Indication of mixed glucose and fatty acid use by inferred brown adipose tissue activity in Samoans.

OBJECTIVES: Despite the growing rates of global obesity and the known positive associations between brown adipose tissue (BAT) and cardiovascular health, little is known about the metabolic effects of BAT activity in Samoans, a population at high risk of obesity and type II diabetes. Here we assessed the potential effects of inferred BAT activity on metabolic health markers in Samoan adults exposed to mild cold. METHODS: Using point-of-care finger prick technology we measured fasting glucose, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels before and after 30 min of cold exposure among 61 individuals (38 females, 23 males, ages 31-54) from 'Upolu Island, Samoa. Respiratory quotient was measured by indirect calorimetry to determine substrate metabolism at room temperature and cold exposure. RESULTS: Fasting glucose levels decreased significantly (p < .001) after cold exposure while neither total cholesterol (p = .88), HDL (p = .312), nor LDL (p = .089) changed. Respiratory quotient decreased significantly (p = .009) between exposures, suggesting an increased preference for lipid metabolism as a response to cold. CONCLUSIONS: The observed effects of inferred BAT activity on biomarkers suggest BAT activity utilizes both glucose and lipid-derived fatty acids as fuel for thermogenesis. Our work provides evidence for the beneficial metabolic effects of BAT and emphasizes the need for the population-specific development of metabolic treatments involving BAT to ensure the successful and equitable minimization of extreme consequences of obesity and metabolic health.

Association between age at menarche and cardiometabolic risk among Samoan adults.

OBJECTIVES: Recent studies suggest that early menarche may increase cardiometabolic morbidity and mortality. Yet few studies have examined this association in the Pacific Islands, where obesity prevalence is among the highest globally. We sought to examine associations between age at menarche and cardiometabolic risk in Samoa. METHODS: Participants were from the Soifua Manuia study (n = 285, age 32-72 years) conducted in Samoa from 2017 to 2019. Logistic regressions were conducted to estimate odds of obesity, hypertension, diabetes, dyslipidemia, and metabolic syndrome per one-year increase in age at menarche. Linear regressions were conducted to examine associations between age at menarche and continuous measures of adiposity, blood pressure, insulin resistance, and serum lipids. RESULTS: Median age at menarche was 14 years (IQR = 2). After controlling for relevant covariates, each one-year increase in age at menarche was associated with a 15% decrease (OR = 0.85, 95% CI: 0.72-1.01, p = .067) in odds of hypertension, but a 21% increase (OR = 1.21, 95% CI: 1.01-1.45, p = .044) in odds of diabetes and 18% increase (OR = 1.18, 95% CI: 0.98-1.42, p = .081) in odds of high total cholesterol. Each additional year in age at menarche was associated with a 1.60 ± 0.52 kg (p = .002) decrease in lean mass and 1.56 ± 0.51 kg (p = .003) decrease in fat-free mass. CONCLUSIONS: Associations between age at menarche and cardiometabolic risk may be population-specific and are likely influenced by both current and historical nutritional and epidemiological contexts. Prospective studies are needed to clarify the role of childhood adiposity and other early life exposures on age at menarche and subsequent cardiometabolic risk.

Cardiovascular risk factors across different levels of urbanization in Brazilian Afro-derived communities (quilombos).

OBJECTIVES: The frequency of cardiovascular diseases has increased throughout the world. People of African descent have been disproportionately affected, particularly if they reside in urban settings. In this work, we evaluate risk factors associated with cardiovascular diseases (CVD) and other chronic diseases in rural and urban Afro-derived communities (quilombo) in Central Brazil. We also determine if there are associations between the frequency of CVD risk factors, sex, and proximity to urban environments. METHODS: Through a cross-sectional study of participants (n = 347) within three Brazilian Afro-derived communities: Kalunga (a semi-isolated rural community; n = 214), Cocalinho (a non-isolated rural village; n = 70), and Pé do Morro (an urban community; n = 63), we collected data regarding chronic disease (i.e., CVD, diabetes, and hypertension) risk through questionnaires, anthropometrics, blood pressure, and blood samples using standard protocols. Differences between variables were tested by the Chi-square test of Pearson and Fisher's Exact Test, independent sample t-tests, analysis of variances, and Kruskal-Wallis tests (p ≤ .05). RESULTS: The prevalence of hypertension, overweight, obesity, and other cardiovascular risk factors were higher in the non-isolated rural and urban communities than in the semi-isolated rural community. We found significant sex differences in the distribution of the CVD risk factors, with all occurring at a higher frequency among females. CONCLUSIONS: Our findings indicate that Brazilian Afro-derived communities are currently going through an epidemiological transition. The urban lifestyle and its environmental factors are likely contributing to an escalation in cardio-metabolic disease risk. However, the magnitude of this transition differentially impacts the sexes, as females suffer a higher frequency of risk factors compared to males.

