Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study.

AIMS/HYPOTHESIS: We determined the effects of 6 years of lifestyle intervention in persons with impaired glucose tolerance (IGT) on the development of retinopathy, nephropathy and neuropathy over a 20 year period. METHODS: In 1986, 577 adults with IGT from 33 clinics in Da Qing, China were randomly assigned by clinic to a control group or one of three lifestyle intervention groups (diet, exercise, and diet plus exercise). Active intervention was carried out from 1986 to 1992. In 2006 we conducted a 20 year follow-up study of the original participants to compare the incidence of microvascular complications in the combined intervention group vs the control group. RESULTS: Follow-up information was obtained on 542 (94%) of the 577 original participants. The cumulative incidence of severe retinopathy was 9.2% in the combined intervention group and 16.2% in the control group (p = 0.03, log-rank test). After adjusting for clinic and age, the incidence of severe retinopathy was 47% lower in the intervention group than the control group (hazard rate ratio 0.53, 95% CI 0.29-0.99, p = 0.048). No significant differences were found in the incidence of severe nephropathy (hazard rate ratio 1.05, 95% CI 0.16-7.05, intervention vs control, p = 0.96) or in the prevalence of neuropathy (8.6% vs 9.1%, p = 0.89) among the 20 year survivors. CONCLUSIONS/INTERPRETATION: Lifestyle intervention for 6 years in IGT was associated with a 47% reduction in the incidence of severe, vision-threatening retinopathy over a 20 year interval, primarily due to the reduced incidence of diabetes in the intervention group. However, similar benefits were not seen for nephropathy or neuropathy.

Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians.

The introduction of more efficacious treatments for diabetic kidney disease may slow its progression, but evidence for their effectiveness in populations is sparse. We examined trends in the incidence of clinical proteinuria, defined as a urinary protein-to-creatinine ratio >0.5 g/g, and diabetic end-stage renal disease (ESRD), defined as death from diabetic nephropathy or onset of dialysis, in Pima Indians with type 2 diabetes between 1967 and 2002. The study included 2189 diabetic subjects >/=25 years old. During follow-up, 366 incident cases of proteinuria occurred in the subset of 1715 subjects without proteinuria at baseline. The age-sex-adjusted incidence rate of proteinuria increased from 24.3 cases/1000 person-years (pyrs) (95% confidence interval (CI) 18.7-30.0) in 1967-1978 to 35.4 cases/1000 pyrs (95% CI 28.1-42.8) in 1979-1990 and 38.9 cases/1000 pyrs (95% CI 31.2-46.5) in 1991-2002 (P(trend)<0.0002). In each period, the age-sex-adjusted incidence of proteinuria increased with diabetes duration, but diabetes duration-specific incidence was stable throughout the study period (P=0.8). The age-sex-adjusted incidence of ESRD increased between 1967 and 1990 and declined thereafter. The incidence of proteinuria increased over 36 years in Pima Indians as the proportion of people with diabetes of long duration increased. On the other hand, the incidence of ESRD declined after 1990, coinciding with improved control of blood pressure, hyperglycemia, and perhaps other risk factors.

Diet, nutrition and the prevention of type 2 diabetes.

OBJECTIVES: The overall objective of this study was to evaluate and provide evidence and recommendations on current published literature about diet and lifestyle in the prevention of type 2 diabetes. DESIGN: Epidemiological and experimental studies, focusing on nutritional intervention in the prevention of type 2 diabetes are used to make disease-specific recommendations. Long-term cohort studies are given the most weight as to strength of evidence available. SETTING AND SUBJECTS: Numerous clinical trials and cohort studies in low, middle and high income countries are evaluated regarding recommendations for dietary prevention of type 2 diabetes. These include, among others, the Finnish Diabetes Prevention Study, US Diabetes Prevention Program, Da Qing Study; Pima Indian Study; Iowa Women's Health Study; and the study of the US Male Physicians. RESULTS: There is convincing evidence for a decreased risk of diabetes in adults who are physically active and maintain a normal body mass index (BMI) throughout adulthood, and in overweight adults with impaired glucose tolerance who lose weight voluntarily. An increased risk for developing type 2 diabetes is associated with overweight and obesity; abdominal obesity; physical inactivity; and maternal diabetes. It is probable that a high intake of saturated fats and intrauterine growth retardation also contribute to an increased risk, while non-starch polysaccharides are likely to be associated with a decreased risk. From existing evidence it is also possible that omega-3 fatty acids, low glycaemic index foods and exclusive breastfeeding may play a protective role, and that total fat intake and trans fatty acids may contribute to the risk. However, insufficient evidence is currently available to provide convincing proof. CONCLUSIONS: Based on the strength of available evidence regarding diet and lifestyle in the prevention of type 2 diabetes, it is recommended that a normal weight status in the lower BMI range (BMI 21-23) and regular physical activity be maintained throughout adulthood; abdominal obesity be prevented; and saturated fat intake be less than 7% of the total energy intake.

Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians.

We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/m(2)) and age-adjusted diabetes to loci derived from either father (LOD(FA)) or mother (LOD(MO)) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 (LOD(MO) = 1.5) and 14 (LOD(MO) = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 (LOD(MO) = 1.7) and to paternally derived alleles on chromosome 10p (LOD(FA) = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 (LOD(MO) = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles (LOD(FA) = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians.

The appearance of retinopathy and progression to proliferative retinopathy: the WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to estimate incidences of any retinopathy and proliferative diabetic retinopathy (PDR) by direct ophthalmoscopy and relate them to baseline risk factors in re-examined diabetic survivors from 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes. METHODS: After a mean follow-up of 8.4years (11.7 years in Oklahoma), 2877 (71.6%) survivors were resubmitted to standardised direct ophthalmoscopy as at baseline. The presence of any retinopathy and PDR were recorded at each centre and their incidence estimated in those without retinopathy and PDR at baseline. The independent associations of these incidences with baseline risk factors are expressed as odds ratios derived from multiple logistic regression analyses, within individual centres (which included fasting plasma glucose in 8 and triglyceride in 5) and in pooled data. RESULTS: Of the 4662 original patients, 465 (10.4%) of those without and 77 (43.0%) of those with baseline PDR had died (p < 0.001). Any retinopathy was newly reported at follow-up in 47.7 % and PDR in 9.7 % of those free of them at baseline, with reported incidences varying substantially among centres. Incident retinopathy appeared earlier in the known course of diabetes but incidence rates rose more slowly with duration in patients with Type II (non-insulin-dependent) diabetes mellitus than in those with Type I (insulin-dependent) diabetes mellitus. In pooled data and in some individual centres, any retinopathy incidence gave significantly positive odds ratios with age, diabetes duration, systolic pressure, plasma cholesterol, BMI, insulin treatment and proteinuria, and with fasting plasma glucose in the centres where it was measured. Positive odds ratios for PDR were similarly obtained for age, duration, insulin treatment, cholesterol, proteinuria and fasting glycaemia. Smoking status odds ratios were negative for both outcomes. CONCLUSION/INTERPRETATION: Incidence of ophthalmoscopically ascertained any retinopathy varied about twofold and of PDR about threefold among centres. Although, in part attributable to differences between observers, variation in incidence in all centres and in some cases within centres was associated with a number of baseline risk factors. Such associations are not likely due to observer variation or selection biases and emerged despite the imprecision of clinical ophthalmoscopy. Improved detection and control of these risk factors should reduce the impact of diabetic retinopathy and its consequences.

Follow-up of the WHO Multinational Study of Vascular Disease in Diabetes: general description and morbidity.

AIMS: The incidence of retinal, renal and cardiovascular complications and their relation to baseline risk factors was documented in this follow-up study of 10 of the 14 original centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). METHODS: The incidence of specified items of vascular disease and some associated risk factors was ascertained after 7 to 9 years (11-12 years in Oklahoma, USA) follow-up, re-using baseline examination methodology in 3165 patients (66.9 %) and, through secondary information in 717 (15.2%) of the 4729 original patients, of whom 540 (11.4%) had died and 307 (6.5 %) were untraceable. RESULTS: During follow-up, approximately one third of the patients developed hypertension and one third started insulin. Coronary heart disease incidence varied 10 to 20-fold among centres as did limb amputation rates. Inter-centre differences in incident retinopathy and severe visual impairment were smaller but incident clinical proteinuria and renal failure varied markedly. Vascular disease incidence of all categories was high in Native Americans though coronary heart disease incidence was relatively low in Pima Indians and absolutely low in Hong Kong and Tokyo patients. Specific vascular events and their relation with baseline risk factors are analysed in accompanying papers, summarised in the Epilogue. CONCLUSION/INTERPRETATION: These 10 centres reported very different incidence rates of vascular complications. Observer variation, selection biases and competing causes of mortality contributed to these differences but their validity is supported by the more objective outcome indicators. The following papers also suggest that baseline factors such as raised arterial pressure, cholesterol and fasting glucose (in the centres where it was measured) were important and potentially reversible predictors of risk.

