Diabetes In Later Life Research Articles

Less myostatin and more lean mass in large-born infants from nondiabetic mothers.

Sexagenarians born large are at lower risk for type 2 diabetes than those born small, a key feature of their body composition being a higher muscle mass, which explains their higher body mass index and also their lower fat-to-lean-mass ratio. Myogenesis is completed in early infancy under the inhibitory control of myostatin. We tested whether large-born infants from nondiabetic mothers develop an early surplus of lean mass while having a lower myostatinemia. Design, Methods, Study Participants, and Main Outcomes: In a longitudinal study (0-4 mo), we compared the body composition and endocrine markers (fasting glucose, insulin, IGF-1, high molecular weight adiponectin) of breast-fed appropriate- vs large-for-gestational-age infants (n = 125) from nondiabetic mothers. Circulating myostatin concentrations were assayed after collection of the above-mentioned data. The study was conducted at the University Hospital for Women and Children. There were no interventions. Between 0-4 months, large-for-gestational-age infants switched from an adipose to a lean body composition (due to a nearly 20% excess of lean mass) and to an insulin-sensitive and hyperadiponectinemic state while having low IGF-1 concentrations and the lowest myostatinemia hitherto reported in the human (all between P ≤ .01 and P ≤ .0001). Large-born infants from nondiabetic mothers were found to combine a low myostatinemia with an excess of lean mass. The fetal-neonatal control of myostatinemia deserves further attention because it could become a target of interventions that aim at reducing the risk for diabetes in later life by augmenting myogenesis in early life.

Parity and the risk of diabetes mellitus among Chinese women: a cross-sectional evidence from the Tongji-Dongfeng cohort study.

ObjectivesLittle is known about the long-term health impact of pregnancy on women. The objective of this study was to examine the association between parity and the risk of diabetes among a population of Chinese women.Study designA total of 14,196 women (aged ≥45 years) from the Dongfeng-Tongji Cohort study who had experienced at least one live birth completed baseline questionnaires, medical examinations, and provided baseline blood samples. Participants were categorized into four groups according to parity (one, two, three, or four or more live births). Logistic regression models were used to investigate the association between parity and the risk of diabetes after controlling potential confounders.ResultsThe prevalence of diabetes in the study population was 18.0% (2,552/14,196). Fasting plasma glucose levels increased with the increasing number of live births (P<0.001) and parity had a positive graded association with diabetes without adjustment for any covariates (P for trend <0.001). After adjusting for potential confounders, women who had had two, three, and four or more live births had 1.35 times (95% CI, 1.20–1.52), 1.59 times (95% CI, 1.39–1.82) and 1.44 times (95% CI, 1.21–1.71), respectively, higher risk of diabetes compared with women who had had one live birth.ConclusionMultiparity was associated with increasing risk of diabetes in this population of Chinese women. These findings suggested that multiparity may be a risk factor for the development of diabetes among Chinese women. Future studies are needed to examine the physiological changes during pregnancy for risk of diabetes in later life.

Effect of hyperglycaemia in pregnancy on adiposity in their infants in India: a protocol of a multicentre cohort study

IntroductionThe carbohydrate ‘fuel’ metabolism in a pregnant woman may have a long-term impact on the development of her offspring (‘fuel-mediated teratogenesis’ hypothesis) including in utero exposure to maternal hyperglycaemia leading...

The role of childhood social position in adult type 2 diabetes: evidence from the English Longitudinal Study of Ageing