Validity of anthropometric equation-based estimators of fat mass in Samoan adults.

INTRODUCTION: In 1999, a set of highly accurate Polynesian-specific equations to estimate adult body fat from non-invasive field measures of age, sex, height, and weight (Equation 1), age, sex, height, weight, and bioelectrical impedance analysis (BIA) resistance (Equation 2), and age, sex, height, weight, and the sum of two skinfold thicknesses (Equation 3) were published. The purpose of this study was to evaluate the performance of the equation-based estimators in a sample of Samoan adults recruited 20 years later between 2017 and 2019. METHODS: Age, sex, height, weight, BIA resistance, skinfold thickness, and fat mass as measured using dual energy x-ray absorptiometry (DXA) were available for 432 Samoan adults (mean age 50.9 years, 56% female) seen in 2017/2019. We compared equation-derived fat mass and DXA-derived fat mass using scatterplots and Pearson correlation coefficients. We then updated the equation coefficient estimates in a training set (2/3 of the sample) and evaluated the performance of the updated equations in a testing set (the remaining 1/3 of the sample). RESULTS: Equation-derived fat mass was strongly correlated with DXA-derived fat mass for Equation (1) (r2  = 0.95, n = 432), Equation (2) (r2  = 0.97, n = 425), and Equation (3) (r2  = 0.95, n = 426). Updating the equation coefficient estimates resulted in mostly similar coefficients and nearly identical testing set performance for Equation (1) (r2  = 0.96, n = 153), Equation (2) (r2  = 0.98, n = 150), and Equation (3) (r2  = 0.96, n = 150). CONCLUSIONS: The Polynesian-specific body fat estimation equations remained stable despite changing social and environmental factors and marked increase in obesity prevalence in Samoa.

C-reactive protein in adult Samoans: Population variation and physiological correlates.

OBJECTIVES: C-reactive protein (CRP) has been associated with adiposity and cardiometabolic disease risk in many populations but remains remarkably understudied in Pacific Islander populations. Here, we provide the first examination of correlates of CRP in adult Samoans (n = 108, ages 35-55 years) to test the hypotheses that CRP exhibits sex-dependent associations with measures of BMI, adiposity, and cardiometabolic disease risks. METHODS: We analyzed associations between measures of adiposity (total fat mass, visceral fat mass, percent total body fat), body mass index (BMI), cardiometabolic risks, behaviors, demographics, and CRP. Unadjusted analyses of CRP were undertaken using Pearson's pairwise, and Spearman's rank correlations; one-way analysis of variance and Kruskal-Wallis tests assessed variables by CRP quartiles. Adjusted analyses of CRP correlates were examined using generalized linear regression. RESULTS: Serum CRP ranged from 0.08 to 13.3 mg/L (median 1.4 mg/L) and varied significantly by sex t (108) = -2.47, p = .015. CRP was weakly to moderately associated with measures of adiposity and BMI (r and ρ ranged between 0.25 and 0.50, p < .05) and some cardiometabolic markers (including HbA1c, fasting insulin, and insulin resistance). CRP was significantly associated with percent body fat in women and men, adjusting for other variables. CONCLUSIONS: These data are among the first to demonstrate CRP correlates in a sample of adult Samoans. CRP differed by sex and was associated with BMI, adiposity, and some cardiometabolic risk markers. These data align with findings in other populations.

Persistence of anaemia among Samoan preschool age children: a longitudinal study.

