathy (ON)., Methods: We prospectively followed up 174 individuals with childhood-onset T1D and ON (albumin excretion rate >200 microg/min in multiple urine samples) from the Pittsburgh Epidemiology of Diabetes Complications Study cohort for 12 years. One hundred forty persons had ON at baseline, whereas another 34 were followed up from their incidence of ON as determined by biennial examinations., Results: Baseline HGB inversely predicted ESRD (hazard ratio [HR] = 0.70, 0.61-0.80) and mortality (HR = 0.84, 0.72-0.98), but not CAD (HR = 0.91, 0.79-1.0). After adjustment for sex, diabetes duration, and other known risk factors, HGB remained significantly predictive of ESRD (HR = 0.72, 0.61-0.85), but not CAD (HR = 0.94, 0.80-1.10) or overall mortality (HR = 0.92, 0.77-1.10). However, in those who never progressed to ESRD, HGB was significantly predictive of mortality (HR = 0.59, 0.39-0.89). After including ESRD as a time-dependent, HGB was significantly predictive of overall mortality (HR = 0.75, 0.59-0.93). Gender-specific analyses, although limited by sample size, suggests similarity in the association between absolute HGB and ESRD in both genders, but differences for CAD and mortality., Conclusion: Our data suggest that in T1D with ON, a higher HGB level is associated not only with reduced risk of ESRD, but also of mortality, particularly in those who do not develop ESRD. HGB, even in the clinically normal range, is able to predict long-term complications in those with T1D and ON.

Enteropathic arthritis is a form of arthritis associated with the chronic inflammatory bowel diseases, ulcerative colitis, and Crohn's disease. This form of arthritis is classified as one of the group of seronegative spondyloarthropathies, which also includes psoriatic arthritis, reactive arthritis, and idiopathic ankylosing spondylitis. Joint involvement also occurs with other gastrointestinal diseases such as Whipple's disease, celiac disease, and following intestinal bypass surgery for morbid obesity. In these conditions, abnormal bowel permeability and immunologic and genetic influences are probably involved in the pathogenesis of the joint disease, although the exact mechanisms remain uncertain.

Objective: The Oral Health Science Institute at the University of Pittsburgh has completed a cross-sectional epidemiologic study of 406 subjects with type 1 diabetes and 268 control subjects without diabetes that assessed the associations between oral health and diabetes. This report describes the prevalence of dry-mouth symptoms (xerostomia), the prevalence of hyposalivation in this population, and the possible interrelationships between salivary dysfunction and diabetic complications., Study Design: The subjects with diabetes were participants in the Pittsburgh Epidemiology of Diabetes Complications study who were enrolled in an oral health substudy. Control subjects were spouses or best friends of participants or persons recruited from the community through advertisements in local newspapers. Assessments of salivary function included self-reported xerostomia measures and quantification of resting and stimulated whole saliva flow rates., Results: Subjects with diabetes reported symptoms of dry mouth more frequently than did control subjects. Salivary flow rates were also impaired in the subjects with diabetes. Regression models of potential predictor variables were created for the 3 self-reported xerostomia measures and 4 salivary flow rate variables. Of the medical diabetic complications studied (ie, retinopathy, peripheral and autonomic neuropathy, nephropathy, and peripheral vascular disease), only neuropathy was found to be associated with xerostomia and decreased salivary flow measures. A report of dry-mouth symptoms was associated with current use of cigarettes, dysgeusia (report of a bad taste), and more frequent snacking behavior. Xerogenic medications and elevated fasting blood glucose concentrations were significantly associated with decreased salivary flow. Resting salivary flow rates less than 0.01 mL/min were associated with a slightly higher prevalence of dental caries. Subjects who reported higher levels of alcohol consumption were less likely to have lower rates of stimulated salivary flow., Conclusions: Subjects with type 1 diabetes who had developed neuropathy more often reported symptoms of dry mouth as well as symptoms of decreased salivary flow rates. Because of the importance of saliva in the maintenance and the preservation of oral health, management of oral diseases in diabetic patients should include a comprehensive evaluation of salivary function.

