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Prospective studies in informative populations are crucial to increasing our knowledge of disease. In this perspective, we describe a half century of studies in an American Indian population that transformed our understanding of kidney disease in type 2 diabetes, now recognized as the leading cause of kidney failure worldwide. Serial examinations conducted for many years that included the collection of data and samples across multiple domains captured an unprecedented volume of clinical, physiologic, morphometric, genomic, and transcriptomic data. This work permitted us to extensively characterize the course and determinants of diabetic kidney disease, its pathophysiologic underpinnings, and important secular trends of urgent concern to populations worldwide, including the emergence of youth-onset type 2 diabetes and its effect on development of diabetic kidney disease in midlife. By combining these data using the tools of integrative biology, we are developing new mechanistic insights into the development and progression of diabetic kidney disease in type 2 diabetes. These insights have already contributed to the identification and successful therapeutic targeting of a novel pathway in DKD. We anticipate that this work will continue to expand our understanding of this complex disease and influence its management in the coming years. [ABSTRACT FROM AUTHOR]

Abstract: Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome‐wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; β = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10−11), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10–9); genetic distances at HLA were greater than at random markers (P = 1.6 × 10–46). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10–10). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations. [ABSTRACT FROM AUTHOR]

Objective: The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle.Research Design and Methods: Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995.Results: During this 15-year period, age-adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women).Conclusions: Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Familial aggregation of diabetic nephropathy suggests the existence of genes determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) > or = 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/g were considered unaffected. Segregation analysis was performed both for nephropathy at the last examination (prevalent cases) and for duration of diabetes at the onset of nephropathy (incident cases). The REGD program was used for the analysis of the prevalent cases and the REGTL program for the incident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 504 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no transmission of a major effect were rejected (P = 0.00001; P = 0.003), whereas Mendelian transmission was not rejected (P = 0.85). A dominant model provided the best fit, but a recessive model could not be rejected. The analysis of incident cases, however, did not support a major gene effect on duration of diabetes at the onset of nephropathy, and analyses of lifetime occurrence of nephropathy were inconclusive. The analysis of prevalent cases supports the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not support a genetic effect on duration of diabetes at the onset of nephropathy. The discrepancy may reflect the difficulty in precisely dating onset of nephropathy. The parameters of the model derived from segregation analysis of prevalent cases may be useful in linkage studies to detect nephropathy susceptibility loci. [ABSTRACT FROM AUTHOR]

The effect of plasma glucose concentration on overall and cause-specific mortality was examined in 1,745 Pima Indians (725 men, 1,020 women) > or = 15 years old with type 2 diabetes. During a median follow-up of 10.6 years (range 0.1-24.8), 533 subjects (275 men, 258 women) died; 113 of the deaths were attributable to cardiovascular disease, 96 to diabetes-related diseases (diabetic nephropathy for 92 of these), 249 to other natural causes, and 75 to external causes. After adjusting for age, sex, duration of diabetes, and BMI in a generalized additive proportional hazards model, higher baseline 2-h postload plasma glucose concentration predicted deaths from cardiovascular disease (P = 0.007) and diabetes-related diseases (P = 0.003), but not from other natural causes (P = 0.73). An increment of 5.6 mmol/l (100 mg/dl) in the 2-h plasma glucose concentration was associated with 1.2 times (95% CI 1.1-1.4) the death rate from cardiovascular disease, 1.3 times (95% CI 1.1-1.5) the death rate from diabetes-related diseases, and almost no change in the death rate from other natural causes (rate ratio = 1.0; 95% CI 0.94-1.1). In Pima Indians with type 2 diabetes, higher plasma glucose concentration predicts deaths from cardiovascular and diabetes-related diseases but has little or no effect on deaths from other natural or external causes. [ABSTRACT FROM AUTHOR]