The incidence of visual impairment and its determinants in the WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: Incidence of severe visual impairment and the ultimate prevalence of all grades of impairment were estimated in the 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participating in the follow-up. METHODS: Visual function was ascertained at follow-up in 2994 (77.9 %) of the 3845 eligible participating survivors of the 4709 originally recruited for the WHO MSVDD using the same baseline enquiry method. The associations between incident severe visual impairment, follow-up prevalence of all grades of impairment and baseline risk factors were examined by univariate and stepwise multiple logistic regression analysis. RESULTS: Overall, 8.4 year incidence of severe visual impairment was 1.94 % and showed statistically significant univariate correlations with age at diagnosis, diabetes duration, systolic blood pressure, fasting blood glucose and cholesterol, insulin treatment and strongly with baseline retinopathy. Baseline retinopathy, systolic pressure and cholesterol were statistically significant in multivariable analysis. Differences between centres (0.3% to 3.45%) were not significant. Ultimate prevalence of all grades of impairment differed between centres and within almost all of them was correlated in multivariable analysis with baseline retinopathy and proteinuria. CONCLUSION/INTERPRETATION: Comparisons of incident severe visual impairment between centres are restricted by selective mortality, low incidence rates and relatively small numbers in each centre but before retinopathy, baseline systolic pressure and cholesterol predicted severe visual impairment. Follow-up prevalence of all degrees of impairment varied among centres and were associated with prior retinopathy and renal disease at baseline.

Increased urinary albumin excretion and its associations in the WHO Multinational Study of Vascular Disease in Diabetes.

AIM/HYPOTHESIS: We aimed to determine variations in the prevalence of increased urinary albumin excretion, associated risk factors and complications in patients with diabetes participating in the WHO Multinational Study of Vascular Disease in Diabetes follow-up. METHODS: Urinary albumin to urinary creatinine ratios were measured centrally in 2,033 of the 2,550 (79.7%) re-examined patients from eight centres in seven countries and the frequency of microalbuminuria and macroalbuminuria and their associations with risk factors and complications were examined. RESULTS: Macroalbuminuria prevalence (overall 15.6%) varied tenfold (3-37%) among centres, was higher in American Indian and Asian centres and not clearly related to type of diabetes. Microalbuminuria (overall 19.7 %) varied less (12-31%). Increased albumin excretion was related overall to baseline fasting plasma glucose in the pooled group in whom it was measured and to increased arterial pressure, insulin use, coronary heart disease, lower extremity amputation, retinopathy and stroke in most centres. CONCLUSION/INTERPRETATION: Centres varied widely in the prevalence of increased albumin excretion but associations with risk factors and vascular complications were generally similar in most centres and in both major types of diabetes with ethnic and genetic differences probably contributing.

Risk factors for renal failure: the WHO Mulinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. METHODS: Risk factors for renal failure were examined in 3,558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). RESULTS: In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2,559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years (+/- 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1,000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. CONCLUSION/INTERPRETATION: We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure.

Vascular disease in younger-onset diabetes: comparison of European, Asian and American Indian cohorts of the WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: This study compared the incidence of vascular disease in subjects with younger-onset diabetes from different ethnic groups. METHODS: The incidence of vascular disease endpoints has been studied in a sub-group (n = 994) of participants of the World Health Organization Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) who had younger-onset diabetes (diagnosed before the age of 30 years). The study participants have been divided into European (n = 631), Asian (n = 84) and American Indian (n = 91) cohorts. RESULTS: For Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus, American Indian men had a higher incidence of lower-extremity amputation and renal failure than the other cohorts, whereas European women had a higher incidence of angina than other cohorts. American Indians also had a higher incidence of any retinopathy, clinical proteinuria and albuminuria than the European and Asian cohorts. CONCLUSION/INTERPRETATION: This study confirms the high burden of large and small-vessel disease complications manifest in American Indian people with younger-onset diabetes.