Background: It has been proposed that hyperlipidemia contributes to the progression of renal disease. A large trial has not been performed; however, a number of small, controlled trials have been reported. We examined the effects of antilipemic agents on glomerular filtration rate and proteinuria or albuminuria in patients with renal disease., Methods: We used Medline, abstracts from scientific meetings, and bibliographies from recent reviews and scientific reports to locate pertinent studies. Thirteen prospective controlled trials examining the effects of antilipemic agents on renal function, proteinuria, or albuminuria were included. Studies were published as full reports or abstracts and were at least three months in duration. For five of the studies, individual patient data were obtained. Other summary data were independently extracted from the published reports by two investigators and included study quality, subject characteristics, cause of renal disease, change in serum cholesterol, blood pressure, glomerular filtration rate, proteinuria, and albuminuria., Results: There was a lower rate of decline in glomerular filtration rate with treatment compared with controls (treated controls, 0.156 mL/min/month; 95% CI, 0.026 to 0. 285 mL/min/month, P = 0.008). The study results were statistically homogeneous, and in a regression analysis, the effect of treatment on glomerular filtration rate did not correlate with study quality, the percentage change in cholesterol, the type of lipid-lowering agent, or the cause of renal disease. However, longer follow-up correlated with the amount of improvement in glomerular filtration rate from treatment (P = 0.007). There was a tendency for a favorable effect of treatment on protein or albumin excretion [Ln (treatment) - Ln (control) = -0.248, 95% CI, -0.562 to 0.064, P = 0. 077]. However, these results were statistically heterogeneous between studies (P < 0.001). No obvious explanation for this heterogeneity was apparent in a regression analysis examining potential reasons for differences in study results., Conclusions: Lipid reduction may preserve glomerular filtration rate and may decrease proteinuria in patients with renal disease.

Background: Diabetes is a chronic metabolic disease known to affect oral disease progression. The authors surveyed health behaviors essential for preventing dental and periodontal diseases and maintaining oral health is a population of adult patients with type 1 (insulin-dependent) diabetes. The goals of this study were to assess these patients' oral health behaviors, access to dental care and need for improved health education., Methods: As part of a dental and periodontal examination, 406 subjects with type 1 diabetes completed a questionnaire regarding their oral health attitudes, behaviors and knowledge. The authors also evaluated 203 age-matched nondiabetic control subjects., Results: The authors found that diabetic subjects' tobacco use and oral hygiene behaviors were similar to those of the nondiabetic control subjects. Diabetic subjects, however, more frequently reported the cost of dental care as a reason for avoiding routine visits. Most of these subjects were unaware of the oral health complications of their disease and the need for proper preventive care., Conclusions: Patients with diabetes appear to lack important knowledge about the oral health complications of their disease. The results of this survey did not indicate improved prevention behaviors among the subjects with diabetes compared with nondiabetic control subjects., Clinical Implications: Dentists have an opportunity and the responsibility to promote good oral health behaviors such as regular dental examinations, proper oral hygiene and smoking cessation that may significantly affect the oral health of their diabetic patients.

Objective: To assess the prevalence of Candida albicans and oral infection with Candida in patients with insulin-dependent diabetes mellitus (IDDM)., Study Design: This cross-sectional study compared the prevalence of candidiasis in 405 subjects with IDDM and 268 nondiabetic control subjects. Assessments included evidence of clinical manifestations of candidiasis and a quantitative measure of Candida pseudohyphae in a cytologic smear from the midline posterior dorsal tongue., Results: More subjects with IDDM than control subjects without IDDM (15.1% vs 3.0%) were found to have clinical manifestations of candidiasis, including median rhomboid glossitis, denture stomatitis, and angular cheilitis. IDDM subjects were also more likely to have any Candida pseudohyphae in their cytologic smears (23.0% vs 5.7%; P <.0001), as well as pseudohyphae counts of >10/cm(2) (7.1% vs 0.8%; P <.0001). Diabetic subjects with median rhomboid glossitis were more likely to have a longer duration of IDDM and complications of nephropathy and retinopathy. Denture stomatitis was associated with smoking, retinopathy, higher Candida counts, poor glycemic control, and longer duration of IDDM. A multivariate regression analysis found 3 factors to be significantly associated with the presence of Candida pseudohyphae in the subjects with IDDM: current use of cigarettes (odds ratio, 2:4), use of dentures (odds ratio, 2:3), and elevated levels of glycosylated hemoglobin (odds ratio, 1:9). The use of antimicrobials, immunosuppressants, or drugs with xerostomic side effects was not related to the presence of Candida., Conclusions: Candida pseudohyphae and oral soft tissue manifestations of candidiasis were more prevalent in subjects with IDDM than in control subjects without diabetes. The presence of Candida pseudohyphae was significantly associated with cigarette smoking, use of dentures, and poor glycemic control.