OBJECTIVE: To characterise the prevalence and persistence of anaemia among Samoan children over a 2-3-year period. DESIGN: Data were from two consecutive waves (2015 and 2017-2018) of the Ola Tuputupua'e 'Growing up' study. Anaemia (Hb < 11·0 or 11·5 g/dl for 2-4 and ≥ 5 years old, respectively) was considered 'transient' when it occurred at only one wave or 'persistent' if it was present at two consecutive waves. Child, maternal and household correlates of anaemia were examined using log-binomial and modified Poisson regressions. SETTING: Eleven Samoan villages. PARTICIPANTS: Mother-child pairs (n 257) recruited in 2015 and reassessed in 2017-2018. RESULTS: Anaemia prevalence was 33·9 % in 2015 and 28·0 % in 2017-2018; 35·6 % of cases identified in 2015 were persistent. Risk of anaemia at only one wave was lower among children who were older in 2015 (age 4 v. 2 years, adjusted relative risk (aRR) = 0·54, (95 % CI 0·35, 0·84), P = 0·007), had older mothers (≥ 40 v. 18-29 years, aRR = 0·61, (95 % CI 0·39, 0·95), P = 0·029) and had higher daily sodium intake (for every 100 mg/d, aRR = 0·97, (95 % CI 0·95, 0·99), P = 0·003) than children with no anaemia. Children whose anaemia persisted were more likely to have had a mother with anaemia (aRR = 2·13, (95 % CI 1·17, 3·89), P = 0·013) and had higher daily dietary iron intake (for every 10 mg/d, aRR = 4·69, (95 % CI 1·33, 16·49), P = 0·016) than those with no anaemia. CONCLUSIONS: Alongside broadly targeted prevention efforts, which are warranted given the moderate-high anaemia prevalence observed, specific attention should be paid to children with risk factors for persistent anaemia. Routine screening of children whose mothers have anaemia should be encouraged.

Assessing the impact of high blood pressure referrals on hypertension awareness and management, BMI, and blood pressure values in adult Samoans 2010-2019.

The Samoan population has experienced rapid increases in the prevalence of non-communicable diseases (NCDs) and NCD risk factors over the last 30 years. However, understanding how increased awareness and treatment of these conditions in reducing disease burden remains understudied. Using data from a longitudinal study (2010-2019) of cardiometabolic health among Samoan adults, we assess the impact of a referral for elevated blood pressure (BP) on changes in BP, physician's diagnoses of hypertension and medication use, body mass index (BMI), and other risk factors for elevated BP. Analyses compared adult Samoans (n = 328) who in 2010 either (1) received a referral for elevated BP (BP ≥ 140/90 mmHg) or (2) had measured BP indicative of pre-hypertension (BP ≥ 120/80 mmHg) but were not referred. Data were analysed using linear and logistic regression, paired T- and McNemar's tests, and Wilcoxon Rank Sum assessments. Referrals in 2010 significantly increased the odds of reporting a physician's diagnosis of hypertension (OR 2.16; 1.18, 3.95) and hypertension medication use (OR 3.52; 1.86, 6.73) in 2018; however, referrals, medication use, and diagnoses were not associated with BP values or reduced odds of having elevated BP. Despite the referral having positive effects on hypertension-related health care, our results demonstrate that other factors are influencing effective BP/hypertension control. We advocate for greater engagement of health researchers with local health sector actors to improve the probability that researcher-provided health referrals will result in long-term health improvements.

Early maturity, shortened stature, and hardship: Can life-history trade-offs indicate social stratification and income inequality in the United States?

OBJECTIVE: Life-history strategies promote reproductive fitness and survival. Limited energy availability and competing energetic demands between life-history decisions may result in organismal trade-offs leading to selection for "optimal" traits that facilitate fitness and survival in present environmental conditions. Few life-history analyses have been conducted in food abundant/high resource human populations. Here, we use a life-history theory framework integrated with a biocultural approach to assess whether trade-offs between growth (height) and the onset of reproductive maturation (ages at menarche) were observed in a sample of adult women living in the United States. METHODS: Adult women (18 years and older) from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2006 were analyzed using complex survey regression to evaluate associations between ages at menarche, height, and biological, socio-economic, demographic, and anthropometric variables. Associations between stature, ages at menarche, and socio-economic status (household income and education level) suggest life-history trade-offs in this populations may be mitigated by access to resources and marginalization. CONCLUSIONS: These study results have applied public health implications. We demonstrate that females who experience early menarche in the US population achieve short stature. Our study also demonstrates the need for implementing life-history analyses in Western affluent populations, where marginalization may result in life-history trade-offs.