Vascular disease prevalence in diabetic patients in China: standardised comparison with the 14 centres in the WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: Rates of vascular complications of diabetes in a cohort of mainland Chinese patients with diabetes, ascertained and examined by similar methodology, are compared with those of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). METHODS: The standardised procedures carried out in the WHO MSVDD were followed in assembling and examining a Chinese cohort of 447 diabetic patients recruited in Beijing and Tianjin [2]. RESULTS: Compared with the WHO MSVDD centres, the Chinese cohort was slightly older, had a shorter duration of known diabetes and had fewer insulin-treated patients. Arterial pressure, total blood cholesterol and body mass index were substantially lower. Large vessel disease rate for age, sex and duration adjusted data (17.9 % ) was about half that of the combined WHO MSVDD centres (33.5 % p < 0.001). However, retinopathy (47.4% vs 35.8% p < 0.001) and proteinuria (57.1 vs 24.9 % p < 0.001) rates were significantly higher. CONCLUSION/INTERPRETATION: Relatively low arterial pressures and blood cholesterol are likely contributors to the notably low arterial disease rates in this Chinese diabetic cohort; they reflect low rates in the Chinese mainland general population and resemble the Tokyo and Hong Kong centres of the WHO MSVDD. The high rates of retinopathy and proteinuria could relate to later diagnosis, degree of hyperglycaemia and/or increased susceptibiltiy to microangiopathy.

Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians.

BACKGROUND: The present analyses were conducted to examine the extent to which insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic factors, and to assess whether these genetic factors overlap with those influencing susceptibility to type 2 diabetes in Pima Indians. METHODS: Indices calculated from fasting and 2-h post-load insulin (I(0), I(120)) and glucose (G(0), G(120)) concentrations included insulin sensitivity index [ISI(0)=10(4)/(I(0).G(0))] and corrected insulin response [CIR(120)=I(120)/[G(120).(G(120)-70 mg/dl)]]. Heritability (h(2)) was determined using variance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait linkage analyses of ISI(0) and CIR(120) were conducted and affected-sibling analyses of diabetic siblings stratified by prediabetic measurements of ISI(0) and CIR(120) were also performed. RESULTS: Both ISI(0) (h(2)=0.37+/-0.06) and CIR(120) (h(2)=0.25+/-0.07) were moderately heritable. Modest evidence for linkage with CIR(120) (logarithm of odds (LOD)=1.6) was observed on chromosome 1q in a region previously shown to have linkage with young-onset diabetes in Pimas. When diabetic siblings were stratified by CIR(120), evidence for linkage in this region was strongest (LOD=1.5) among those with a low CIR(120). Additional regions with modest evidence for linkage with ISI(0) were observed on chromosomes 9p (LOD=2.0) and 14p (LOD=1.7). CONCLUSIONS: The present analyses suggest that insulin sensitivity and insulin secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromosome 1q affects insulin secretion. Published in 2001 by John Wiley & Sons, Ltd.

Gamma globulin levels predict type 2 diabetes in the Pima Indian population.

It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune system, predicted changes in glucose tolerance in 2,530 members of the Pima Indian population, a group with a marked predisposition to type 2 diabetes. Cross-sectionally, gamma globulin was positively related to age (r = 0.08, P < 0.0005), BMI (r = 0.09; P < 0.0001), and female sex (P < 0.0001). Gamma globulin concentrations were familial, being positively correlated among siblings (r = 0.23; P < 0.0001) and between parents and their children (mother/child: r = 0.17, P < 0.0001; father/child: r = 0.25, P < 0.0001). Gamma globulin concentrations were higher with greater degrees of American Indian heritage (P < 0.004, with adjustment for age, sex, and BMI) and in the presence of a family history of type 2 diabetes (P < 0.04). Higher gamma globulin levels predicted risk of diabetes. In univariate analysis, a 1 SD difference in gamma globulin was associated with a 20% higher incidence of diabetes in those who were normal glucose tolerant at baseline (hazard rate ratio 1.20 [CI 1.11-1.30]; P < 0.0001) and remained as a significant predictor of diabetes, even when controlled for effects of sex, BMI, and 2-h glucose as additional predictors (hazard rate ratio for 1 SD difference in gamma globulin, 1.14 [1.05-1.24]; P = 0.002). Gamma globulin was also associated in univariate analysis with later development of impaired glucose tolerance (IGT) (hazard rate ratio 1.15 [1.07-1.23]; P < 0.0001), but not with the transition from IGT to diabetes (hazard rate ratio 1.04 [0.90-1.20]; P = 0.6). Thus, gamma globulin levels predict increased risk of diabetes in the Pima population. We suggest that immune function or activation may play a role in the development of type 2 diabetes.

