Association of physical activity with all-cause mortality and incident and prevalent cardiovascular disease among patients with type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: The aim of this study was to examine the association of physical activity (PA) with all-cause mortality and incident and prevalent cardiovascular disease (CVD) among patients with type 1 diabetes. METHODS: The EURODIAB Prospective Complications Study is a cohort including 3,250 male and female patients with type 1 diabetes (mean age 32.7 ± 10.2 years) from 16 European countries, of whom 1,880 participated in follow-up examinations. In analysis 1 (longitudinal), the association of baseline PA (based on the reported number of hours per week spent in mild, moderate and vigorous PA) with all-cause mortality and incident CVD was examined by performing survival analysis. In analysis 2 (cross-sectional), we focused on the association between PA at follow-up (data on sports, walking distance and regular bicycling) and prevalent CVD by performing logistic regression analysis. Adjustments were made for age, sex, BMI, smoking, consumption of alcohol, consumption of certain nutrients and diabetic complications. RESULTS: Analysis 1 (longitudinal): participation in moderate or vigorous PA once a week or more was borderline inversely associated with all-cause mortality (men and women combined) (HR 0.66, 95% CI 0.42, 1.03) and incident CVD (women only) (HR 0.66, 95% CI 0.40, 1.08). No association was found in men. Analysis 2 (cross-sectional): total PA (indexed by sports, walking, bicycling) and distance walked were inversely associated with prevalent CVD (OR(totalPA) 0.66, 95% CI 0.45, 0.97; and OR(walking) 0.61, 95% CI 0.42, 0.89). CONCLUSIONS/INTERPRETATION: PA showed a borderline inverse association with both all-cause mortality (both sexes) and incident CVD (women only) in patients with type 1 diabetes. Since this is an under-researched clinical population, future longitudinal studies with objective PA measurements are needed to expand on these results.

Unhealthy dietary patterns associated with inflammation and endothelial dysfunction in type 1 diabetes: the EURODIAB study.

BACKGROUND AND AIMS: A healthy diet has been inversely associated with endothelial dysfunction (ED) and low-grade inflammation (LGI). We investigated the association between nutrient consumption and biomarkers of ED and LGI in type 1 diabetes. METHODS AND RESULTS: We investigated 491 individuals. Nutrient consumption and lifestyle risk factors were measured in 1989 and 1997. Biomarkers of ED (von Willebrand factor, soluble vascular cell adhesion molecule-1 and soluble endothelial selectin) and LGI (C-reactive protein, interleukin 6 and tumour necrosis factor α) were measured in 1997 and averaged into Z-scores. The nutrient residual method was used to adjust individual nutrient intake for energy intake. Data were analysed with generalised estimation equations. We report increments/decrements in nutrient consumption, averaged over time, per +1 standard deviation (SD) of 1997 ED or LGI Z-scores, after adjustment for sex, age, duration of diabetes, investigation centre, body mass index, energy intake, smoking behaviour, alcohol consumption, and each of the other nutrients. One SD elevation in ED Z-score was associated with a diet lower in fibre [ß(95%CI);-0.09(-0.18;-0.004)], polyunsaturated fat [-0.18(-0.31;-0.05)] and vegetable protein [-0.10(-0.20;-0.001)]. For the LGI Z-score results showed associations with fibre [-0.09(-0.17;-0.01)], polyunsaturated fat [-0.14(-0.24;-0.03)] and cholesterol [0.10(0.01; 0.18)]. CONCLUSION: In type 1 diabetes, consumption of less fibre, polyunsaturated fat and vegetable protein, and more cholesterol over the study period was associated with more ED and LGI. Following dietary guidelines in type 1 diabetes may reduce cardiovascular disease risk by favourably affecting ED and LGI.