Pregnancy and immune stimulation: re-imagining the fetus as parasite to understand age-related immune system changes in US women.

OBJECTIVES: Pregnancy can increase production of Immunoglobulin E (IgE), an immune response more often directed towards parasite infections. An absence of parasitism makes the US population ideal to test the hypothesis that the maternal immune system recognizes a fetus as a parasite. We predict that total IgE levels are positively associated with a history of pregnancy across all ages of adult women, mirroring patterns of IgE in parasitized populations. METHODS: Reproductive-aged women (n = 2201) from the National Health and Nutrition Examination Survey 2005-2006 were analyzed in a cross-sectional design using complex survey regression and multiple imputation to evaluate associations between total IgE levels, pregnancy history, and interactions between age and pregnancy. RESULTS: Women with a history of pregnancy have significantly higher IgE levels and a significantly shallower slope of IgE levels across ages (P = .031). CONCLUSIONS: This research supports the hypothesis that maternal immune systems respond to prior pregnancies as they do to macro-parasitic exposures, and may modify the expected linear declines of IgE levels in women that accompanies aging. These finding have implications for understanding the evolution of internal gestation in mammals.

When the cold gets under your skin: Evidence for brown adipose tissue activity in Samoan adults.

OBJECTIVES: Brown adipose tissue (BAT) is a heat-producing organ aiding nonshivering thermogenesis (NST) during cold stress. Due to its potential cold-adaptive role BAT has been predominantly studied in cold and temperate climate populations, but not among warm-climate adults. This work explores if BAT activity can be inferred in Samoans. MATERIALS AND METHODS: We inferred BAT activity by comparing metabolic rate and surface heat dissipation using indirect calorimetry and thermal imaging between room temperature and cold exposure among Samoans (N = 61, females: n = 38) from 'Upolu Island, Samoa. BAT activity was inferred using ANOVA linear regression models with the variables measured at cold exposure as outcomes. T-tests were used to compare changes in surface temperature between room temperature and cold exposure. RESULTS: Metabolic rate significantly increased after cooling. In both the supraclavicular area, a known BAT location, and the sternum, a non-BAT location, temperatures decreased significantly upon cold exposure. Differences in supraclavicular temperatures between room temperature and cold were significantly smaller than differences in sternum temperatures between exposures. These results suggest that BAT thermogenesis occurred in known BAT-locations and thus contributed to NST during cooling. CONCLUSIONS: This study adds to our understanding of BAT activity across different populations and climates. Further study may illuminate whether the cold-adaptive properties of BAT may have played a role in the successful expansion of populations across the globe, including warm-climate groups.

Accelerometer-Based Estimates of Physical Activity and Sedentary Time Among Samoan Adults.

BACKGROUND: The prevalence of obesity-related cardiometabolic disease in Samoa is among the highest globally. While physical activity is a modifiable risk factor for obesity-related disease, little is known about physical activity levels among adult Samoans. Using wrist-worn accelerometer-based devices, this study aimed to characterize physical activity among Samoan adults. METHODS: Samoan adults (n = 385; 55% female, mean [SD] age 52 [10] y) wore Actigraph GT3X+ devices for 7 to 10 days. General linear models were used to examine mean daily minutes of sedentary time, light physical activity, and moderate to vigorous physical activity by various participant characteristics. RESULTS: Time spent in moderate to vigorous physical activity did not differ statistically between men (88 [5] min; 95% confidence interval [CI], 80-97) and women (78 [4] min; 95% CI, 70-86; P = .08). Women, however, spent more time than men in light physical activity: 380 (7) minutes (95% CI, 367-393) versus 344 (7) minutes (95% CI, 329-358; P < .001). While there were no differences in physical activity by census region, education, or occupation among women, men in urban areas spent significantly less time in moderate to vigorous physical activity than those in peri-urban and rural areas (P = .015). Women with class II/III obesity spent more time in sedentary activities than those with healthy weight or overweight/class I obesity (P = .048). CONCLUSIONS: This study characterizes physical activity among Samoan adults and highlights variation by sex, urbanicity, and weight status. In providing initial device-measured estimates of physical activity in Samoa, this analysis establishes a baseline from which the success of future attempts to intervene on physical activity may be assessed.

