Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations.

Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage disequilibrium generally was found not to exist between RFLPs at opposite ends of the gene but was found to exist among the RFLPs clustered at each end. We have now undertaken the first global survey of normal variation and disequilibrium across the PAH gene. Four well-mapped single-nucleotide polymorphisms (SNPs) spanning approximately 75 kb, two near each end of the gene, were selected to allow linkage disequilibrium across most of the gene to be examined. These SNPs were studied as PCR-RFLP markers in samples of, on average, 50 individuals for each of 29 populations, including, for the first time, multiple populations from Africa and from the Americas. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies >5% somewhere in the world, no haplotype was seen in all populations. Overall linkage disequilibrium is highly significant in all populations, but disequilibrium between the opposite ends is significant only in Native American populations and in one African population. This study demonstrates that the physical extent of linkage disequilibrium can differ substantially among populations from different regions of the world, because of both ancient genetic drift in the ancestor common to a large regional group of modern populations and recent genetic drift affecting individual populations.

Daily energy expenditure in Mexican and USA Pima indians: low physical activity as a possible cause of obesity.

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+/-12 y, 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. International Journal of Obesity (2000)24, 55-59

Plasma leptin concentrations in Pima Indians living in drastically different environments.

OBJECTIVE: Plasma leptin, an important signal for the regulation of energy stores, is known to be influenced by many hormonal factors, but may also be affected by behavioral and environmental factors. The purpose of this study was to investigate the impact of lifestyle (diet composition, level of physical activity) on plasma leptin concentrations among Pima Indians living in drastically different environments. RESEARCH DESIGN AND METHODS: We studied 224 Mexican Pima Indians (115 women, 109 men) living a traditional lifestyle in a remote, mountainous area of northwest Mexico and 418 U.S. Pima Indians (281 women, 137 men) living a North American lifestyle on the Gila River Indian Reservation in Arizona. We hypothesized that the absolute value of leptin would be lower in Mexican Pima Indians because of their lower percent body fat, but could be further influenced by their lifestyle, independent of body composition. RESULTS: Leptin concentration (enzyme-linked immunosorbent assay [ELISA]) was strongly correlated with percent fat (bioimpedance) in Mexican Pima Indians (r = 0.83, P < 0.0001) and U.S. Pima Indians (r = 0.86, P < 0.0001). Among U.S. Pima Indians, independent of percent fat, subjects with type 2 diabetes had lower leptin than nondiabetic subjects (difference = 6.9 +/- 1.0 ng/ml, P < 0.002). Among nondiabetic subjects, Mexican Pima Indians had lower absolute leptin concentrations than U.S. Pima Indians, but higher after adjustment for percent body fat, waist circumference, age, and sex. In a subset of 70 pairs of subjects matched for sex and percent body fat, leptin concentration was 4.4 +/- 1.0 ng/ml (P < 0.0001) higher in Mexican Pima Indians versus U.S. Pima Indians. CONCLUSIONS: These results suggest that independent of body composition, leptin concentration may be increased by environmental factors, such as a high-carbohydrate diet and a high level of physical activity.

Is a low leptin concentration, a low resting metabolic rate, or both the expression of the "thrifty genotype"? Results from Mexican Pima Indians.