Dietary saturated fat and fibre and risk of cardiovascular disease and all-cause mortality among type 1 diabetic patients: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: Low adherence to recommendations for dietary saturated fatty acid (SFA) and fibre intake in patients with type 1 diabetes mellitus may heighten their increased risk of cardiovascular disease (CVD) and mortality. We examined the relationship of SFA and total, soluble and insoluble fibre with incident CVD and all-cause mortality in type 1 diabetic patients. METHODS: A prospective cohort analysis was performed in 2,108 European type 1 diabetic patients aged 15-60 years who were free of CVD at baseline and enrolled in the EURODIAB Prospective Complications Study (51% male). Diet was assessed from a standardised 3 day dietary record. HR were calculated using Cox proportional hazards models. RESULTS: During a mean follow-up of 7.3 years, 148 incident cases of fatal and non-fatal CVD and 46 all-cause deaths were documented. No statistically significant association was found between SFA and CVD and all-cause mortality. Total dietary fibre, per 5 g/day, was associated with lower all-cause mortality risk (HR 0.72; 95% CI 0.55, 0.95). This association was stronger for soluble fibre (per 5 g/day, HR 0.34; 95% CI 0.14, 0.80) compared with insoluble fibre (per 5 g/day; HR 0.66; 95% CI 0.45, 0.97). Similar results were found for the association with CVD. CONCLUSIONS/INTERPRETATION: This study suggests that reported dietary SFA is not significantly associated with CVD and all-cause mortality in type 1 diabetic patients. On the contrary, higher dietary fibre consumption, especially soluble fibre, within the range commonly consumed by type 1 diabetic patients, may contribute to the prevention of CVD and all-cause mortality in type 1 diabetic patients.

Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.

AIMS/HYPOTHESIS: The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy. METHODS: Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies). RESULTS: More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group. CONCLUSIONS/INTERPRETATION: The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694. FUNDING: The study was funded jointly by AstraZeneca and Takeda.

Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule.

AIMS/HYPOTHESIS: Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria. METHODS: Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study). RESULTS: Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively). CONCLUSIONS/INTERPRETATION: We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications.

Helping students become the medical teachers of the future--the Doctors as Teachers and Educators (DATE) Programme of Barts and the London School of Medicine and Dentistry, London.

CONTEXT: In the United Kingdom (UK), learning about teaching is an integral part of the General Medical Council's recommendations for the undergraduate medical curriculum. Yet often, implementing this aspect of learning presents a challenge to curriculum organisers in terms of content, timing and student interest. PROGRAMME OBJECTIVES AND STRUCTURE: The Doctors as Teachers and Educators (DATE) programme was set up at Barts and the London School of Medicine and Dentistry specifically to meet the requirements for development in teaching. Although largely practical, the two-day programme offers an introduction to educational theory and the teaching requirements for junior doctors in training. The methods used are lectures and group work within plenary sessions, followed by small group micro-teaching sessions. The DATE programme has now been undertaken by over 900 graduates. EVALUATION METHODS: We evaluated the Date programme by means of end-of-course questionnaires completed by two cohorts of students during the 2007/8 academic year and through the use of Nominal Group Technique in 2008/9. In line with the goals of the evaluation, the data on students' views were analysed to elicit self-reported learning and develop the programme. RESULTS: Response rates of the two cohorts to the surveys were high (80% and 98%). Nearly 100% of the students reported through the survey that they had gained confidence in teaching. In the nominal groups, students indicated that they had gained insight into educational principles like student-centredness and gained an appreciation for the nature of educational evidence and scholarship. They challenged the curriculum organisers to achieve an appropriate balance between theory and practice. CONCLUSIONS: A programme about teaching at the undergraduate medical level can be well-received by students; the DATE model could be transferred to other international contexts.

Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: Plasma soluble receptor for AGE (sRAGE) may reflect the activity of the AGE-RAGE axis, which has been proposed as a potential mechanism linking hyperglycaemia to vascular complications in diabetes. We have therefore investigated: (1) whether sRAGE is associated with greater prevalence of cardiovascular disease (CVD) and microvascular complications in type 1 diabetic individuals; and (2) the extent to which any such associations are explained by markers of endothelial and renal dysfunction and inflammation. METHODS: The study included 477 individuals (234 women; mean age 42 +/- 10 [SD] years) from the EURODIAB Prospective Complications Study. We used linear regression analyses to investigate the differences in sRAGE levels between individuals with and without vascular complications. All analyses were adjusted for age, sex, HbA(1c), duration of diabetes and other risk factors. RESULTS: Individuals with CVD (n = 116) had higher levels of sRAGE than those without CVD or any microvascular complications (n = 178): beta = 0.15 (95% CI 0.04-0.27). Further adjustments for markers of endothelial (beta = 0.13 [0.02-0.24]) and renal dysfunction (beta = 0.10 [-0.01, 0.20]) and inflammation (beta = 0.12 [0.01-0.23]) attenuated these differences; altogether these variables explained about 50% of the association between sRAGE and prevalent CVD. sRAGE levels tended to be higher in the presence and across the levels of severity of albuminuria (p for trend = 0.087) and retinopathy (p for trend = 0.057); adjustments for endothelial and renal dysfunction and inflammation also attenuated these differences. CONCLUSIONS/INTERPRETATION: sRAGE is associated with greater prevalence of CVD in type 1 diabetic individuals, and these associations may be partly explained by endothelial and renal dysfunction and low-grade inflammation.

ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/ macrovascular complications in type 1 diabetes: the EURODIAB Study.

OBJECTIVES: The heat shock proteins 60 and 70 (HSP60, HSP70) play an important role in cytoprotection. Under stress conditions they are released into the circulation and elicit an immune response. Anti-HSP60 and anti-HSP70 antibody levels have been associated with cardiovascular disease. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications. Therefore, we investigated whether anti-HSP60 and anti-HSP70 antibody levels were associated with micro- and macrovascular complications in type 1 diabetic patients. DESIGN: A cross-sectional nested case-control study from the EURODIAB Study of 531 type 1 diabetic patients was performed. SUBJECTS: Cases (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were all those with no evidence of any complication. We measured anti-HSP60 and anti-HSP70 antibody levels and investigated their cross-sectional associations with diabetic complications. RESULTS: Anti-HSP70 antibody levels were significantly greater in control than in case subjects, whereas anti-HSP60 antibody levels were similar in the two groups. In logistic regression analysis, anti-HSP70 levels in the upper quartiles were associated with a 47% reduced odds ratio of micro/macrovascular complications, independently of conventional risk factors, markers of inflammation and endothelial dysfunction [odds ratio (OR) = 0.53, 95% confidence intervals (CI): 0.28-1.02]. CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found an independent and inverse association between serum anti-HSP70 antibody levels and diabetic micro/macrovascular complications. This suggests that anti-HSP70 antibody levels may be a novel marker of protection from chronic diabetic complications.

Visual tracking and the primate flocculus.

Purkinje cells in the primate flocculus discharge specifically in relation to visual tracking, effectively generating a velocity profile of the target during pursuit. It is suggested that these neurons supply oculomotor centers with the velocity command signals needed to support pursuit eye movements.

Antibodies to periodontal pathogens and coronary artery calcification in type 1 diabetic and nondiabetic subjects.

BACKGROUND AND OBJECTIVE: The aim of this study was to examine whether serum immunoglobulin G (IgG) levels to Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans are higher in type 1 diabetic patients than in controls and are associated with coronary artery calcification, a measure of atherosclerosis. MATERIAL AND METHODS: One-hundred and ninety nine type 1 diabetic patients (mean age 38 +/- 4 years) and 201 age- and gender-matched nondiabetic subjects had coronary artery calcification, as measured by electron beam computed tomography. Serum IgG levels to P. gingivalis W50 and to A. actinomycetemcomitans HK1651 whole cells were measured by enzyme-linked immunosorbent assay. RESULTS: A similar proportion of diabetic patients (29%) and controls (31%, p = 0.7) had elevated serum IgG to periodontal bacteria, defined as being above the median antibody level for both microorganisms. Elevated antibody levels were associated with higher systolic blood pressure (p = 0.02) and an increased odds of coronary artery calcification in all subjects combined (odds ratio = 1.7, p = 0.047) and in diabetic subjects examined separately (odds ratio = 2.01, p = 0.027). Association of serum IgG levels with coronary artery calcification was independent of social class, lipids and antibody levels to other microorganisms, but not systolic blood pressure (odds ratio = 1.4, p = 0.1 on adjustment for blood pressure). There was no association between serum IgG level and vascular endothelial function. CONCLUSION: Elevated levels of serum IgG to P. gingivalis and A. actinomycetemcomitans are associated with coronary artery atherosclerosis. This may reflect a direct role for periodontal infection or a role for the host response to infection in coronary atherosclerosis, particularly in patients with type 1 diabetes.