Objective: A large epidemiologic study on oral health has found that several oral soft tissue lesions were more prevalent in subjects with insulin-dependent diabetes mellitus than in control subjects without diabetes. Our objective in part I of this article is to characterize those lesions not associated with Candida., Study Design: This cross-sectional study determined the prevalence and characteristics of oral soft tissue diseases identified during a comprehensive oral evaluation of 405 adult subjects with diabetes and 268 control subjects without diabetes., Results: Twenty specific oral soft tissue lesions were identified. Nearly twice as many subjects with diabetes as subjects without diabetes were found to have one or more oral soft tissue lesions (44.7% vs 25.0%; P <.0001). Subjects with diabetes also had significantly higher prevalence rates for 7 lesions, 3 of which were non-candidal: fissured tongue, irritation fibroma, and traumatic ulcers. (Four lesions generally associated with Candida infection-median rhomboid glossitis, denture stomatitis, generalized atrophy of the tongue papillae, and angular cheilitis-will be described in part II of this article.) There were no differences found between the subjects with diabetes and the control subjects for lichen planus, gingival hyperplasia, or salivary gland disease., Conclusions: Oral soft tissue lesions were seen more frequently in subjects with insulin-dependent diabetes than in the control subjects. Characterization of 3 non-candidal lesions suggests that they are associated with trauma, delayed healing, or both.

In the Type 1 diabetes population, coronary heart disease (CHD) and lower-extremity arterial disease (LEAD) are the two common macrovascular complications leading to early mortality and morbidity. However, it is not clear if these two complications share the same risk factors. The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study prospectively examined and compared the risk factors for LEAD and CHD (including CHD morbidity and mortality). EDC subjects (332 men and 325 women), all diagnosed at Children's Hospital of Pittsburgh between 1950 and 1980, were first examined at baseline (1986-1988), and then biennially, for diabetes complications and their risk factors. Data used in the current analysis were from the first 6 years of follow-up, 98% provided at least some follow-up data for these analyses. CHD was defined as the presence of angina (diagnosed by the EDC examining physician) or a history of confirmed myocardial infarction or CHD death. An ankle-to-arm ratio of less than 0.9 at rest was considered to be evidence of LEAD. Among 635 subjects without CHD at baseline, 57 developed CHD (1.69/100 person-years), and among 579 without LEAD at baseline, 70 developed LEAD (2.31/100 person-years). CHD incidence rate was slightly higher in males, while LEAD incidence rate was slightly higher in females. Compared to non-incident cases, subjects who developed either complication were older, had a longer diabetes duration, higher LDL and total cholesterol, and were more likely to be hypertensive. In multivariate analyses, hypertension, low HDL cholesterol level, high white cell count, depression, and nephropathy were the independent risk factors for CHD (including morbidity and mortality). For LEAD, higher HbA1 level, higher LDL cholesterol level and smoking were the important contributing factors. In conclusion, the risk factor patterns differ between the two vascular complications. Glycemic control does not predict CHD overall but does predict LEAD, while hypertension and inflammatory markers are more closely related to CHD than to LEAD.