Objective: To determine if gallstone disease is associated with an increased risk for malignancy and higher total mortality in Pima Indians.Design: Inception cohort.Setting: American Indian community.Participants: Age- and sex-stratified random population-based sample.Measurements: Between 1966 and 1969, an age- and sex-stratified random sample of Pima Indians from the Gila River Indian Community in Arizona was examined to identify evidence of gallstone disease defined as either gallstones (oral cholecystography) or previous cholecystectomy. During 20 years of follow-up, deaths were recorded and underlying causes of death, according to death certificates, were determined.Results: Among 383 persons with known gallbladder status, 186 (49%) died: 133 among the 222 persons with gallstone disease and 53 among the 161 without. The overall death rate was higher in persons with gallstone disease than in those with normal gallbladders. The age- and sex-adjusted death rate ratio was 1.9 (95% Cl, 1.3 to 2.7). Furthermore, the death rate attributed to malignancies was 6.6 times (Cl, 1.3 to 33.1) as high in persons with gallstone disease as in those with normal gallbladders. Of the 20 fatal malignancies in persons with gallstone disease, 11 occurred in the digestive tract, of which six involved the gallbladder or bile ducts.Conclusions: Increased cancer mortality and total mortality were found in Pima Indians with gallstone disease. Although plausible explanations exist for the increased cancer mortality, the increased death rates due to other causes are unexplained. Whether cholecystectomy would change this risk is unknown. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We examined secular trends in the frequency distribution of albuminuria and estimated glomerular filtration rate (eGFR) in subjects with type 2 diabetes in 1982-1988 and 2001-2006, two periods associated with major changes in the management of diabetes. RESEARCH DESIGN AND METHODS--The cross-sectional study included Pima Indians ≥15 years old with type 2 diabetes and measures of serum creatinine and urinary albumin-to-creatinine ratios (ACR). The continuous probability density distributions of ACR and eGFR were compared for the two time periods, eGFR was calculated using the Modification of Diet in Renal Disease Study equation. RESULTS--The overall standardized distribution of ACR shifted toward lower values between time periods (P = 0.001), whereas the standardized distribution of eGFR did not (P = 0.45). In the first period, eGFR was <60 ml/min per 1.73 m² in 6.5% of the 837 subjects. Of these, 9.3% had normal ACR, 7.4% had microalbuminuria, and 83.3% had macroalbuminuria. In the second period, the prevalence of low eGFR was similar (6.6% of the 1,310 subjects). Among those with low eGFR, normal ACR prevalence doubled to 17.2%, microalbuminuria prevalence nearly tripled to 19.5%, and macroalbuminuria prevalence declined to 63.2%. Twice as many subjects in the second period received antihypertensive medicines and 30% more received hypoglycemic medicines than in the first period. CONCLUSIONS--The distribution of albuminuria changed significantly among diabetic Pima Indians over the past 20 years, as treatment with medicines to control hyperglycemia and hypertension increased. The distribution of eGFR, however, remained unchanged. Consequently, the frequency of chronic kidney disease characterized by normoalbuminuria and low eGFR doubled. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To evaluate whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality and prevalent ischemic heart disease (IHD) and to analyze if the increased risk of death is dependent on subsequent development of diabetes in Pima Indians. RESEARCH DESIGN AND METHODS -- A total of 2,993 Pima Indians aged ≥35 years were included. Prevalent IHD, defined by major ischemic electrocardiogram changes, was evaluated according to the following glucose/diabetes categories: normal glucose regulation (NGR), IFG and/or IGT, and diabetic groups by duration. During a median follow-up of 10.4 years, 780 subjects died from natural causes and 156 of these died from IHD. Mortality was analyzed according to the same glucose/diabetes categories at baseline and then as time-dependent variables. RESULTS -- Only subjects with diabetes ≥ 15 years of duration have a higher prevalence of IHD (odds ratio 1.9 [95% CI 1.4-2.5]) relative to NGR. In baseline and time-dependent models, age- and sex-adjusted death rates from natural causes and from IHD were similar among the nondiabetic groups. Among diabetic subjects, natural mortality was higher in those with ≥ 15 years diabetes duration (death rate ratio [DRR] relative to NGR = 2.6 [95% CI 2.1-3.3]). IHD mortality was higher in subjects with long diabetes duration (DRR for diabetes 10-15 years = 3.8 [1.5-9.5]; DRR for diabetes ≥15 years = 8.6 [3.8-19.4]) in the time-dependent model. CONCLUSIONS -- Natural and IHD mortality are not increased in Pima Indians with IFG and/or IGT. Only after the onset of diabetes do the rates of these events increase relative to NGR. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The rising prevalence of obesity and high prevalence of diabetes among Pima Indians suggest that the incidence of diabetes has risen over time. We examined trends in the incidence rate of type 2 diabetes among Pima Indians between 1965 and 2003. RESEARCH DESIGN AND METHODS -- Incidence rates were computed independently in three 13-year time periods in Pima Indians aged ≥5 years. Diabetes was defined by the presence of at least one of two criteria: 1) 2-h plasma glucose concentration ≥200 mg/dl (11.1 mmol/l) or 2) hypoglycemic treatment. RESULTS -- Among 8,236 subjects without diabetes at baseline, 1,005 incident cases occurred during follow-up. Age- and sex-adjusted incidence rates of diabetes were 25.3 cases/ 1,000 patient-years (95% CI 22.5-28.0) in 1965-1977, 22.9 cases/i,000 patient years (20.0-25.8) in 1978-1990, and 23.5 cases/1,000 patient years (20.5-26.5) in 1991-2003 (P = 0.3). The incidence rate in subjects aged 5-14 years was 5.7 (1.9-17.4) times as high in the last as in the first period, but the rate declined in those aged 25-34 years (incidence rate ratio 0.6 [0.4-0.8]). Sex-adjusted prevalence increased significantly over time only in those aged 5-24 years (Ptrend < 0.0001). CONCLUSIONS -- The overall incidence of diabetes among Pima Indians remained stable over the past four decades, with a significant rise occurring only in the youth. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS -- Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS -- The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS -- The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Context The long-term outcome of persons with youth-onset type 2 diabetes melli- tus has not been well described. Objective To compare incidence of diabetic end-stage renal disease (ESRD) and mortality in Pima Indians with youth- and older-onset type 2 diabetes mellitus. Design, Setting, and Participants Longitudinal population-based study conducted between 1965 and 2002 in Pima Indians from the state of Arizona. Participants were divided into 2 groups: (1) youth-onset type 2 diabetes mellitus (onset <20 years of age) and (2) older-onset type 2 diabetes mellitus (onset >20 - <55 years of age). Events and person-years of follow-up were stratified in a time-dependent fashion by decades of age. End-stage renal disease was defined as dialysis attributed to diabetic nephropathy or death from diabetic nephropathy. Main Outcome Measures Incidence rate of diabetic ESRD and mortality between 25 and 55 years of age, according to age at onset of type 2 diabetes mellitus. Results Among the 1856 diabetic participants, 96 had youth-onset type 2 diabetes mellitus. The age-sex-adjusted incidence of diabetic ESRD was 25.0 cases per 1000 person- years (95% confidence interval [Cl], 6.7-43.1) in youth-onset diabetes mellitus and 5.4 cases per 1000 person-years (95% Cl, 4.4-6.4) in older-onset diabetes mellitus (incidence rate ratio, 4.6; 95% Cl, 2.2-9.8). Age-specific incidence rates were higher in participants with youth-onset diabetes mellitus at all ages. Between 25 and 55 years of age, the age-sex-adjusted death rate from natural causes was 15.4 deaths per 1000 person- years (95% Cl, 0.2-30.5) in participants with youth-onset diabetes mellitus and 7.3 deaths per 1000 person-years (95% Cl, 5.9-8.7) in individuals with older-onset diabetes mellitus (death rate ratio, 2.1; 95% Cl, 0.8-5.7). Compared with nondiabetic participants, the death rate was 3.0 times as high in individuals with youth-onset diabetes mellitus (95% Cl, 1.1 -8.0) and 1.4 times as high in individuals with older-onset diabetes mellitus (95% Cl, 1.1-1.8). In a subset of 1386 participants with complete data for all covariates who were observed from the onset of diabetes mellitus, the age at onset of diabetes mellitus was not associated with the incidence of ESRD (hazard ratio, 1.0; 95% Cl, 0.9-1.2) after adjusting for sex, mean arterial pressure, body mass index (calculated as weight in kilograms divided by height in meters squared), plasma glucose concentration, smoking, hy- poglycemic medicines, and blood pressure medicines in a Cox proportional-hazards model. Conclusions Early-onset type 2 diabetes mellitus is associated with substantially increased incidence of ESRD and mortality in middle age. The longer duration of diabetes mellitus by middle age in individuals diagnosed younger than age 20 years largely accounts for these outcomes. [ABSTRACT FROM AUTHOR]