Incidence of prolonged QTc and severe hypoglycemia in type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS: To assess the independent role of severe hypoglycemia on 7-year cumulative incidence of prolonged QTc in a large cohort of patients with type 1 diabetes. METHODS: People with type 1 diabetes recruited by the EURODIAB Prospective Complications Study who had normal QTc were examined at baseline and after 7 years with standardized methods (n = 1415; mean age ± SD 32.1 ± 9.6 years; diabetes duration 14.2 ± 8.8 years). Hypoglycemic episodes were assessed by a questionnaire. QTc was calculated according to Bazett's formula. In logistic regression analysis, we examined the role of severe hypoglycemia (none, 1-2, or 3 and more episodes/year) on the cumulative incidence of prolonged QTc, independently of age, sex, HbA1c, blood pressure, BMI, physical activity, distal symmetrical and autonomic neuropathy. RESULTS: In total, 264/1415 (17%) patients had incident prolonged QTc. Compared to those with persistently normal QTc, a greater proportion of incident cases had 3 and more hypoglycemic episodes at baseline (16.3 vs 11.2%, p = 0.03) and after 7 years (15.2 vs 9.6%, p = 0.01). In logistic regression analysis, 3 or more episodes of severe hypoglycemia at baseline did not increase cumulative incidence of prolonged QTc (OR 1.34, 95% CI 0.88-2.03). By contrast, severe hypoglycemia at the follow-up examination was associated with higher incidence of QTc prolongation (OR 1.68, 1.09-2.58), which reverted to not significant after adjustment for diabetic neuropathy. CONCLUSIONS: Severe hypoglycemia was not associated with incidence QTc prolongation in type 1 diabetic patients from the EURODIAB PCS.

Association of diet and lifestyle with glycated haemoglobin in type 1 diabetes participants in the EURODIAB prospective complications study.

BACKGROUND/OBJECTIVES: Diet and lifestyle advice for type 1 diabetes (T1DM) patients is based on little evidence and putative effects on glycaemic control. Therefore, we investigated the longitudinal relation between dietary and lifestyle variables and HbA1c levels in patients with type 1 diabetes. SUBJECTS/METHODS: A 7-year prospective cohort analysis was performed in 1659 T1DM patients (52% males, mean age 32.5 years) participating in the EURODIAB Prospective Complications Study. Baseline dietary intake was assessed by 3- day records and physical activity, smoking status and alcohol intake by questionnaires. HbA1c during follow-up was centrally assessed by immunoassay. Analysis of variance (ANOVA) and restricted cubic spline regression analyses were performed to assess dose-response associations between diet and lifestyle variables and HbA1c levels, adjusted for age, sex, lifestyle and body composition measures, baseline HbA1c, medication use and severe hypoglycaemic attacks. RESULTS: Mean follow-up of our study population was 6.8 (s.d. 0.6) years. Mean HbA1c level was 8.25% (s.d. 1.85) (or 66.6 mmol/mol) at baseline and 8.27% (s.d. 1.44) at follow-up. Physical activity, smoking status and alcohol intake were not associated with HbA1c at follow-up in multivariable ANOVA models. Baseline intake below the median of vegetable protein (<29 g/day) and dietary fibre (<18 g/day) was associated with higher HbA1c levels. Restricted cubic splines showed nonlinear associations with HbA1c levels for vegetable protein (P (nonlinear)=0.008) and total dietary fibre (P (nonlinear)=0.0009). CONCLUSIONS: This study suggests that low intake of vegetable protein and dietary fibre are associated with worse glycaemic control in type 1 diabetes.

Hyperglycemia and arterial disease.