BACKGROUND: The high prevalence of obesity and type 2 diabetes in some populations is believed to be the expression of a "thrifty genotype," which conferred survival advantages during periods of harsh environmental conditions, but has become a liability in industrialized environments of abundance. Low plasma leptin concentrations and a low metabolic rate may be the phenotypic expression of this genotype. OBJECTIVE: We hypothesized that plasma leptin concentrations and resting metabolic rate would be lower in Mexican Pima Indians not yet exposed to an affluent lifestyle than in non-Pima Mexicans living in the same environment. DESIGN: We studied 208 nondiabetic Pima Indians (105 women and 103 men) living a traditional lifestyle in a remote, mountainous area of northwest Mexico and 183 nondiabetic non-Pima Mexicans (90 women and 93 men) living in the same environment. A subset of 40 (17 women and 23 men) Pima Indians and 40 (19 women and 21 men) non-Pima Mexicans was selected for studies of energy metabolism with a ventilated-hood system. RESULTS: Leptin concentrations were strongly correlated with percentage body fat in both groups (r = 0.83, P < 0.0001). There was no significant difference in plasma leptin concentration between groups in absolute value (P = 0.90) or after adjustment for percentage body fat, waist circumference, age, and sex (P = 0.40). Similarly, there was no significant difference in resting metabolic rate between groups in absolute value (P = 0.27) or after adjustment for fat-free mass (P = 0.32). CONCLUSIONS: These results do not support the hypothesis that hypoleptinemia, a relatively low resting metabolic rate, or both are expressions of the thrifty genotype.

Adaptation of the doubly labeled water method for subjects consuming isotopically enriched water.

The use of doubly labeled water (DLW) to measure energy expenditure is subject to error if the background abundance of the oxygen and hydrogen isotope tracers changes during the test period. This study evaluated the accuracy and precision of different methods by which such background isotope changes can be corrected, including a modified method that allows prediction of the baseline that would be achieved if subjects were to consume water from a given source indefinitely. Subjects in this study were eight women (4 test subjects and 4 control subjects) who consumed for 28 days water enriched to resemble drinking water aboard the United States space shuttle. Test subjects and control subjects were given a DLW dose on days 1 and 15, respectively. The change to an enriched water source produced a bias in expenditure calculations that exceeded 2.9 MJ/day (35%), relative to calculations from intake-balance. The proposed correction based on the predicted final abundance of 18O and deuterium after equilibration to the new water source eliminated this bias, as did the traditional use of a control group. This new modified correction method is advantageous under field conditions when subject numbers are limited.

Prevalence of diabetes and factors associated with diabetic complications in Oneida Indians.

The study objective was to determine the prevalence of diabetes mellitus among Oneida Indians and to identify factors associated with the development of medical complications. After identifying patients with diabetes (N = 373) treated at the Oneida Community Health Center, their medical records were reviewed to determine age, body mass index (BMI), types of medication used, HbAlc, and the presence of diabetic complications. The age and sex-adjusted prevalence of diabetes was 86.5/1000 population. Where type of diabetes could be determined (N = 345) 96% were non-insulin dependent; 67% were afflicted with diabetic complications. 56% had hypertension. Age, BMI, and HbAlc were significant variables with respect to the presence of certain complications. Although lower than the prevalence for some other groups of Native Americans, diabetes and its complications represent a serious problem for the Oneida Indians. Consistent screening, intensive intervention and culture-sensitive prevention efforts focussing on weight control are needed.

Glucose tolerance and physical activity in a Mexican indigenous population.

OBJECTIVE: To assess diabetes prevalence and physical activity among an indigenous population in Mexico. RESEARCH DESIGN AND METHODS: A total of 101 adult (mean age = 38 years) Mixtec Indians living on the outskirts of Huajuapan de Leon, Oaxaca, Mexico, volunteered to be measured for height, weight, blood pressure, glucose tolerance, and physical activity. RESULTS: According to World Health Organization criteria, 2 women were diabetic and 42 subjects (15 men, 27 women) had impaired glucose tolerance (IGT). Although the population was generally lean, with a mean +/- SD body mass index (BMI) of 23.0 +/- 2.7 kg/m2 for men (n = 47) and 22.8 +/- 3.0 kg/m2 for women (n = 54), the group with normal glucose tolerance had a significantly lower BMI than those with abnormal glucose tolerance (IGT or diabetes). Men were significantly more physically active than women, and a larger percentage of women (54%) than men (32%) had abnormal glucose tolerance. However, within gender groups, there was not a significant effect of physical activity on status of glucose tolerance. CONCLUSIONS: The Mixtec population may be genetically predisposed to non-insulin-dependent diabetes, although their current lifestyle provides a protective effect. Less of a protective effect is seen for females, however. It is expected that further environmental changes impacting energy balance will have the most damaging repercussions for diabetes prevalence among Mixtec women.