Background: We examined the effect of kidney disease (KD) on mortality in nondiabetic and diabetic Pima Indians aged > or = 45 years old.Methods: Deaths and person-years of follow-up were stratified in a time-dependent fashion into categories of (1) no proteinuria and normal serum creatinine (SCr); (2) proteinuria and normal SCr; (3) high SCr [SCr > or = 133 micromol/L (1.5 mg/dL) in men, > or = 124 micromol/L (1.4 mg/dL) in women] but not on renal replacement therapy (RRT); or (4) RRT.Results: Among 1993 subjects, 55.8% had type 2 diabetes at baseline. Overall death rates increased with declining kidney function in both the nondiabetic and diabetic subjects (P < 0.0001). Death rates were similar in nondiabetic and diabetic subjects with comparable levels of kidney function, although the number of deaths among nondiabetic subjects with advanced KD was small. Infections and malignancy were the leading causes of death in nondiabetic subjects with KD. Among diabetic subjects, overall mortality increased with diabetes duration (P = 0.0001) and was highest in those on RRT (P < 0.0001). High SCr was associated with higher death rates from cardiovascular disease (CVD), diabetic nephropathy (DN), infections, and malignancy.Conclusion: Death rates increased comparably with worsening kidney function in both nondiabetic and diabetic subjects and were similar in nondiabetic and diabetic subjects without KD. KD was associated with excess mortality from DN, CVD, infections, and malignancy in diabetic subjects, and from infections in those without diabetes. [ABSTRACT FROM AUTHOR]