Clinical and autopsy evidence support the increased risk of atherosclerotic disease in diabetes mellitus (DM). However, mechanisms other than arterial occlusion may also contribute to clinical syndromes often assumed to be atherosclerotic in origin. There is considerable geographical variability in the frequency of arterial disease in the diabetic. Glucose intolerance short of unequivocal DM is found in some (though not all) populations to carry increased atherosclerotic risk. Morbidity and mortality data suggest that women are particularly vulnerable (as with DM). The Whitehall prospective study of cardiovascular mortality shows that risk does not rise smoothly with increasing degrees of glucose intolerance but that it doubles sharply at the 95th percentile of the 2-h post-glucose blood sugar distribution.

Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ACE inhibition in IDDM patients: findings from the EUCLID Randomized Controlled Trial. EURODIAB Controlled Trial of Lisinopril in IDDM.

We examined whether the ACE gene insertion/deletion (I/D) polymorphism modulates renal disease progression in IDDM and how ACE inhibitors influence this relationship. The EURODIAB Controlled Trial of Lisinopril in IDDM is a multicenter randomized placebo-controlled trial in 530 nonhypertensive, mainly normoalbuminuric IDDM patients aged 20-59 years. Albumin excretion rate (AER) was measured every 6 months for 2 years. Genotype distribution was 15% II, 58% ID, and 27% DD. Between genotypes, there were no differences in baseline characteristics or in changes in blood pressure and glycemic control throughout the trial. There was a significant interaction between the II and DD genotype groups and treatment on change in AER (P = 0.05). Patients with the II genotype showed the fastest rate of AER progression on placebo but had an enhanced response to lisinopril. AER at 2 years (adjusted for baseline AER) was 51.3% lower on lisinopril than placebo in the II genotype patients (95% CI, 15.7 to 71.8; P = 0.01), 14.8% in the ID group (-7.8 to 32.7; P = 0.2), and 7.7% in the DD group (-36.6 to 37.6; P = 0.7). Absolute differences in AER between placebo and lisinopril at 2 years were 8.1, 1.7, and 0.8 microg/min in the II, ID, and DD groups, respectively. The significant beneficial effect of lisinopril on AER in the II group persisted when adjusted for center, blood pressure, and glycemic control, and also for diastolic blood pressure at 1 month into the study. Progression from normoalbuminuria to microalbuminuria (lisinopril versus placebo) was 0.27 (0.03-2.26; P = 0.2) in the II group, and 1.30 (0.33-5.17; P = 0.7) in the DD group (P = 0.6 for interaction). Knowledge of ACE genotype may be of value in determining the likely impact of ACE inhibitor treatment.

Lipid transfer protein activities in type 1 diabetic patients without renal failure and nondiabetic control subjects and their association with coronary artery calcification.

This study examined the role of cholesteryl ester transfer (CET), cholesteryl ester transfer protein (CETP) activity, and phospholipid transfer protein (PLTP) activity in the increased prevalence of coronary artery calcification (CAC) in diabetic subjects compared with nondiabetic subjects and in the loss of the sex difference in CAC in diabetes. CETP activity, PLTP activity, and CET were measured in 195 type 1 diabetic subjects without renal failure and 194 nondiabetic control subjects of similar age (30-55 years) and sex distribution (50% female). CAC was quantified with electron beam computed tomography. CETP activity was higher in diabetic subjects (mean 84 arbitrary units [AU]) than in nondiabetic subjects (80 AU, P = 0.028). PLTP activity was also higher in diabetic subjects (96 AU) than in nondiabetic subjects (81 AU, P < 0.001). However, CET was lower in diabetic men (geometric mean 32 nmol. ml(-1).h(-1)) than nondiabetic men (37 nmol.ml(-1).h(-1), P = 0.004) and did not differ between diabetic (30 nmol. ml(-1).h(-1)) and nondiabetic (32 nmol.ml(-1).h(-1), P = 0.3) women. CETP and PLTP activities were not associated with CAC. CET was positively associated with CAC in both diabetic and nondiabetic subjects (odds ratio per 10 nmol.ml(-1).h(-1) increase in CET in all subjects = 1.4, P = 0.001). The prevalence of CAC was similar in diabetic (51%) and nondiabetic (54%, P = 0.7) men but was much higher in diabetic (47%) than nondiabetic (21%, odds ratio 3.6, P < 0.001) women so that there was no sex difference in CAC in diabetic subjects. The odds of CAC in diabetic women compared with nondiabetic women was altered little by adjustment for CETP activity, PLTP activity, or CET (odds ratio on adjustment 3.7, P < 0.001). The greater effect of diabetes on CAC in women than in men, i.e., the loss of the sex difference in CAC, was independent of CETP and PLTP activity and CET. In conclusion, among both diabetic and nondiabetic subjects, higher cholesteryl ester transfer is a risk factor for CAC. However, abnormalities in cholesteryl ester transfer or lipid transfer protein activities do not underlie the increased CAC risk in diabetic women compared with nondiabetic women or the loss of the sex difference in CAC in diabetes.