BackgroundSocioeconomic circumstances in childhood and early adulthood may influence the later onset of chronic disease, although such research is limited for type 2 diabetes and its risk factors at the different stages of life. The main aim of the present study is to examine the role of childhood social position and later inflammatory markers and health behaviours in developing type 2 diabetes at older ages using a pathway analytic approach.MethodsData on childhood and adult life circumstances of 2,994 men and 4,021 women from English Longitudinal Study of Ageing (ELSA) were used to evaluate their association with diabetes at age 50 years and more. The cases of diabetes were based on having increased blood levels of glycated haemoglobin and/or self-reported medication for diabetes and/or being diagnosed with type 2 diabetes. Father’s job when ELSA participants were aged 14 years was used as the measure of childhood social position. Current social characteristics, health behaviours and inflammatory biomarkers were used as potential mediators in the statistical analysis to assess direct and indirect effects of childhood circumstances on diabetes in later life.Results12.6 per cent of participants were classified as having diabetes. A disadvantaged social position in childhood, as measured by father’s manual occupation, was associated at conventional levels of statistical significance with an increased risk of type 2 diabetes in adulthood, both directly and indirectly through inflammation, adulthood social position and a risk score constructed from adult health behaviours including tobacco smoking and limited physical activity. The direct effect of childhood social position was reduced by mediation analysis (standardised coefficient decreased from 0.089 to 0.043) but remained statistically significant (p = 0.035). All three indirect pathways made a statistically significantly contribution to the overall effect of childhood social position on adulthood type 2 diabetes.ConclusionsChildhood social position influences adult diabetes directly and indirectly through inflammatory markers, adulthood social position and adult health behaviours.

Association between Gestational Weight Gain and Postpartum Diabetes: Evidence from a Community Based Large Cohort Study

We have investigated the prospective association between excess gestational weight gain (GWG) and development of diabetes by 21 years post-partum using a community-based large prospective cohort study in Brisbane, Australia. There were 3386 mothers for whom complete data were available on GWG, pre-pregnancy BMI and self-reported diabetes 21 years post-partum. We used The Institute of Medicine (IOM) definition to categorize GWG as inadequate, adequate and excessive. We found 839 (25.78%) mothers gained inadequate weight, 1,353 (39.96%) had adequate weight gain and 1,194 (35.26%) had gained excessive weight during pregnancy. At 21 years post-partum, 8.40% of mothers self-reported a diagnosis of diabetes made by their doctor. In the age adjusted model, we found mothers who gained excess weight during pregnancy were 1.47(1.11,1.94) times more likely to experience diabetes at 21 years post-partum compared to the mothers who gained adequate weight. This association was not explained by the potential confounders including maternal age, parity, education, race, smoking, TV watching and exercise. However, this association was mediated by the current BMI. There was no association for the women who had normal BMI before pregnancy and gained excess weight during pregnancy. The findings of this study suggest that women who gain excess weight during pregnancy are at greater risk of being diagnosed with diabetes in later life. This relationship is likely mediated through the pathway of post-partum weight-retention and obesity. This study adds evidence to the argument that excessive GWG during pregnancy for overweight mothers has long term maternal health implications.

Sending me up, sending me down

Sending me up, sending me down

A former career as a male elite athlete—does it protect against type 2 diabetes in later life?

The aim of this study was to determine the prevalence of impaired glucose regulation in male Finnish former elite athletes and age- and area-matched controls. We hypothesised that vigorous physical activity during young adulthood protects from disturbances in glucose regulation in later life. In 2008, 392 former male elite athletes (mean age 72.7 ± 6.1years) and 207 controls (mean age 71.6 ± 5.6years) participated in a clinical study (participation rate: 50.6%). The former athletes were divided into three groups based on their active career sport: endurance, mixed and power sports. Participants without a history of diabetes (n = 537) underwent a 2h 75g OGTT. Current volume of leisure-time physical activity (LTPA) was determined by self-reported questionnaires and expressed in metabolic equivalent hours (MET-h). Data on reimbursable diabetes medication from participants and non-participants was obtained from the register of the Finnish Social Insurance Institution. Compared with the controls, the former elite athletes had a significantly lower risk of type 2 diabetes (OR 0.72, 95% CI 0.53, 0.98). The risk of type 2 diabetes decreased with increased LTPA volume (OR 0.98, 95% CI 0.97, 0.99 per 1 MET-h/week). The former elite athletes also had a significantly lower risk of impaired glucose tolerance (IGT) than the controls (OR 0.58, 95% CI 0.38, 0.87). A former career as an elite athlete protected from both type 2 diabetes and IGT in later life. In addition, the volume of current LTPA was inversely associated with the prevalence of type 2 diabetes.