Association of physical activity and serum insulin concentrations in two populations at high risk for type 2 diabetes but differing by BMI.

OBJECTIVE: Physical activity and insulin sensitivity are related in epidemiological studies, but the consistency of this finding among populations that greatly differ in body size is uncertain. The present multiethnic epidemiological study examined whether physical activity was related to insulin concentrations in two populations at high risk for diabetes that greatly differ by location, ethnic group, and BMI. RESEARCH DESIGN AND METHODS: The study populations consisted of 2,321 nondiabetic Pima Indian men and women aged 15-59 years from Arizona and 2,716 nondiabetic men and women aged 35-54 years from Mauritius. Insulin sensitivity was estimated by mean insulin concentration (average of the fasting and postload insulin), and total (i.e., leisure and occupational) physical activity was assessed by questionnaire. RESULTS: Pima men and women who were more active had significantly (P < 0.05) lower mean insulin concentrations than those less active (BMI and age-adjusted means were 179 vs. 200 and 237 vs. 268 pmol/l). Similar findings were noted in Mauritian men and women (94 vs. 122 and 127 vs. 148 pmol/l). In both populations, activity remained significantly associated with mean insulin concentration controlled for age, BMI, waist-to-thigh or waist-to-hip ratio, and mean glucose concentrations. CONCLUSIONS: Physical activity was negatively associated with insulin concentrations both in the Pima Indians, who tend to be overweight, and in Mauritians, who are leaner. These findings suggest a beneficial role of activity on insulin sensitivity that is separate from any influence of activity on body composition.

The effect of Indian or Anglo dietary preference on the incidence of diabetes in Pima Indians.

OBJECTIVE: In short-term studies, adoption of a traditional diet is associated with reduction in metabolic abnormalities often found in populations experiencing rapid lifestyle changes. We examined the long-term effects of a self-assessed traditional or nontraditional dietary pattern on the development of type 2 diabetes in 165 nondiabetic Pima Indians. RESEARCH DESIGN AND METHODS: Dietary intake was assessed in 1988 by a quantitative food frequency method, and subjects were asked to classify their diet as "Indian," "Anglo," or "mixed." The Indian diet reflects a preference for Sonoran-style and traditional desert foods. The Anglo diet reflects a preference for non-Sonoran-style foods typical of the remaining regions of the U.S. RESULTS: In women, the intake of complex carbohydrates, dietary fiber, insoluble fiber, vegetable proteins, and the proportion of total calories from complex carbohydrate and vegetable proteins were significantly higher (P < 0.05) in the Indian than in the Anglo diet. The mixed diet was intermediate in of all these constituents. In men, the intake for these nutrients was also higher in the Indian than in the Anglo group, but not significantly. Diabetes developed in 36 subjects (8 men and 28 women) during 6.2 years of follow-up (range 0.9-10.9). The crude incidence rates of diabetes were 23. 35, and 63 cases per 1,000 person-years in the Indian. mixed, and Anglo groups, respectively. After adjustment for age, sex, BMI, and total energy intake in a proportional hazards model, the risk of developing diabetes in the Anglo-diet group was 2.5 times as high (95%) CI 0.9-7.2) and the rate in the mixed-diet group was 1.3 times as high (0.6-3.3) as in the Indian-diet group. CONCLUSIONS: This study suggests that the adoption of an Anglo diet may increase the risk of developing diabetes in Pima Indians, but it does not provide unequivocal evidence for or against this hypothesis.

Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians.

OBJECTIVE: Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. METHODS: Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. RESULTS: During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (Ptrend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]). CONCLUSION: Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD.

Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships.

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.

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.