The effect of type 1 diabetes mellitus on the gender difference in coronary artery calcification.

OBJECTIVES: To examine whether the gender difference in coronary artery calcification, a measure of atherosclerotic plaque burden, is lost in type 1 diabetic patients, and whether abnormalities in established coronary heart disease risk factors explain this. BACKGROUND: Type 1 diabetes abolishes the gender difference in coronary heart disease mortality because it is associated with a greater elevation of coronary disease risk in women than men. The pathophysiological basis of this is not understood. METHODS: Coronary artery calcification and coronary risk factors were compared in 199 type 1 diabetic patients and 201 nondiabetic participants of similar age (30 to 55 years) and gender (50% female) distribution. Only one subject had a history of coronary disease. Calcification was measured with electron beam computed tomography. RESULTS: In nondiabetic participants there was a large gender difference in calcification prevalence (men 54%, women 21%, odds ratio 4.5, p < 0.001), half of which was explained by established risk factors (odds ratio after adjustment = 2.2). Diabetes was associated with a greatly increased prevalence of calcification in women (47%), but not men (52%), so that the gender difference in calcification was lost (p = 0.002 for the greater effect of diabetes on calcification in women than men). On adjustment for risk factors, diabetes remained associated with a threefold higher odds ratio of calcification in women than men (p = 0.02). CONCLUSIONS: In type 1 diabetes coronary artery calcification is greatly increased in women and the gender difference in calcification is lost. Little of this is explained by known coronary risk factors.

A locus influencing total serum cholesterol on chromosome 19p: results from an autosomal genomic scan of serum lipid concentrations in Pima Indians.

A genome-wide linkage study was analyzed to identify loci that influence serum lipid concentrations in Pima Indians. Linkage analyses were conducted for total cholesterol measured in 998 siblings from 292 nuclear families, for total triglycerides in 547 siblings from 188 families, and for high density lipoprotein (HDL) cholesterol in 590 siblings from 201 families. Genotypes were generated for 516 autosomal microsatellite markers. Multipoint variance components methods were used to assess linkage. The strongest evidence for linkage with total cholesterol was on chromosome 19p (lod score 3.89), in the vicinity of the marker D19S1034, which is near the low density lipoprotein receptor gene. The strongest evidence for linkage with HDL cholesterol was on chromosome 3q (lod score 2.64) near D3S3053. For triglycerides, the strongest evidence for linkage was on chromosome 2p near D2S1788 (lod score 1.70) and on chromosome 3p near D3S2406 (lod score 1.77). This genomic scan provides evidence for a locus influencing total cholesterol concentration on chromosome 19p. It also suggests a locus influencing HDL cholesterol on chromosome 3q.

Mortality risk by body weight and weight change in people with NIDDM. The WHO Multinational Study of Vascular Disease in Diabetes.