Background: We aimed to compare the prevalence of abnormal glucose tolerance identified by the 1985 WHO and the 1997 American Diabetes Association (ADA) diagnostic categories based on information collected in the Cardiovascular Health Study, an epidemiological study of elderly people., Methods: We measured glucose concentrations during fasting and 2 h after a 75 g oral glucose-tolerance test in participants aged 65-100 years in the Cardiovascular Health Study. From a 1989 cohort, we analysed the glucose measurements of 4515 individuals without a previous diagnosis of diabetes and of 262 additional measurements from an African-American cohort recruited in 1992-93., Findings: In the 1989 cohort, the prevalence of untreated diabetes with ADA diagnostic fasting criteria was 7.7% versus a prevalence of 14.8% by the WHO criteria. In the African-American cohort, the prevalence of untreated diabetes was 2.7% with ADA criteria and 11.8% with WHO criteria. 3509 (77.7%) of the 4515 participants in the 1989 cohort had normal glucose concentrations according to ADA fasting criteria, compared with 2401 (53.2%) according to WHO criteria. In the African-American cohort, the corresponding numbers were 239 (91.2%) versus 153 (58.4%). All differences in prevalence of abnormal glucose tolerance between ADA and WHO classifications were significant (p<0.0001)., Interpretation: Among elderly individuals, there was a significant difference in the prevalence of diabetes identified by the WHO diagnostic criteria based on oral glucose-tolerance test and the ADA fasting criteria. Consequently, many individuals currently classified as non-diabetic according to ADA criteria would previously have had a diagnosis of diabetes according to WHO criteria. Longitudinal studies are needed to assess the value of the criteria in the identification of individuals at increased risk of diabetes-associated chronic complications.

Administration of prophylactic antibiotics to a dental patient with a history of heart murmur, rheumatic fever or mitral valve prolapse should be based on a reliable diagnosis of heart valve disease. The authors conducted a study of 68 diabetic patients who reported having these conditions and found that at least 65 percent of these patients actually had no evidence of a pathological heart murmur during two previous physical examinations. They concluded that a self-reported history of heart valve disease should not be the sole criterion for antibiotic premedication.

3-Deoxyglucosone (3DG), a reactive dicarbonyl, is an important intermediate in the formation of advanced glycation end products (AGEs). The AGEs are particularly important in diabetes since they have been correlated with the development of diabetic complications. Consequently, measurements of 3DG are likely to provide valuable insights into the role of this metabolite in the etiology of diabetic complications. While several methods of 3DG quantitation in human plasma have been previously published, a significant discrepancy (over 30-fold) exists in the reported values. Knecht et al. (Arch. Biochem. Biophys. 294, 130-137, 1992) have reported the levels of plasma 3DG in normoglycemics to be 61 nM, using a GC/MS procedure. In contrast to this, Niwa et al. (Biochem. Biophys. Res. Commun. 196, 837-843, 1993) reported 3DG levels to be 1800 nM in normoglycemics, using a totally independent GC/MS method. To resolve this disagreement and fill the need for a robust assay for this dicarbonyl, suitable for absolute quantitation, a GC/MS procedure was devised for its measurement. Plasma samples were deproteinized either by ultrafiltration or by addition of ethanol as described by Niwa et al. (Biochem. Biophys. Res. Commun. 196, 837-843, 1993). 3DG in the ultrafiltrate or the supernatant was conjugated with 2,3-diamino-naphthalene to produce a stable adduct which was then converted to a silyl ether and analyzed by GC/MS. The analyte was monitored by selected ion monitoring at an m/z of 295 and 306 and quantitated using an internal standard of [U-13C]3DG. Using this approach, 3DG levels in plasma deproteinized by ultrafiltration were found to be significantly elevated from 58.5 +/- 14 (SD) nM in normoglycemics to 98.5 +/- 34 (SD) nM in type I diabetics. When deproteinization of the plasma was carried out using ethanol, the levels of 3DG from normoglycemic plasma were similar to those reported by Niwa et al. (1710 +/- 750 (SD) nM). These results suggest that 3DG levels measured by ultrafiltration may represent the free circulating 3DG and those obtained by ethanol extraction may represent aform of 3DG bound to a macromolecule (presumbaly protein).