A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1.

Loss-of-function mutations in the KATP channel genes KCNJ11 and ABCC8 cause neonatal hyperinsulinism in humans. Dominantly inherited mutations cause less severe disease, which may progress to glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). We generated a mouse expressing SUR1-E1506K in place of SUR1. KATP channel inhibition by MgATP was enhanced in both homozygous (homE1506K) and heterozygous (hetE1506K) mutant mice, due to impaired channel activation by MgADP. As a consequence, mutant β-cells showed less on-cell KATP channel activity and fired action potentials in glucose-free solution. HomE1506K mice exhibited enhanced insulin secretion and lower fasting blood glucose within 8 weeks of birth, but reduced insulin secretion and impaired glucose tolerance at 6 months of age. These changes correlated with a lower insulin content; unlike wild-type or hetE1506K mice, insulin content did not increase with age in homE1506K mice. There was no difference in the number and size of islets or β-cells in the three types of mice, or evidence of β-cell proliferation. We conclude that the gradual development of glucose intolerance in patients with the SUR1-E1506K mutation might, as in the mouse model, result from impaired insulin secretion due a failure of insulin content to increase with age.

At the crossroads: transforming health systems to address women’s health across the life course

In 2010, the World Health Organization (WHO) published a report titled Women and health: today’s evidence, tomorrow’s agenda. The report summarized the evidence surrounding the health-related issues affecting girls and women throughout their life course1 and signalled the need for innovative strategies and new health service delivery models. Since then, other global initiatives, including the Women Deliver 2013 conference, the United Nations Commission on Information and Accountability for Women’s and Children’s Health, Family Planning 2020 and the call of the Global Fund to Fight AIDS, Tuberculosis and Malaria in support of child and maternal health, have kept the world focused on women’s health issues, particularly maternal mortality and universal access to reproductive health. Yet these initiatives do not address all the health problems that women are facing in the 21st century as a result of the epidemiological and demographic transitions. According to the Global Burden of Disease Study 2010, the years of life lost (YLLs) on account of conditions addressed under the Millenium Development Goals (MDGs) declined by 2.0% per year between 1990 and 2010, but those attributable to conditions not targeted under the MDGs increased by 0.8% per year. If these trends continue, by 2015 more than two thirds of all YLLs will be caused by conditions not included in the MDG framework.2 Noncommunicable diseases (NCDs) already represent 54% of the world’s burden of disability-adjusted life years; injuries represent an additional 11%.3 This is one reason that WHO, together with key global partners, conceived this theme issue on women’s health beyond reproduction. Our intention is to underscore the changing nature of the health problems confronting women and to highlight policies and strategies that low- and middle-income countries can implement.4 A life course approach to women’s health makes sense because many of the health problems faced by adult women have their roots in early life. Interventions that promote good nutrition during pregnancy, optimize early child development and facilitate access to health information, especially during adolescence, can lay the foundations for a healthy life in later years. Changing exposures across the life course, particularly in terms of harmful tobacco and alcohol use, unhealthy dietary habits and poor physical activity, pay important health dividends in the long term. This continuum can best be promoted by building on existing reproductive and maternal health services “diagonally” – i.e. by expanding the role of health workers, strengthening their skills and reorienting services towards the prevention and early detection and management of NCDs and their risk factors.5 For example, women with gestational diabetes have a significantly elevated risk of developing type 2 diabetes in later life, and antenatal care provides an opportunity to intervene early to try to prevent the subsequent onset of diabetes in this group. The life-course approach to women’s health involves several health system challenges. We need to better understand the epidemiological characteristics of diseases affecting adult women and the overlapping effects of gender inequalities and advancing age on women’s health. Data are still not regularly disaggregated by sex when collected or reported and age disaggregation is seldom done beyond 50 years of age. Particular attention should be paid to the consequences of harmful gender norms and roles and to the effects of stigma and social isolation among older people on patterns of disease, illness and mortality. The development of an evidence-based policy framework on the health of women across the life course is a formidable task for which WHO and its partners are seeking to bring together policy-makers and public health experts from around the world. The life-course approach to women’s health has three innovative aspects. First, it marks the convergence of three complementary domains: maternal and reproductive health, ageing and noncommunicable diseases. Second, it involves the development, piloting and testing of new health-care delivery systems featuring diagonal approaches and private–public partnerships. Third, it is driven by policy-makers engaged in applying knowledge translation methods that encourage the use of research and evidence in policy development and planning. This theme issue of the Bulletin and other initiatives, such as the Lancet Commission on Women’s Health, are intended to stimulate interest in women’s health beyond reproduction and to encourage joint, decisive action on the part of multiple stakeholders in promoting a life-course approach to women’s health.

Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes.

The development of the endocrine pancreas is controlled by a hierarchical network of transcriptional regulators. It is increasingly evident that this requires a tightly interconnected epigenetic "programme" to drive endocrine cell differentiation and maintain islet function. Epigenetic regulators such as DNA and histone-modifying enzymes are now known to contribute to determination of pancreatic cell lineage, maintenance of cellular differentiation states, and normal functioning of adult pancreatic endocrine cells. Persistent effects of an early suboptimal environment, known to increase risk of type 2 diabetes in later life, can alter the epigenetic control of transcriptional master regulators, such as Hnf4a and Pdx1. Recent genome-wide analyses also suggest that an altered epigenetic landscape is associated with the β cell failure observed in type 2 diabetes and aging. At the cellular level, epigenetic mechanisms may provide a mechanistic link between energy metabolism and stable patterns of gene expression. Key energy metabolites influence the activity of epigenetic regulators, which in turn alter transcription to maintain cellular homeostasis. The challenge is now to understand the detailed molecular mechanisms that underlie these diverse roles of epigenetics, and the extent to which they contribute to the pathogenesis of type 2 diabetes. In-depth understanding of the developmental and environmental epigenetic programming of the endocrine pancreas has the potential to lead to novel therapeutic approaches in diabetes.

In Hindsight

This study examines sex differences in the association between migration and exposure to an urban environment and overweight, hypertension and diabetes in later life. Interviews were conducted with 3,604 adults aged 50 and older in the Mexican Family Life Survey (MxFLS). Logistic regression analyses were used to examine the association between previous migration, urban exposure, and risk of overweight, hypertension, and diabetes. Migration itself was not associated with health outcomes after controlling for urban exposure. The risk of overweight and diabetes associated with urban exposure appeared to be greater for men. Sex differences were found in the covariates that helped explain differences in health between those with high and low urban exposure. These findings underscore the need to consider heterogeneity in health by urban exposure and by sex.

175 Maternal Diet and Type 2 Diabetes in the Offspring

It is over twenty years since epidemiological studies revealed that there was a relationship between patterns of early growth and risk of developing type 2 diabetes in later life. Studies...

Genetic origins of low birth weight

Smaller size at birth is associated with a higher risk of type 2 diabetes in later life, but the mechanisms behind this association are poorly understood. Genetic variants which influence susceptibility to type 2 diabetes via effects on insulin secretion or action are good candidates for association with birth weight because foetal insulin is a key foetal growth factor. This review will focus on recent progress in identifying associations between common genetic variants and birth weight. Foetal genetic variants at two loci (near CCNL1 and in ADCY5) were robustly associated with birth weight via the foetal genotype in the first genome-wide association study of birth weight. The birth weight-lowering allele at ADCY5 also predisposes to type 2 diabetes. In addition, evidence from studies of other type 2 diabetes loci is accumulating for association between the foetal risk alleles at CDKAL1 and HHEX-IDE and lower birth weight, and the maternal risk alleles at GCK and TCF7L2 and higher birth weight. The associations with birth weight at ADCY5, CDKAL1 and HHEX-IDE support the foetal insulin hypothesis, which proposed that type 2 diabetes and lower birth weight could be two phenotypes of the same genotype. The associations at GCK and TCF7L2 illustrate that maternal genes are also important determinants of birth weight.