A compilation of total daily energy expenditures and body weights in healthy adults.

Measurements of total energy expenditure (TEE) by the doubly labeled water method were compiled from 22 studies to identify the range of variation and significant determinants of energy requirements in healthy adults. The 126 male and 173 female subjects (aged 18-78 y) were separated into four groups: athletes, Pima Indians, people in developing countries, and others. The groups differed significantly (P < 0.001) with respect to TEE, TEE/BMR, TEE-BMR divided by weight, and TEE-BMR. Stepwise multiple regression demonstrated that fat-free mass (FFM) and age are significant variables that can explain 65% of the variation in TEE. These data demonstrate that total daily energy expenditure varies dramatically among healthy, free-living adults. The relationship between body fatness and nonbasal energy expenditure was negative at high energy outputs but considerable variation in body fatness was present among sedentary individuals, suggesting that a low rate of nonbasal energy expenditure is a permissive factor for obesity.

Energy intake and physical activity in Pima Indians: comparison with energy expenditure measured by doubly-labeled water.

To test the validity of survey techniques for measuring diet and activity patterns of Pima Indians, sequential 24-hour recalls, a food frequency questionnaire (FFQ), and an activity questionnaire were compared to free-living energy expenditure. Total energy expenditure (TEE) measured by doubly labeled water was 13.27 +/- 2.95 MJ/d for the 12 males (mean +/- SD: 35 +/- 14 yr; 97 +/- 35 kg; 32 +/- 9% body fat) and 11.67 +/- 1.85 MJ/d for the 9 females (31 +/- 13 yr; 106 +/- 32 kg; 49 +/- 6% body fat). Energy intake assessed by 24-hour recall was 13.59 +/- 7.81 MJ/d for men and 9.29 +/- 2.77 MJ/d for women, compared to 12.84 + 2.85 and 9.40 + 2.61 MJ/d for men and women, respectively, by FFQ. Both dietary methods indicated significant underreporting by women when compared to TEE. Energy intake assessed by FFQ was significantly correlated with TEE (r=0.48, p=0.03). This was true with 24-hour recall energy intake only when data from two extremely large alcohol consumers were eliminated (r=0.64, p=0.03, N=19). Although a low level of activity was apparent, the activity questionnaire produced significant correlations with measurements of energy expenditure and therefore represents an important tool for examining the relationship between physical activity and diseases.

Effects of a traditional lifestyle on obesity in Pima Indians.

OBJECTIVE: The Pima Indians of Arizona have the highest reported prevalences of obesity and non-insulin-dependent diabetes mellitus (NIDDM). In parallel with abrupt changes in lifestyle, these prevalences in Arizona Pimas have increased to epidemic proportions during the past decades. To assess the possible impact of the environment on the prevalences of obesity and NIDDM, data were collected on members of a population of Pima ancestry (separation 700-1,000 years ago) living in a remote mountainous location in northwestern Mexico, with a lifestyle contrasting markedly with that in Arizona. RESEARCH DESIGN AND METHODS: Pima heritage was established by history and by use of Pima language. Measurements of weight, height, body fat (bioimpedance), blood pressure, plasma levels of glucose, cholesterol, and HbA1c were obtained in 19 women (36 +/- 13 years of age) and 16 men (48 +/- 14 years of age) and compared with sex-, age- and diabetes status-matched Pimas living in Arizona (10 Arizona Pimas for each Mexican Pima). RESULTS: Mexican Pimas were lighter (64.2 +/- 13.9 vs. 90.2 +/- 21.1 kg, P < 0.0001; means +/- SD) and shorter (160 +/- 8 vs. 164 +/- 8 cm, P < 0.01) with lower body mass indexes (24.9 +/- 4.0 vs. 33.4 +/- 7.5 kg/m2, P < 0.0001) and lower plasma total cholesterol levels (146 +/- 30 vs. 174 +/- 31 mg/dl, P < 0.0001) than Arizona Pimas. Only two women (11%) and one man (6%) had NIDDM, contrasting with the expected prevalences of 37 and 54% in female and male Arizona Pimas, respectively. CONCLUSIONS: This preliminary investigation shows that obesity, and perhaps NIDDM, is less prevalent among people of Pima heritage living a "traditional" lifestyle than among Pimas living in an "affluent" environment. These findings suggest that, despite a similar potential genetic predisposition to these conditions, a traditional lifestyle, characterized by a diet including less animal fat and more complex carbohydrates and by greater energy expenditure in physical labor, may protect against the development of cardiovascular disease risk factors, obesity, and NIDDM.