Objective: Diabetic nephropathy (DN) became the leading cause of death in diabetic Pima Indians in the 1970s, but was superseded by ischemic heart disease (IHD) in the 1980s. This study tests the hypothesis that the rise in the IHD death rate between 1965 and 1998 is attributable to access to renal replacement therapy (RRT).Research Design and Methods: Underlying causes of death were determined among 2,095 diabetic Pima Indians > or = 35 years old during four 8.5-year time intervals. To assess the effect of access to RRT on IHD death rates, trends were reexamined after subjects receiving RRT were classified as if they had died of DN.Results: During a median follow-up of 11.1 years (range 0.01-34), 818 subjects died. The age- and sex-adjusted DN death rate decreased over the 34-year study (P = 0.05), whereas the IHD death rate increased from 3.3 deaths/1,000 person-years (95% CI 1.4-5.2) to 6.3 deaths/1,000 person-years (95% CI 4.5-8.0; P = 0.03). After 151 subjects on RRT were reclassified as if they had died of DN, the death rate for DN increased from 4.8 deaths/1,000 person-years (95% CI 2.6-7) to 11.3 deaths/1,000 person-years (95% CI 9-13.6; P = 0.0007), whereas the increase in the IHD death rate disappeared (P = 0.57).Conclusions: The incidence rate of renal failure attributable to diabetes has increased rapidly over the past 34 years in Pima Indians. IHD has emerged as the leading cause of death due largely to the availability of RRT and to changes in the pattern of death among those with DN. [ABSTRACT FROM AUTHOR]

Adiponectin is a circulating protein secreted by adipocytes and is thought to have insulin-sensitizing effects. We present genetic analysis of adiponectin levels in 517 Pima Indians without diabetes (from 162 families, 750 sib-pairs). Adiponectin concentrations were heritable, with 39% of the variance of age- and sex-adjusted adiponectin potentially accounted for by additive genetic influences in this population. In genome-wide linkage analyses, suggestive linkage (logarithm of odds [LOD] = 3.0) of adiponectin adjusted for age and sex was found on chromosome 9p at 18 cM. Linkage was also present after inclusion of adiponectin concentrations of siblings with type 2 diabetes not treated pharmacologically (total siblings 582, 182 families, 860 sib-pairs: LOD = 3.5). Tentative evidence of linkage was also found on chromosomes 2 (LOD = 1.7 at 89 cM), 3 (LOD = 1.9 at 124 cM), and 10 (LOD = 1.7 at 70 cM), offering some support to findings of a previous genome-wide scan of adiponectin. Our data suggest that quantitative trait loci on chromosomes 2, 3, 9, and 10 may influence circulating adiponectin concentrations in the Pima population. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined the long-term effects of a self-assessed traditional or nontraditional dietary pattern on the development of type 2 diabetes in Pima Indians. Research design and methods; Results; Conclusion.