Autoimmune thyroiditis is the most common cause of subclinical hypothyroidism in North America, is more common in women than men, and is a risk factor for the development of coronary heart disease (CHD). We measured thyroid-stimulating hormone (TSH) and two thyroid antibodies, thyroid peroxidase and thyroglobulin, in stored sera of the participants (aged 44 to 54 years) of the Healthy Women Study. We selected 254 samples from the premenopausal baseline examination in 1983 to 1985 and from a follow-up examination that occurred an average of 5.7 years later (range, 3 to 7.7 years). At follow-up, 95 women remained premenopausal, 98 had ceased menstruating for at least 12 months, and 61 were taking postmenopausal hormone therapy. Overall, the prevalence of the thyroid antibodies in this healthy population was high at both time points (21 to 26%). Women with antibodies had higher TSH concentrations than did those with no antibodies (2.68 +/- 1.3 versus 1.51 +/- .73 mU/L, P < 0.001); this relationship was statistically significant even after excluding those with subclinical hypothyroidism (TSH > 6.0 mU/L). TSH and antibody levels did not differ by menopausal status or hormone therapy use at follow-up. Given the high prevalence of thyroid antibodies among healthy middle-aged women, long-term follow-up is warranted to ascertain whether the presence of antibodies is associated with subsequent excess risk of disease, in particular, CHD.

Cross-sectional data from the Epidemiology of Diabetes Complications Study were used to examine the relationships between waist to hip circumference ratio (WHR) and the presence of diabetes complications in IDDM adults ages 18-45 years (N = 586). Significantly higher WHRs were observed among both genders with proliferative retinopathy or peripheral vascular disease and only among males with either neuropathy or nephropathy compared to those free of these complications. Logistic regression to determine the strength of association between WHR and each complication demonstrated that although WHR was significantly related to each complication (except nephropathy among females), WHR was only independently related to neuropathy in males and PVD in females in the final model when hypertension, LDL- and HDL-cholesterol and fibrinogen were included. These findings suggest that WHR acts as a marker of risk for diabetes complications mainly through an influence on other complication risk factors.

The objective of this study was to examine whether fasting serum insulin is a predictor of coronary heart disease in high-risk US men, and whether any such predictive role explains the enhanced cardiovascular risk seen in subjects with the apolipoprotein (Apo) E 3/2 phenotype. This was a nested case-control study of participants in the Multiple Risk Factor Intervention Trial. Ninety-four subjects who died from coronary heart disease (post-trial follow-up) and 114 case patients with myocardial infarction (during trial) were compared to control subjects (n = 414) matched (1:2) by age, center, randomization date, and intervention group. Overall, fasting serum insulin at baseline was not associated with case-control status. (Means for cases versus controls: 16.8 and 16.6 microU/mL), although serum insulin showed significant correlations with low-density-lipoprotein cholesterol, triglycerides, and uric acid. When stratified by the three Apo E phenotypes, 3/2, 3/3, 3/4, a significant association of fasting insulin with case-control status was seen for Apo E 3/2 individuals (19.9 versus 14.5 microU/mL; P = 0.02) but not for those with the other two phenotypes. Though fasting insulin is not a risk factor overall in this high-risk male population, it appears to contribute to cardiovascular risk in those with the Apo E 3/2 phenotype but does not explain the increased risk seen in these subjects. This new finding, if confirmed, may throw further light on the role of insulin in atherosclerosis.

The relationship between leisure-time physical activity and diabetes complications was examined in 628 individuals with insulin-dependent diabetes mellitus. Neuropathy was based upon clinical exam; retinopathy by fundus photographs; nephropathy by urine samples and macrovascular disease by clinician diagnosis. Past week physical activity was found to be inversely related to complication status but since current inactivity could be the result of the complications, historical activity (estimated leisure activity during ages 14-17) was also examined in relation to complication status. Males reporting higher levels of historical physical activity had a significantly lower prevalence of nephropathy and neuropathy but not retinopathy as demonstrated by multivariate analysis (controlling for duration of disease, age, and current activity levels). The lack of similar findings in women may be due to their low levels of reported physical activity. The consistent relationship between historical leisure physical activity and development of complications in males suggests that activity may be protective or at least not detrimental to the individual with insulin-dependent diabetes.

