Evolutionary origins of insulin resistance: a behavioral switch hypothesis

<p>Abstract</p> <p>Background</p> <p>Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate.</p> <p>Presentation of the hypothesis</p> <p>We propose a hypothesis that insulin resistance is a socio-ecological adaptation that mediates two phenotypic transitions, (i) a transition in reproductive strategy from "r" (large number of offspring with little investment in each) to "K" (smaller number of offspring with more investment in each) and (ii) a transition from "stronger to smarter" or "soldier to diplomat" i.e. from relatively more muscle dependent to brain dependent lifestyle. A common switch could have evolved for the two transitions since the appropriate environmental conditions for the two transitions are highly overlapping and interacting.</p> <p>Testing the hypothesis</p> <p>Gestational insulin resistance diverts more energy through the placenta, resulting in increased investment per offspring. On the other hand, insulin resistance is associated with reduced ovulation. The insulin signaling pathway is also related to longevity. Insulin resistance diverts more nutrients to the brain as compared to muscle. Also, hyperinsulinemia has direct positive effects on cognitive functions of the brain. The hypothesis gets support from known patterns in human clinical data and recent research on the molecular interactions in the insulin signaling pathway. Further we state many predictions of the hypothesis that can be tested experimentally or epidemiologically.</p> <p>Implications of the hypothesis</p> <p>The hypothesis can bring about a significant change in the line of treatment as well as public health policies for the control of metabolic syndrome.</p

Developmental origins of secondary school dropout in rural India and its differential consequences by sex: A biosocial life-course analysis

We developed a biosocial life-course conceptual approach to investigate maternal and household predictors of secondary school dropout, and to ascertain whether the consequences of dropout differ between girls and boys. We analysed longitudinal biomedical data on 648 mother-child dyads from rural Maharashtra, India. Both maternal (low education, early marriage age, shorter pregnancy duration) and household (low paternal education, low socio-economic status) traits independently predicted dropout. Poor child growth and educational trajectories also predicted dropout, mediating the association of only maternal education. Some girls married despite completing secondary education, suggesting the value of education may be subordinated to the marriage market

Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight:a systematic review and meta-analysis

Background: Vitamin B-12 and folate are micronutrients essential for normal embryogenesis. Vitamin B-12 insufficiency in pregnancy is high in certain parts of the world, such as India, and although this has been linked to low birth weight (LBW) in these populations, the relation between vitamin B-12 and birth weight (BW) elsewhere is unknown. Objectives: We performed a systematic review to assess 1) the worldwide prevalence of vitamin B-12 insufficiency in pregnancy and 2) its association with BW. Design: A search of 5 electronic databases was performed to identify eligible articles. Random-effects meta-analysis was conducted according to geographic regions and pregnancy trimesters for the prevalence subreview and by categorical measures of BW. Results: A total of 57 and 23 articles were included for the prevalence and BW subreviews, respectively. The pooled estimates of vitamin B-12 insufficiency were 21%, 19%, and 29% in the first, second, and third trimesters, respectively, with high rates for the Indian subcontinent and the Eastern Mediterranean. The large heterogeneity between studies was partially addressed by creating a standardized score for each study (mean vitamin B-12 insufficiency ÷ cutoff value), which internally corrected for geographic region, trimester, and assay type. Twelve of the 13 longitudinal studies included showed a decrease in mean or median vitamin B-12 across trimesters. Pooled analysis showed nonsignificantly lower maternal vitamin B-12 concentrations in LBW than in normal-BW infants and higher odds of LBW with lower vitamin B-12 values (adjusted OR: 1.70; 95% CI: 1.16, 2.50), but studies from India largely contributed to the latter. Conclusions: Our review indicates that vitamin B-12 insufficiency during pregnancy is common even in nonvegetarian populations and that concentrations of vitamin B-12 decrease from the first to the third trimester. There is no consistent association between vitamin B-12 insufficiency and LBW. However, given the long-term risks of LBW, this observation warrants further cohort studies and randomized controlled trials

Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children

AIMS/HYPOTHESIS: In an Indian birth cohort, higher maternal homocysteine concentration in pregnancy was associated with lower birthweight of the offspring. Lower maternal vitamin B12 and higher folate concentrations were associated with higher offspring insulin resistance. Disordered one-carbon metabolism during early development may increase later metabolic risk. We explored these associations in another birth cohort in India at three age points.METHODS: We measured plasma vitamin B12, folate and homocysteine concentrations at 30 ± 2 weeks' gestation in 654 women who delivered at one hospital. Neonatal anthropometry was recorded, and the children's glucose and insulin concentrations were measured at 5, 9.5 and 13.5 years of age. Insulin resistance was estimated using HOMA of insulin resistance (HOMA-IR).RESULTS: Maternal homocysteine concentrations were inversely associated with all neonatal anthropometric measurements (p &lt; 0.05), and positively associated with glucose concentrations in the children at 5 (30 min; p = 0.007) and 9.5 years of age (120 min; p = 0.02). Higher maternal folate concentrations were associated with higher HOMA-IR in the children at 9.5 (p = 0.03) and 13.5 years of age (p = 0.03). Maternal vitamin B12 concentrations were unrelated to offspring outcomes.CONCLUSIONS/INTERPRETATION: Maternal vitamin B12 status did not predict insulin resistance in our cohort. However, associations of maternal homocysteine and folate concentrations with birth size, and with childhood insulin resistance and glycaemia in the offspring, suggest a role for nutritionally driven disturbances in one-carbon metabolism in fetal programming of diabetes

Daily Folic Acid and/or Vitamin B12 Supplementation Between 6 and 30 Months of Age and Cardiometabolic Risk Markers After 6–7 Years: A Follow-Up of a Randomized Controlled Trial

Background Deficiencies of vitamin B12 and folate are associated with elevated concentrations of metabolic markers related to CVDs. Objectives We investigated the effect of supplementation of vitamin B12 with or without folic acid for 6 mo in early childhood on cardiometabolic risk markers after 6–7 y. Methods This is a follow-up study of a 2 × 2 factorial, double-blind, randomized controlled trial of vitamin B12 and/or folic acid supplementation in 6–30-mo-old children. The supplement contained 1.8 μg of vitamin B12, 150 μg of folic acid, or both, constituting >1 AI or recommended daily allowances for a period of 6 mo. Enrolled children were contacted again after 6 y (September 2016–November 2017), and plasma concentrations of tHcy, leptin, high molecular weight adiponectin, and total adiponectin were measured (N = 791). Results At baseline, 32% of children had a deficiency of either vitamin B12 (<200 pmol/L) or folate (<7.5 nmol/L). Combined supplementation of vitamin B12 and folic acid resulted in 1.19 μmol/L (95% CI: 0.09; 2.30 μmol/L) lower tHcy concentration 6 y later compared to placebo. We also found that vitamin B12 supplementation was associated with a lower leptin–adiponectin ratio in subgroups based on their nutritional status. Conclusions Supplementation with vitamin B12 and folic acid in early childhood was associated with a decrease in plasma tHcy concentrations after 6 y. The results of our study provide some evidence of persistent beneficial metabolic effects of vitamin B12 and folic acid supplementation in impoverished populations.publishedVersio

Biosocial life‐course factors associated with women's early marriage in rural India: The prospective longitudinal Pune Maternal Nutrition Study