Abundance of Circulating Preadipocyte Factor 1 in Early Life

OBJECTIVESoluble preadipocyte factor 1 (Pref-1) inhibits adipocyte differentiation. We tested whether circulating levels of soluble Pref-1 are higher in smaller fetuses.RESEARCH DESIGN AND METHODSWe performed longitudinal assessments of circulating Pref-1 in infants born appropriate for gestational age (AGA) or small for gestational age (SGA) and also in late-gestational women and in newborns on days 2 and 3.RESULTSAt birth, Pref-1 levels were ~100-fold higher than in adults, being in SGA fetuses ~50% higher than in AGA fetuses. By age 4 months, Pref-1 had reached near-adult levels and the original AGA versus SGA difference had disappeared. Pref-1 levels were low in late-gestational women and were still elevated in newborns.CONCLUSIONSPref-1 is abundantly present in the fetus, is higher in SGA than in AGA fetuses, and is likely to be of fetal origin. We speculate that Pref-1 in early life contributes to variation in postnatal adipocyte numbers, in the subsequent expandability of adipose tissue, and thus in the susceptibility to diabetes in later life.

Pregnancy Is a Screening Test for Later Life Cardiovascular Disease: Now What? Research Recommendations

Several months ago, we wrote a commentary describing pregnancy as a screening test for later life cardiovascular diseases in mothers (Roberts & Hubel, 2010). We emphasized the wellestablished relationship of preeclampsia and gestational diabetes with later life cardiovascular disease and carbohydrate intolerance, respectively. We also pointed out the less wellestablished relationships of preterm birth, other pregnancy disorders associated with abnormal placental implantation, and even pregnancy itself with later life heart disease. We further considered the purported protective effect of breastfeeding to reduce cardiovascular disease. In the presentation, we complained that the 2007 American Heart Association’s “Evidence Based Guidelines for Cardiovascular Disease Prevention in Women” (Mosca et al., 2007) did not include a pregnancy history as a part of the evaluation of cardiovascular risk for women. We are happy to point out that the new 2011 guidelines from the American Heart Association do include a recommendation to obtain a pregnancy history and also consider both preeclampsia and gestational diabetes as risk factors for later life maternal cardiovascular disease (Mosca et al., 2011). The question that now arises is how are we to use this information? For gestational diabetes, we need to determine themost cost-effective follow-up to at least identify and perhaps prevent diabetes in later life. For preeclampsia (and by extension other relevant pregnancy disorders), the answer is not at all obvious. Once the pregnancy history of preeclampsia is determined, what is next? Little information is available to guide actions for clinicians.What testing shouldbedone?When should this be done? Is there information to justify testing women with a history of

Offspring Birth Weight and Cardiovascular Risk in Parents—A Population-based HUNT 2 Study

Low birth weight is associated with increased risk of cardiovascular disease and type 2 diabetes in later life. The fetal insulin hypothesis suggests that shared genetic factors partly explain this association. If fetal genes predispose to both low birth weight and cardiovascular disease in adulthood, fathers of offspring with low birth weight should display an unfavorable profile of cardiovascular risk factors. To study this, the authors linked data on more than 14,000 parents, collected from the second Health Study of Nord Trøndelag County, Norway (HUNT 2, 1995-1997), to offspring data from the Norwegian Medical Birth Registry (1967-2005). Linear regression was used to study associations of offspring birth weight for gestational age with the parents' body mass index, waist circumference, blood pressure, glucose, and serum lipids. All analyses were adjusted for shared environment by means of the socioeconomic measures, lifestyle, and cardiovascular risk factors of the partner. The authors found that low offspring birth weight for gestational age was associated with increased paternal blood pressure, body mass index, waist circumference, and unfavorable levels of glucose and lipids. For mothers, associations similar to those for fathers were found for blood pressure, whereas associations in the opposite direction were found for glucose, lipids, and body mass index. The paternal findings strengthen the genetic hypothesis.