Associations between fasting glucose rate-of-change and the missense variant, rs373863828, in an adult Samoan cohort.

BACKGROUND: The A allele of rs373863828 in CREB3 regulatory factor is associated with high Body Mass Index, but lower odds of type 2 diabetes. These associations have been replicated elsewhere, but to date all studies have been cross-sectional. Our aims were (1) to describe the development of type 2 diabetes and change in fasting glucose between 2010 and 2018 among a longitudinal cohort of adult Samoans without type 2 diabetes or who were not using diabetes medications at baseline, and (2) to examine associations between fasting glucose rate-of-change (mmol/L per year) and the A allele of rs373863828. METHODS: We describe and test differences in fasting glucose, the development of type 2 diabetes, body mass index, age, smoking status, physical activity, urbanicity of residence, and household asset scores between 2010 and 2018 among a cohort of n = 401 adult Samoans, selected to have a ~2:2:1 ratio of GG:AG: AA rs373863828 genotypes. Multivariate linear regression was used to test whether fasting glucose rate-of-change was associated with rs373863828 genotype, and other baseline variables. RESULTS: By 2018, fasting glucose and BMI significantly increased among all genotype groups, and a substantial portion of the sample developed type 2 diabetes mellitus. The A allele was associated with a lower fasting glucose rate-of-change (ß = -0.05 mmol/L/year per allele, p = 0.058 among women; ß = -0.004 mmol/L/year per allele, p = 0.863 among men), after accounting for baseline variables. Mean fasting glucose and mean BMI increased over an eight-year period and a substantial number of individuals developed type 2 diabetes by 2018. However, fasting glucose rate-of-change, and type 2 diabetes development was lower among females with AG and AA genotypes. CONCLUSIONS: Further research is needed to understand the effect of the A allele on fasting glucose and type 2 diabetes development. Based on our observations that other risk factors increased over time, we advocate for the continued promotion for diabetes prevention and treatment programming, and the reduction of modifiable risk factors, in this setting.

Identifying patient preferences for diabetes care: A protocol for implementing a discrete choice experiment in Samoa.

In Samoa, adult Type 2 diabetes prevalence has increased within the past 30 years. Patient preferences for care are factors known to influence treatment adherence and are associated with reduced disease progression and severity. However, patient preferences for diabetes care, generally, are understudied, and other patient-centered factors such as willingness-to-pay (WTP) for diabetes treatment have never been explored in this setting. Discrete Choice Experiments (DCE) are useful tools to elicit preferences and WTP for healthcare. DCEs present patients with hypothetical scenarios composed of a series of multi-alternative choice profiles made up of attributes and levels. Patients choose a profile based on which attributes and levels may be preferable for them, thereby quantifying and identifying locally relevant patient-centered preferences. This paper presents the protocol for the design, piloting, and implementation of a DCE identifying patient preferences for diabetes care, in Samoa. Using an exploratory sequential mixed methods design, formative data from a literature review and semi-structured interviews with n = 20 Samoan adults living with Type 2 diabetes was used to design a Best-Best DCE instrument. Experimental design procedures were used to reduce the number of choice-sets and balance the instrument. Following pilot testing, the DCE is being administered to n = 450 Samoan adults living with diabetes, along with associated questionnaires, and anthropometrics. Subsequently, we will also be assessing longitudinally how preferences for care change over time. Data will be analyzed using progressive mixed Rank Order Logit models. The results will identify which diabetes care attributes are important to patients (p < 0.05), examine associations between participant characteristics and preference, illuminate the trade-offs participants are willing to make, and the probability of uptake, and WTP for specific attributes and levels. The results from this study will provide integral data useful for designing and adapting efficacious diabetes intervention and treatment approaches in this setting.

Protocol: Implementation and evaluation of an adolescent-mediated intervention to improve glycemic control and diabetes self-management among Samoan adults.