We report results from 120 (25- to 34-year-old) participants in a neuropathy substudy of subjects with insulin-dependent diabetes mellitus (IDDM) taking part in a cohort follow-up study. Diabetic neuropathy was evaluated by quantitative sensory testing, nerve conduction studies, and clinical examination. Mean quantitative sensory thresholds differed significantly by clinical category of abnormal sensation and ankle reflex activity. Mean sural and peroneal amplitudes and conduction velocities were also significantly lower for subjects classified as having abnormal ankle reflex activity. Modeling potential correlates in logistic analyses showed glycemic control, triglyceride levels, and hypertension status to be independently associated with clinically overt neuropathy. Similar lipid and hemodynamic parameters were associated with abnormality by any single assessment method used to define neuropathy. Although follow-up is needed to resolve the best assessment methods for determining neuropathy, these results suggest that good glycemic control as well as control of blood pressure and lipids is advisible.

Elevated fasting insulin is an independent risk factor for hyperlipidemia, hypertension, and cardiovascular disease, but determinants of insulin other than age and body mass remain poorly described. Potentially modifiable factors associated with insulin were identified by correlating anthropometric, dietary and physical activity data in the CARDIA cohort of 2643 black and 2472 white men and women aged 18-30 years. Insulin was positively correlated with serum glucose, body mass index (BMI), skinfold thickness, waist/hip ratio and sucrose intake, and negatively correlated with heavy physical activity score, treadmill exercise duration, and magnesium intake (each p less than 0.01). After adjustment for other covariates, the positive association of insulin with waist/hip ratio, skinfold thickness, and sucrose intake remained in the group as a whole, as did the negative associations with magnesium and treadmill duration. These relationships provide insight into potentially modifiable factors affecting insulin levels, and should be considered in interpreting associations between insulin levels and cardiovascular disease.

Lipoprotein changes in diabetes are discussed from both a pathophysiologic and clinical viewpoint. Though differences in concentrations are often small and vary according to the type of diabetes, other changes in lipoprotein metabolism are presented. The interrelationships between diabetes, insulin, and heart disease are also discussed, with the central role of insulin being stressed. Finally, the clinical management of lipid disorders in diabetes is addressed.

The Rose Questionnaire has had high specificity and variable sensitivity when compared to physician identification of the symptom complex of angina pectoris. We assessed the accuracy of a supplemented Rose Questionnaire in a series of 198 patients by comparing the Questionnaire to exercise thallium test evidence of coronary artery disease. The Rose diagnosis of angina had 26% sensitivity, 79% specificity, 42% positive predictive value, and 65% negative predictive value. The Rose diagnosis of myocardial infarction had 26% sensitivity and 90% specificity. The Rose diagnosis of angina or infarction yielded a sensitivity of 44%, specificity of 72%, positive predictive value of 67%, and negative predictive value of 50%. Supplemental questions designed to identify atypical ischemic pain led to increased sensitivity of up to 68% that was offset by decreased specificity. While the Questionnaire's sensitivity for coronary disease was greater for women than men (57 vs 40%), the overall accuracy was the same because specificity was lower (63 vs 80%).

A study was performed to determine the relationship between level of long-term antecedent diabetic control and early diabetic retinopathy changes. Fifty-eight insulin dependent diabetics aged 14 to 17 1/2 years, with duration of diabetes of at least 8 years, were studied. Glycosylated hemoglobins were assessed a mean of 8.5 times per patient, over a mean period of 3.1 years, representing 28% of the mean duration of diabetes in this patient population. Fluorescein angiography, obtained according to a standardized technique, was assessed in masked fashion for number of microaneurysms, presence of abnormal areas of capillary nonperfusion, and presence of intraretinal dye leakage. Sixty-four percent of the study population showed some evidence of retinopathy. There was a high correlation found between degree of metabolic control as measured by glycosylated hemoglobin level, and presence of early retinopathy changes as defined by angiography.

Rowachol, a proprietary choleretic containing 6 pure monoterpenes markedly elevates serum HDL cholesterol (SHDL-C) concentrations in man. The concentration of SHDL-C showed a progressive increase in 16 patients treated with 6-9 capsules of Rowachol daily for periods of 2-28 weeks. There was no accompanying significant change in the concentrations of serum total cholesterol or triglyceride. In view of the significant inverse relationship between SHDL-C concentration and the risk of developing ischaemic heart disease, it is suggested that Rowachol and possibly other terpenes merit further investigation as possible therapeutic agents in the prevention and treatment of atheroma.