Animal models of maternal nutrition and altered offspring bone structure – Bone development across the lifecourse

It is widely accepted that the likelihood of offspring developing heart disease, stroke, or diabetes in later life, is influenced by the their in utero environment and maternal nutrition. There is increasing epidemiological evidence that osteoporosis in the offspring may also be influenced by the mother's nutrition during pregnancy. This review provides evidence from a range of animal models that supports the epidemiological data; suggesting that lifelong bone development and growth in offspring is determined during gestation.

Very low birth weight survivors have reduced peak bone mass and reduced insulin sensitivity

Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long-term effects through reprogramming of metabolic systems. To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function. Cross-sectional, observational, case-control study. Thirty-seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23). Differences between cases and controls in body size, body composition, bone mass and bone geometry [assessed by dual-energy X-ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT)], bone turnover [urine N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX)], aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF-1, PTH and 25-OH vitamin D) and insulin sensitivity (HOMA-IR and oral glucose tolerance testing). VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS-30 controls = 57.0, VLBW subjects = 94.3, P < 0.01), but there were no differences in whole body fat mass or truncal fat mass between VLBW subjects and controls. Young adult VLBW survivors have reduced bone density for their bone size and reduced insulin sensitivity, which may have significant implications for their risk of fracture and diabetes in later life.

Metabolic Profiling Uncovers a Phenotypic Signature of Small for Gestational Age in Early Pregnancy

Being born small for gestational age (SGA) confers increased risks of perinatal morbidity and mortality and increases the risk of cardiovascular complications and diabetes in later life. Accumulating evidence suggests that the etiology of SGA is usually associated with poor placental vascular development in early pregnancy. We examined metabolomic profiles using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) in three independent studies: (a) venous cord plasma from normal and SGA babies, (b) plasma from a rat model of placental insufficiency and controls, and (c) early pregnancy peripheral plasma samples from women who subsequently delivered a SGA baby and controls. Multivariate analysis by cross-validated Partial Least Squares Discriminant Analysis (PLS-DA) of all 3 studies showed a comprehensive and similar disruption of plasma metabolism. A multivariate predictive model combining 19 metabolites produced by a Genetic Algorithm-based search program gave an Odds Ratio for developing SGA of 44, with an area under the Receiver Operator Characteristic curve of 0.9. Sphingolipids, phospholipids, carnitines, and fatty acids were among this panel of metabolites. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of SGA offers insight into disease pathogenesis and offers the promise of a robust presymptomatic screening test.

Epigenetics and Diabetes Risk: Not Just for Imprinting Anymore?

Relationships of maternal obesity, diabetes, and nutrition during pregnancy with birth weight and in turn relationships between birth weight and risk of obesity and diabetes in later life have long been observed (rev. in 1). Elucidating the etiology of these relationships is challenging given that mammalian mothers impart both genes and intrauterine environment to their offspring. One factor that may play a role is epigenetics. Epigenetic effects are defined as heritable changes to DNA structure that do not involve changes to the DNA sequence. Unlike sequence changes, they can be reset or undone under certain conditions such as in early development. Mechanisms include changes in histone deacetylation and methylation of cytosines in CpG clusters (2). An epigenetic phenomenon that is well-documented in humans and may be the first that springs to mind is genomic imprinting, whereby during germ cell development, regulatory regions of certain genes are differentially methylated and expressed depending on whether the gene is inherited from the mother or father (2). Imprinting impacts several genes, including some in which mutation of the expressed copy or disturbance of normal imprinting is involved in both most cases of the rare transient neonatal form of diabetes (3) and, based on recent evidence, apparently some cases of polygenic type 1 (4) and 2 (5) diabetes as well. However, other factors, including environmental stimuli, can induce epigenetic changes as well (6–8); thus imprinting is not the only epigenetic mechanism potentially involved in diabetes and the related phenotypes of obesity and metabolic syndrome (9). Moreover, imprinting is not the only example of the phenomenon of …