BACKGROUND: Diagnoses of Type 2 Diabetes in the United States have more than doubled in the last two decades. One minority group at disproportionate risk are Pacific Islanders who face numerous barriers to prevention and self-care. To address the need for prevention and treatment in this group, and building on the family-centered culture, we will pilot test an adolescent-mediated intervention designed to improve the glycemic control and self-care practices of a paired adult family member with diagnosed diabetes. METHODS: We will conduct a randomized controlled trial in American Samoa among n = 160 dyads (adolescent without diabetes, adult with diabetes). Adolescents will receive either a six-month diabetes intervention or a leadership and life skills-focused control curriculum. Aside from research assessments we will have no contact with the adults in the dyad who will proceed with their usual care. To test our hypothesis that adolescents will be effective conduits of diabetes knowledge and will support their paired adult in the adoption of self-care strategies, our primary efficacy outcomes will be adult glycemic control and cardiovascular risk factors (BMI, blood pressure, waist circumference). Secondarily, since we believe exposure to the intervention may encourage positive behavior change in the adolescent themselves, we will measure the same outcomes in adolescents. Outcomes will be measured at baseline, after active intervention (six months post-randomization) and at 12-months post-randomization to examine maintenance effects. To determine potential for sustainability and scale up, we will examine intervention acceptability, feasibility, fidelity, reach, and cost. DISCUSSION: This study will explore Samoan adolescents' ability to act as agents of familial health behavior change. Intervention success would produce a scalable program with potential for replication in other family-centered ethnic minority groups across the US who are the ideal beneficiaries of innovations to reduce chronic disease risk and eliminate health disparities.

Cascades of diabetes and hypertension care in Samoa: Identifying gaps in the diagnosis, treatment, and control continuum - a cross-sectional study.

BACKGROUND: Samoa is a Pacific Island country facing one of the highest burdens of non-communicable disease globally. METHODS: In this study, we apply a cascade-of-care approach to understand gaps in the awareness, treatment, and control cascade of diabetes and hypertension in a cross-sectional, convenience sample of 703 young, high-risk Samoan adults (29.5-50.9 years). FINDINGS: Non-communicable diseases were prevalent in the study sample: 19.5% (95% CI: 16.6%-22.7%) of participants had diabetes; 47.6% (95% CI: 43.7%-51.4%) presented with pre-diabetes or diabetes; 31.0% (95% CI: 27.5%-34.6%) had hypertension; and nearly 90% (95% CI: 86.7%-91.5%) had overweight or obesity. Among those with diabetes and hypertension, only 20.5% (95% CI: 13.9%-28.4%) and 11.8% (95% CI: 7.8%-16.9%) of participants were aware of their condition, respectively. Only 0.8% (95% CI: 0.0%-4.2%) of all participants with diabetes had achieved glycemic control; only 2.8% (95% CI: 1.1%-6.1%) of those with hypertension achieved control. INTERPRETATION: We found a significant burden of diabetes and hypertension in Samoa, exceeding the recent prevalence estimates of other low- to middle-income countries by nearly two-fold. A severe unmet need in both detection and subsequent control and monitoring of these chronic conditions exists. Our results suggest that the initial diagnosis and surveillance stage in the cascade of care for chronic conditions should be a major focus of primary care efforts; national screening campaigns and programs that leverage village and district nurses to deliver community-based primary care may significantly impact gap closure in the NCD cascade. FUNDING: This study was supported by the U.S. National Institutes of Health R01HL140570 (PIs: McGarvey and DeLany); AR was supported by NIH FIC D43TW010540; HK and AR-C were supported by the Minority Health and Health Disparities International Research Training (MHIRT) Program at Brown University, NIH Grant # 5T37MD008655.

Improving services for chronic non-communicable diseases in Samoa: an implementation research study using the care cascade framework.

OBJECTIVE: Samoa needs to intensify the response to the growing non-communicable disease burden. This study aimed to assess bottlenecks in the care continuum and identify possible solutions. METHODS: The mixed-methods study used the cascade framework as an analysis tool and hypertension as a tracer condition for chronic non-communicable diseases. Household survey data were integrated with medical record data of hypertension patients and results from focus group discussions with patients and healthcare providers. RESULTS: Hypertension prevalence was 38.1% but only 4.7% of hypertensive individuals had controlled blood pressure. There were large gaps in the care continuum especially at screening and referral due to multiple socio-cultural, economic and service delivery constraints. CONCLUSIONS: In Samoa, care for chronic non-communicable diseases is not effectively addressing patient needs. This calls for better health communication, demand creation, treatment support, nutritional interventions and health service redesign, with a focus on primary healthcare and effective patient and community engagement. Implications for public health: The proposed actions can improve the reach, accessibility, quality and effectiveness of Samoa's chronic care services. Health system redesign is necessary to ensure continuity of care and more effective primary prevention. The findings are useful for other countries in the region facing similar challenges.