BACKGROUND: Obesity is caused by an imbalance between energy intake and energy expenditure. However, it is unknown whether increased physical activity protects susceptible populations against the development of obesity and type 2 diabetes. OBJECTIVE: To investigate the potential protective role of environment and physical activity against obesity by measuring total energy expenditure in Mexican and USA Pima Indians. METHODS: We compared the physical activity level of 40 (17 female and 23 male; 37 ± 11 y, 66 ± 13 kg) Mexican Pima Indians from a remote, mountainous area of Northwest Mexico, with 40 age-and-sex matched (17 female and 23 male; 37 ± 12y, 93 ± 22 kg) Pima Indians from the Gila River Indian Community in Arizona, USA. We measured total energy expenditure (TEE) by doubly labeled water and calculated physical activity by different methods: physical activity level (PAL) as the ratio of TEE on resting metabolic rate (RMR), TEE adjusted for RMR by linear regression, activity energy expenditure adjusted for body weight (AEE), and activity questionnaire. RESULTS: Physical activity was higher in Mexican Pima Indians when compared with USA Pima Indians as assessed by PAL (1.97 ± 0.34 vs 1.57 ± 0.16, P < 0.0001), TEE adjusted for RMR (3289 ± 454 vs 2671 ± 454 kcal/day, P < 0.0001) and AEE adjusted for body weight (1243 ± 415 vs 711 ± 415 kcal/day, P < 0.0001). Questionnaires revealed more time spent on occupational activities among Mexican Pima compared with USA Pima (23.9 ± 13.3 vs 12.6 ± 13.9 h/week, P < 0.001). CONCLUSION: These data support a significant role for physical activity in the prevention of obesity in genetically susceptible populations. [ABSTRACT FROM AUTHOR]

Focuses on a study which sought to investigate the mechanisms underlying the association between birth weight and type 2 diabetes in a population of Pima Indian children and adults. Research design and methods; Results; Conclusions.

Presents a study which investigated the impact of diet composition and level of physical activity on plasma leptin concentrations among Pima Indians living in drastically different environments. Research design and methods; Results; Conclusions.

Focuses on the importance of transient impaired glucose tolerance in Pima Indians. Nature of study; Subjects and methodology; Sequential changes in mean body mass index of subjects.

Examines the association between the diabetic intrauterine environment and renal disease in Pima Indians with type 2 diabetes. Prevalence of elevated urinary albumin excretion in patients with diabetic mothers; Association of maternal diabetes discovered as strong risk factor for elevated insulin excretion.

Focuses on a study that examined the association of diabetes and asymptomatic parotid enlargement in Pima Indians. Methods; Results; Discussion.