Abstract Objectives: By convention, women's early marriage is considered a sociocultural decision sensitive to factors acting during adolescence such as poverty, early menarche, and less education. Few studies have examined broader risk factors in the natal household prior to marriage. We investigated whether biosocial markers of parental investment through the daughters' life-course were associated with early marriage risk in rural India. We used an evolutionary perspective to interpret our findings. Materials and Methods: A prospective cohort recruited mothers at preconception. Children were followed from birth to age 21 years. Multivariable logistic regression models estimated odds ratios of marrying early (<19 years) associated first with wealth, age at menarche and education, and then with broader markers of maternal phenotype, natal household characteristics, and girls' growth trajectories. Models adjusted for confounders. Results: Of 305 girls, 71 (23%) had married early. Early married girls showed different patterns of growth compared to unmarried girls. Neither poverty nor early menarche predicted early marriage. Girls' non-completion of lower secondary school predicted early marriage, explaining 19% of the variance. Independent of girls' lower schooling, nuclear household, low paternal education, shorter gestation, and girls' poor infant weight gain were associated with marrying early, explaining in combination 35% of the variance. Discussion: Early marriage reflects “future discounting,” where reduced parental investment in daughters' somatic and educational capital from early in her life favors an earlier transition to the life-course stage when reproduction can occur. Interventions initiated in adolescence may occur too late in the life-course to effectively delay women's marriage.University of Cambridge, Grant/Award Numbers: Mary Euphrasia Mosley Fund, Suzy Paine Fund (Faculty of Economics), William Vaughn Lewis & Philip Lake II (Geography). Medical Research Council, Grant/Award Number: MR/J000094/1

The Elevated Susceptibility to Diabetes in India: An Evolutionary Perspective

India has rapidly become a “diabetes capital” of the world, despite maintaining high rates of under-nutrition. Indians develop diabetes at younger age and at lower body weights than other populations. Here, we interpret these characteristics in terms of a “capacity–load” model of glucose homeostasis. Specifically, we assume that glycemic control depends on whether the body’s “metabolic capacity,” referring to traits, such as pancreatic insulin production and muscle glucose clearance, is able to resolve the “metabolic load” generated by high levels of body fat, high dietary glycemic load, and sedentary behavior. We employ data from modern cohorts to support the model and the interpretation that elevated diabetic risk among Indian populations results from the high metabolic load imposed by westernized lifestyles acting on a baseline of low metabolic capacity. We attribute this low metabolic capacity to the low birth weight characteristic of Indian populations, which is associated with short stature and low lean mass in adult life. Using stature as a marker of metabolic capacity, we review archeological and historical evidence to highlight long-term declines in Indian stature associated with adaptation to several ecological stresses. Underlying causes may include increasing population density following the emergence of agriculture, the spread of vegetarian diets, regular famines induced by monsoon failure, and the undermining of agricultural security during the colonial period. The reduced growth and thin physique that characterize Indian populations elevate susceptibility to truncal obesity, and increase the metabolic penalties arising from sedentary behavior and high glycemic diets. Improving metabolic capacity may require multiple generations; in the meantime, efforts to reduce the metabolic load will help ameliorate the situation

Body size, body composition, and fat distribution: a comparison of young New Zealand men of European, Pacific Island, and Asian Indian ethnicities

Aims To investigate body size and body fat relationships and fat distribution in young healthy men drawn from New Zealand European, Pacific Island, and Asian Indian populations.Method A total of 114 healthy men (64 European, 31 Pacific Island, 19 Asian Indian) aged 17&ndash;30 years underwent measurements of height, weight, and body composition by total body dual-energy X-ray absorptiometry (DXA). Body mass index (BMI) was then calculated. Percent body fat (%BF), fat-free mass, bone mineral content, bone mineral density, abdominal fat, thigh fat, and appendicular skeletal muscle mass (ASMM) were obtained from the DXA scans.Results For the same BMI, %BF for Pacific Island men was 4% points lower and for Asian Indian men was 7&ndash;8% points higher compared to Europeans. Compared to European men for the same %BF, BMI was 2&ndash;3 units higher for Pacific Island, and 3&ndash;6 units lower for Asian Indian. The ratio of abdominal fat to thigh fat, adjusted for height, weight, and %BF, was significantly higher for Asian Indian men than European (p=0.022) and Pacific Island (p=0.002) men. ASMM, adjusted for height and weight, was highest in Pacific Island and lowest in Asian Indian men.Conclusions The relationship between %BF and BMI is different for European, Pacific Island, and Asian Indian men which may, at least in part, be due to differences in muscularity. Asian Indians have more abdominal fat deposition than their European and Pacific Island counterparts. Use of universal BMI cut-off points are not appropriate for comparison of obesity prevalence between these ethnic groups. <br /