Methods of body composition analysis the status of the gold standard.

The prevention, treatment, and comprehension of disease processes can be advanced with improved methods for assessing changes in body composition. Recently developed methodology has expanded our capacity to quantify body constituents and has stimulated a trend away from the two-compartment model (fat mass and fat-free mass) for describing body composition. As these advances take place, the "gold standard" for measuring living human subjects will likely shift from the frequently relied upon underwater weighing method to techniques that further divide the fat-free mass. New and widely used techniques for quantifying various body compartments are described.

Non-insulin-dependent diabetes mellitus in Mexico.

Previous experience throughout the world has suggested that certain populations have a genetic predisposition to the development of non-insulin dependent diabetes mellitus (NIDDM) in response to a changing environment. In particular, Native American admixture presents a genetic risk for NIDDM and modernization represents an environmental change which amplifies the risk. This review discusses these factors with respect to the situation in Mexico, where a significant portion of the population is Native American and industrialization is producing rapid environmental changes. Perhaps, with foresight, the epidemic of NIDDM which has struck Native Americans in the United States and indigenous groups in the South Pacific may be averted in Mexico. Specific aspects of the traditional Mexican lifestyle which could be retained to protect against NIDDM are presented.

Twenty-four-hour energy expenditure in Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus.

To assess the impact of Type 2 (non-insulin-dependent) diabetes mellitus on energy metabolism, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were measured in a respiratory chamber in 151 Pima Indians, 102 with normal glucose tolerance (67 male/35 female, (mean +/- SD) 28 +/- 7 years, 99 +/- 24 kg, 32 +/- 9% body fat) and in 49 with Type 2 diabetes (22 male/27 female, 35 +/- 11 years, 107 +/- 33 kg, 39 +/- 7% body fat), after at least 3 days on a weight maintaining diet. After adjustment for differences in fat-free mass, fat mass, age and sex, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were significantly higher in diabetic patients than in control subjects (72 kcal/day, p less than 0.05; 99 kcal/day, p less than 0.005; 99 kcal/day, p less than 0.001 respectively). Spontaneous physical activity was similar in both groups whereas the thermic effect of food, calculated as the mean energy expenditure corrected for activity throughout the day above sleeping metabolic rate and expressed as a percentage of energy intake, was significantly lower in Type 2 diabetic patients (17.1 +/- 7.1 vs 19.8 +/- 5.6%, p less than 0.05). Adjusted values of 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were correlated with hepatic endogenous glucose production (r = 0.22, p less than 0.05; r = 0.22, p less than 0.05; r = 0.31, p less than 0.01 respectively). Therefore, increased basal and sleeping metabolic rates, resulting in increased 24-h sedentary energy expenditure may play a role in the weight loss so often observed in Type 2 diabetic subjects in addition to the energy loss from glycosuria.

Energy expenditure of elite female runners measured by respiratory chamber and doubly labeled water.