The protective effect of rs373863828 on type 2 diabetes does not operate through a body composition pathway in adult Samoans.

OBJECTIVE: The aim of this study was to understand whether the paradoxical association of missense variant rs373863828 in CREB3 regulatory factor (CREBRF) with higher BMI but lower odds of diabetes is explained by either metabolically favorable body fat distribution or greater fat-free mass. METHODS: This study explored the association of the minor allele with dual-energy x-ray absorptiometry-derived body composition in n = 421 Samoans and used path analysis to examine the mediating role of fat and fat-free mass on the relationship between rs373863828 and fasting glucose. RESULTS: Among females, the rs373863828 minor A allele was associated with greater BMI. There was no association of genotype with percent body fat, visceral adiposity, or fat distribution in either sex. In both females and males, lean mass was greater with each A allele: 2.16 kg/copy (p = 0.0001) and 1.73 kg/copy (p = 0.02), respectively. Path analysis showed a direct negative effect of rs373863828 genotype on fasting glucose (p = 0.004) consistent with previous findings, but also an indirect positive effect on fasting glucose operating through fat-free mass (p = 0.027). CONCLUSIONS: The protective effect of rs373863828 in CREBRF, common among Pacific Islanders, on type 2 diabetes does not operate through body composition. Rather, the variant's effects on body size/composition and fasting glucose likely operate via different, tissue-specific mechanisms.

Exploring the Paradoxical Relationship of a Creb 3 Regulatory Factor Missense Variant With Body Mass Index and Diabetes Among Samoans: Protocol for the Soifua Manuia (Good Health) Observational Cohort Study.

BACKGROUND: The prevalence of obesity and diabetes in Samoa, like many other Pacific Island nations, has reached epidemic proportions. Although the etiology of these conditions can be largely attributed to the rapidly changing economic and nutritional environment, a recently identified genetic variant, rs373863828 (CREB 3 regulatory factor, CREBRF: c.1370G>A p.[R457Q]) is associated with increased odds of obesity, but paradoxically, decreased odds of diabetes. OBJECTIVE: The overarching goal of the Soifua Manuia (Good Health) study was to precisely characterize the association of the CREBRF variant with metabolic (body composition and glucose homeostasis) and behavioral traits (dietary intake, physical activity, sleep, and weight control behaviors) that influence energy homeostasis in 500 adults. METHODS: A cohort of adult Samoans who participated in a genome-wide association study of adiposity in Samoa in 2010 was followed up, based on the presence or absence of the CREBRF variant, between August 2017 and March 2019. Over a period of 7-10 days, each participant completed the main study protocol, which consisted of anthropometric measurements (weight, height, circumferences, and skinfolds), body composition assessment (bioelectrical impedance and dual-energy x-ray absorptiometry), point-of-care glycated hemoglobin measurement, a fasting blood draw and oral glucose tolerance test, urine collection, blood pressure measurement, hand grip strength measurement, objective physical activity and sleep apnea monitoring, and questionnaire measures (eg, health interview, cigarette and alcohol use, food frequency questionnaire, socioeconomic position, stress, social support, food and water insecurity, sleep, body image, and dietary preferences). In January 2019, a subsample of the study participants (n=118) completed a buttock fat biopsy procedure to collect subcutaneous adipose tissue samples. RESULTS: Enrollment of 519 participants was completed in March 2019. Data analyses are ongoing, with results expected in 2020 and 2021. CONCLUSIONS: While the genetic variant rs373863828, in CREBRF, has the largest known effect size of any identified common obesity gene, very little is currently understood about the mechanisms by which it confers increased odds of obesity but paradoxically lowered odds of type 2 diabetes. The results of this study will provide insights into how the gene functions on a whole-body level, which could provide novel targets to prevent or treat obesity, diabetes, and associated metabolic disorders. This study represents the human arm of a comprehensive and integrated approach involving humans as well as preclinical models that will provide novel insights into metabolic disease. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/17329.