An epidemic of proteinuria in Pima Indians with Type 2 diabetes mellitus. Background. The risk of proteinuria in Type 1 diabetes declined ≥30% over the past 50 years, and improvements in metabolic control are believed to be largely responsible. Little is known about secular changes in the risk of proteinuria in Type 2 diabetes. Methods . We examined trends in the incidence rate of proteinuria in Pima Indians ≥20 years of age with diabetes diagnosed between January 1, 1955 and December 31, 1994. Results . Among 1305 initially non-proteinuric diabetic subjects, 433 developed proteinuria during a median follow-up of 8.0 years (range 0.8 to 30.2 years). With subjects with diabetes diagnosed between 1955 and 1964 serving as the reference group, the rate of proteinuria was similar (rate ratio 1.0; 95% confidence interval, 0.79 to 1.3) in the cohort diagnosed between 1965 and 1974, 1.5 times as high (95% confidence interval, 1.1 to 2.0) in the cohort diagnosed between 1975 and 1984, and 1.9 times as high (95% confidence interval, 1.1 to 3.0) in the cohort diagnosed between 1985 and 1994, after adjusting for potential confounders in a generalized additive proportional hazards model. Between the first and last cohorts, plasma glucose concentration declined, on average, by 17% (P = 0.0001) and the mean arterial pressure declined by 11% (P = 0.0001). Conclusions . The incidence rate of proteinuria in Pima Indians with Type 2 diabetes increased nearly twofold in the last 40 years, despite improvements in plasma glucose and blood pressure. Rapidly changing environmental or behavioral factors must play an important role in the pathogenesis of diabetic renal disease in this population. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Understanding why prolonged Bazett-corrected QT interval (QTc) is a risk factor for mortality is difficult, because QTc is positively correlated with heart rate. To optimally distinguish the effects of QT interval and heart rate on mortality, QT interval and heart rate were modeled separately and jointly in Pima Indians. Methods: The effects of QT and heart rate on all-cause and cause-specific mortality were assessed in the overall study population and according to the presence or absence of diabetes using multivariable time-dependent proportional hazards models. Results: Among 1488 nondiabetic and 990 diabetic subjects ≥25 years old, 81 nondiabetic and 149 diabetic subjects died during a median follow-up of 7.3 years. When included in the same regression model, QT and heart rate each predicted all-cause mortality [hazard ratios per standard deviation (SD) (95% confidence interval)=1.31 (1.10–1.57) and 1.57 (1.32–1.87) respectively]. In nondiabetic subjects, hazard ratios for all-cause mortality were 1.54 (1.19–1.99) for QT and 1.86 (1.46–2.37) for heart rate. In diabetic subjects, hazard ratios for all-cause mortality were lower, 1.27 (1.00–1.62) for QT and 1.41 (1.12–1.78) for heart rate. In the overall study population, neither QT nor heart rate significantly predicted cardiovascular disease (CVD) mortality [hazard ratios=1.13 (0.77–1.64) and 1.46 (0.98–2.19)] when adjusted for each other. Heart rate unadjusted for QT, however, predicted CVD mortality [hazard ratio=1.34 (1.00–1.79)] in a separate model. Conclusions: QT prolongation and high heart rate both predict all-cause mortality in Pima Indians, but heart rate was consistently the stronger predictor of the two. [Copyright &y& Elsevier]

Pima Indians in the United States and Mexico share a common genetic background but have very different lifestyles. Comparisons were made of the frequency of obesity, diabetes, hypertension, and kidney disease in these geographically separated but susceptible populations. Mexican Pimas had higher levels of physical activity, less obesity, and a lower prevalence of diabetes than their US Pima counterparts. Mean blood pressure rose with worsening glucose tolerance, and the prevalence of elevated urinary albumin excretion was higher in patients with diabetes than in those without, regardless of whether they lived in the United States or Mexico. These findings illustrate the importance of lifestyle in the development of diabetes and in the subsequent occurrence of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Both insulin resistance and β-cell dysfunction occur during the development of non-insulin-dependent diabetes mellitus (NIDDM), but controversy exists about which lesion is primary. Based on longitudinal studies in the Pima Indians, a population with the world's highest reported prevalence of NIDDM, a two-step model for development of the disease is proposed. The first step is transition from normal to impaired glucose tolerance, for which insulin resistance is the main determinant, and the second and later step is worsening from impaired glucose tolerance to diabetes, in which β-cell dysfunction plays a critical role. This hypothesis is consistent with findings from other ethnic groups from many parts of the world. [ABSTRACT FROM AUTHOR]

Background: The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. Methods: A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic-euglycemic clamp study were performed in 200 nondiabetic Pima Indians (87 women and 113 men; mean [±SD] age, 26 ±6 years). The subjects were followed yearly thereafter for an average of 5.3 years. Results: Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM. The six-year cumulative incidence of NIDDM was 39 percent in persons with values below the median for both insulin action and acute insulin response, 27 percent in those with values below the median for insulin action but above that for acute insulin response, 13 percent in those with values above the median for insulin action and below that for acute insulin response, and 0 in those with values originally above the median for both characteristics. Conclusions: Insulin resistance is a major risk factor for the development of NIDDM. A low acute insulin response to glucose is an additional but weaker risk factor. (N Engl J Med 1993;329:1988-92.) [ABSTRACT FROM AUTHOR]