To determine whether female athletes have unusually low energy requirements as suggested by many food intake studies, energy expenditure (EE) and intake were assessed in nine elite distance runners [26 +/- 3 (SD) yr, 53 +/- 4 kg, 12 +/- 3% body fat, and 66 +/- 4 ml.kg-1.min-1 maximal O2 uptake]. Subjects were admitted to a metabolic ward for 40 h during which 24-h sedentary EE was measured in a respiratory chamber. Free-living EE was then assessed by the doubly labeled water method for the next 6 days while the women recorded all food intake, daily body weight, and training mileage (10 +/- 3 miles/day). Energy intakes estimated from free-living EE (2,826 +/- 312 kcal/day) and body weight changes (-84 +/- 71 g/day) averaged 221 +/- 550 kcal/day in excess of those calculated from food records (2,193 +/- 466 kcal/day). The energy cost of training (1,087 +/- 244 kcal/day) was calculated as the difference between free-living EE and 24-h EE in the respiratory chamber (1,681 +/- 84 kcal/day) corrected for the thermic effect of food of the extra energy intake. These data do not support the hypothesis that training as a distance runner results in metabolic adaptations that lower energy requirements in women.

Effect of endurance training on sedentary energy expenditure measured in a respiratory chamber.

The effect of endurance training on 24-h energy expenditure (EE), basal metabolic rate (BMR), sleeping metabolic rate (SMR), and the thermic effect of food (TEF) was assessed in a respiratory chamber where only spontaneous physical activity (SPA) was allowed. Results from 20 highly trained male endurance athletes (25 +/- 5 yr, 178 +/- 7 cm, 70 +/- 8 kg body wt, 64 +/- 7 kg fat-free mass) were compared with those of 43 untrained males who were matched for age (28 +/- 6 yr), height (175 +/- 5 cm), weight (73 +/- 13 kg), and fat-free mass (62 +/- 8 kg). Subjects were admitted to a metabolic ward, fed a weight-maintenance diet, and refrained from physical activity for at least 2 days before measurements. No significant differences were found with respect to 24-h EE (2,126 +/- 186 vs. 2,154 +/- 245 kcal), BMR (1,808 +/- 342 vs. 1,709 +/- 329 kcal), SMR (1,523 +/- 120 vs. 1,555 +/- 188 kcal), or TEF (24.9 +/- 9.2 vs. 21.3 +/- 6.7% of ingested calories; these values included the energy cost of arousal) between trained and untrained subjects, respectively, before or after adjusting for differences in body composition. Neither the 24-h respiratory quotient nor the level of SPA differed between the two groups. No relationship was found between maximal aerobic capacity and metabolic rate adjusted for differences in fat-free mass and fat mass. These results do not support an effect of fitness level on EE measured under sedentary conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of diabetes on the rat hepatic glucose-6-phosphatase system in endoplasmic reticulum subfractions.

Diabetes-induced alterations in the activities of the components of the glucose-6-phosphatase system (i.e., the enzyme, the glucose-6-P translocase (T(1)), and the phosphate translocase (T(2)) were examined in smooth and rough subfractions of hepatic endoplasmic reticulum from streptozotocin-injected rats. A significant effect of diabetes on the maximal velocity of glucose-6-P hydrolysis by the enzyme was present in both endoplasmic reticulum subfractions (3.1-fold increase in rough endoplasmic reticulum; 3.8-fold increase in smooth endoplasmic reticulum). Based on latency values, diabetes did not result in a proportional increase in capacity of T(1) or T(2). In contrast to the control condition, the relationship between transport capacity and hydrolytic capacity was not significantly different in the two subfractions from diabetic animals. Elucidation of the effects of diabetes on the components of the glucose-6-phosphatase system associated with smooth and rough endoplasmic reticulum membranes enhances our understanding of the hepatic contribution to diabetic hyperglycemia.

Nutrition concerns in Bangladesh: the focus for improvement.

The results of efforts to identify the prevailing nutritional deficiency disorders in Bangladesh and major topics of local scientific investigation influencing those nutrient disorders are reviewed. Primary areas of emphasis include studies addressing nutritional status (especially vitamin A); factors influencing diarrheal incidence, morbidity and mortality; child nutrition; the influence of seasonal variations; and the implementation of successful intervention programs. Programmatic implications of the findings are presented.