OBJECTIVE: Care guidelines for people with non-insulin-dependent diabetes mellitus (NIDDM) emphasize the importance of weight loss in reducing mortality risk. However, existing evidence regarding the relationship between weight and mortality and the effects of weight change is conflicting. We examined these relationships in the World Health Organization Multinational Study of Vascular Disease in Diabetes. RESEARCH DESIGN AND METHODS: This was a cohort study of 1,416 men and 1,544 women. Baseline examinations were performed in 1975 through 1977, a morbidity follow-up was performed in 1983, and a mortality follow-up continued until 1988. Data were analyzed according to geographical groups: Europeans, East Asians, and Native Americans. The relationship between weight change and mortality was analyzed for Europeans only. RESULTS: Generally, body mass index (BMI) was positively associated with age, blood pressure, and cholesterol but was negatively associated with duration of diabetes, prevalence of retinopathy, and use of insulin. There was no clear relationship between BMI and mortality across the geographical groups. In Europeans, weight loss in the leanest subjects at baseline (BMI < 26 kg/m2) was associated with a threefold increase in mortality risk compared with those who had maintained a steady weight (relative risk [RR] 3.05, 95% confidence interval [CI] 1.26-7.36). Only in the most obese group was weight loss associated with a reduction in mortality risk (BMI > 29 kg/m2, RR 0.84, 95% CI 0.40-1.74). CONCLUSIONS: The positive association of BMI with age, blood pressure, and cholesterol and the negative association with duration of diabetes, retinopathy, and use of insulin may explain why there is no strong relationship between BMI and mortality in NIDDM. Weight loss, particularly in the relatively lean diabetic person, may be associated with an increased mortality risk.

Epidemiology of hypertension in diabetic patients and implications for treatment.

We review the epidemiology of hypertension in diabetic patients and discuss the implications for treatment. The relationship between coronary heart disease (CHD) mortality and blood pressure (BP) in the World Health Organization Multinational Study of Vascular Disease in Diabetics (WHO MSVDD) is evaluated. One thousand two hundred seventy-seven patients with insulin-dependent diabetes mellitus (IDDM) and 3463 patients with non-insulin-dependent diabetes mellitus (NIDDM), aged 35-55 yr at baseline, from 10 centers throughout the world were evaluated. CHD mortality after a follow-up of 6-7 yr was measured. Estimates of usual diastolic BP were made with data from the Framingham study. The relative risk (RR) of CHD death was plotted against usual diastolic BP for IDDM and NIDDM, and the shapes of the relationship were compared with a meta-analysis of nine prospective studies in nondiabetic populations. For the NIDDM group, the CHD RRs were significantly greater than 1.0 only for the uppermost diastolic BP category (RR 2.23, 95% confidence interval 1.14-4.40). For the IDDM group, the shape of the diastolic BP-CHD relationship was difficult to assess in view of the small number of events. In neither diabetic group was the evidence for a J-shaped relationship. Elevated BP is associated with increased cardiovascular/renal mortality in both types of diabetes. However, the efficacy of antihypertensive therapy in the prevention of these outcomes remains unclear. Prospective data from the WHO MSVDD do not provide clear evidence of benefit from treating diastolic BP less than 95-100 mmHg in NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Mortality and morbidity associated with body weight in people with IDDM. The WHO Multinational Study of Vascular Disease in Diabetes.

OBJECTIVE: Strict glycemic control in people with insulin-dependent diabetes mellitus (IDDM) reduces the risk of microvascular complications, but improvements in control are also associated with weight gain. Fears about the mortality risks of obesity may limit the acceptability of tight control. Therefore, we examined morbidity and mortality risks associated with body weight in people with IDDM. RESEARCH DESIGN AND METHODS: This was a cohort study of 644 men and 576 women with IDDM from nine centers worldwide. Baseline examinations were performed in 1975-1977, and mortality follow-up continued until 1988. RESULTS: Body weight was positively associated with blood pressure and, in men, with cholesterol. Fasting blood glucose was higher in the most obese groups in women only. There were 204 deaths among the men and 148 among the women. There was a reverse J-shaped relationship between body weight and all-cause mortality, with the highest mortality rates occurring in the leanest body mass index (BMI) category. The age-, duration-, and center-adjusted mortality rate ratio (95% confidence interval) comparing BMI category < 20 kg/m2 with BMI category > or = 22 and < 24 kg/m2 was 2.64 (1.59-4.38) in men and 1.54 (0.77-3.06) in women. Additional adjustment for smoking, blood pressure, glucose, cholesterol, and proteinuria did not qualitatively alter these findings. CONCLUSIONS: We conclude that except in very lean people with IDDM, body weight is not significantly associated with mortality. Thus, efforts to improve glycemic control should not be restricted by concerns about the effects of weight gain on mortality.