Iodine status during pregnancy in India and related neonatal and infant outcomes

Objective: To document iodine status in Indian pregnancies, associations with maternal diet and demographics, and offspring developmental measures. Design: Longitudinal study following mothers through pregnancy and offspring up to 24 months. Setting: Rural health-care centre (Vadu) and urban antenatal clinic (Pune) in the Maharashtra region of India. Subjects: Pregnant mothers at 17 (n 132) and 34 weeks’ (n 151) gestation and their infants from birth to the age of 24 months. Results: Median urinary iodine concentration (UIC) was 203 and 211 μg/l at 17 and 34 weeks of pregnancy, respectively (range 26–800 μg/l). Using the UIC distribution adjusted for within-person variation, extreme UIC quartiles were compared for predictors and outcomes. There was no correlation between UIC at 17 and 34 weeks, but 24 % of those with UIC in the lowest quartile at 17 weeks had UIC in the same lowest quartile at 34 weeks. Maternal educational, socio-economic status and milk products consumption (frequency) were different between the lowest and highest quartile of UIC at 34 weeks. Selected offspring developmental outcomes differed between the lowest and highest UIC quartiles (abdominal circumference at 24 months, subscapular and triceps skinfolds at 12 and 24 months). However, UIC was only a weak predictor of subscapular skinfold at 12 months and of triceps skinfold at 24 months. Conclusions: Median UIC in this pregnant population suggested adequate dietary provision at both gestational stages studied. Occasional high results found in spot samples may indicate intermittent consumption of iodine-rich foods. Maternal UIC had limited influence on offspring developmental outcomes

Association of preeclampsia with anthropometric measures and blood pressure in Indian children.

BACKGROUND AND OBJECTIVE: Birth weight and post-natal growth are important predictors of adult health. Preeclampsia (PE) is associated with low birth weight and may have long term effects on the health of the children. The current study aims to compare anthropometry and blood pressure between children of mothers with and without PE in an Indian cohort. METHODS: We studied children born to women with (PE; n = 211) and without preeclampsia (non-PE; n = 470) at Bharati Hospital, Pune, India. Anthropometry and blood pressure were measured in children at 3-7 years of age. Weight and height Z-scores were calculated using the WHO 2006 growth reference. Independent t-tests were used to compare means between the two groups, and associations between preeclampsia and child outcomes were analyzed using multiple linear regression, adjusting for potential confounders. RESULTS: Weight and height Z-scores (p = 0.04 and 0.008), and subscapular skinfold thickness (p = 0.03) were higher among children of PE compared with children of non-PE mothers. Systolic blood pressure was also higher in children of PE mothers (1.70 mmHg [95% CI 0.05, 2.90] p = 0.006). BMI and diastolic blood pressure did not differ between groups. In regression models adjusted for newborn weight and gestational age, current age and sex, and maternal height, BMI and socio-economic status, children of PE mothers had higher weight Z-score (0.27 SD [95%CI 0.06, 0.48] p = 0.01), height Z-score (0.28 SD [95%CI 0.09, 0.47] p = 0.005), and subscapular skinfold thickness (0.38 mm [95%CI 0.00, 0.76] p = 0.049). A trend for higher systolic blood pressure (1.59 mmHg [95%CI -0.02, 3.20] p = 0.053) in the children was also observed in the adjusted model. The difference in systolic blood pressure was attenuated after adjusting further for the child's weight and height (1.09 mmHg [95%CI -0.48, 2.67] p = 0.17). There was no evidence of differences in effects between boys and girls. CONCLUSION: Children of PE mothers were taller and heavier, and had higher systolic blood pressure, partly explained by their increased body size, than children of non-PE mothers. In utero exposure to preeclampsia may increase the risk of future cardiovascular disease