Skeletal muscle fibre type and enzymatic activity in adult offspring following placental and peripheral malaria exposure in foetal life

BackgroundMaternal malaria may restrict foetal growth. Impaired utero-placental blood flow due to malaria infection may cause hypoxia-induced altered skeletal muscle fibre type distribution in the offspring, which may contribute to insulin resistance and impaired glucose metabolism. This study assessed muscle fibre distribution 20 years after placental and/or peripheral in-utero malaria exposure compared to no exposure, i.e., PPM+, PM+, and M-, respectively.MethodsWe traced 101 men and women offspring of mothers who participated in a malaria chemosuppression study in Muheza, Tanzania. Of 76 eligible participants, 50 individuals (29 men and 21 women) had skeletal muscle biopsy taken from m. vastus lateralis in the right leg. As previously reported, fasting and 30 min post-oral glucose challenge plasma glucose values were higher, and insulin secretion disposition index was lower, in the PPM+ group. Aerobic capacity (fitness) was estimated by an indirect VO2max test on a stationary bicycle. Muscle fibre sub-type (myosin heavy chain, MHC) distribution was analysed, as were muscle enzyme activities (citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase, myophosphorylase, phosphofructokinase, lactate dehydrogenase, and creatine kinase activities. Between-group analyses were adjusted for MHC-I %.ResultsNo differences in aerobic capacity were found between groups. Despite subtle elevations of plasma glucose levels in the PPM+ group, there was no difference in MHC sub-types or muscle enzymatic activities between the malaria-exposed and non-exposed groups.ConclusionThe current study did not show differences in MHC towards glycolytic sub-types or enzymatic activity across the sub-groups. The results support the notion of the mild elevations of plasma glucose levels in people exposed to placental malaria in pregnancy being due to compromised pancreatic insulin secretion rather than insulin resistance

Fish Intake in Pregnancy and Offspring Metabolic Parameters at Age 9⁻16-Does Gestational Diabetes Modify the Risk?

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadOily fish, an important source of marine n-3 long-chain polyunsaturated fatty acids (LCPUFA), has shown to reduce cardiometabolic risk in adults. Whether maternal fish intake affects offspring metabolic health is less established, especially among high-risk pregnancies. We aimed to examine the association of fish intake in pregnancy with offspring metabolic health who were either exposed or unexposed to gestational diabetes mellitus (GDM). Our study included 1234 mother-offspring dyads (608 with a GDM index pregnancy and 626 control dyads) nested within the Danish National Birth Cohort, which is a prebirth cohort. Maternal seafood and marine n-3 LCPUFA consumption was quantified by a food frequency questionnaire (gestational week 25) and a sub-sample with interview data (weeks 12 and 30). The offspring were clinically examined at 9⁻16 years, including a Dual energy X-ray Absorptiometry (DXA) scan and a fasting blood sample. We calculated multivariable effect estimates and 95% confidence intervals (CI) for anthropometric, adiposity, and metabolic parameters. The median (IQR) intake of total seafood was 23(24) g/day. We found largely no association for total seafood and marine n-3 LCPUFA with offspring metabolic parameters in either group. Using interview data, GDM-exposed women reporting no fish in week 12 and 30 (versus intake >2 times/week) had offspring with a higher Body Mass Index (BMI) (ratio of geometric means (RGM): 1.28, 95% CI: 1.06, 1.55), waist circumference (RGM: 1.22, 95% CI: 1.05, 1.40), triglycerides (RGM: 1.77, 95% CI: 1.03, 3.03), and homeostatic model assessment of insulin resistance HOMA-IR (RGM: 2.16, 95% CI: 1.17, 3.97). We found no associations of n-3 LCPUFA and seafood intake with offspring metabolic outcomes. However, GDM-exposed women who consistently reported eating no fish had offspring with a poorer metabolic profile. Fish intake in pregnancy may mitigate some adverse effects of intrauterine hyperglycemia, however, these findings need replication in better powered studies.European Commission Danish Diabetes Academy - Novo Nordisk Foundation Danish Council for Strategic Research Innovation Fund Denmark Rigshospitalet, Copenhagen University Hospita

Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes.

AIMS/HYPOTHESIS: We aimed to identify microRNAs (miRNAs) associated with type 2 diabetes and risk of developing the disease in skeletal muscle biopsies from phenotypically well-characterised twins. METHODS: We measured muscle miRNA levels in monozygotic (MZ) twins discordant for type 2 diabetes using arrays. Further investigations of selected miRNAs included target prediction, pathway analysis, silencing in cells and association analyses in a separate cohort of 164 non-diabetic MZ and dizygotic twins. The effects of elevated glucose and insulin levels on miRNA expression were examined, and the effect of low birthweight (LBW) was studied in rats. RESULTS: We identified 20 miRNAs that were downregulated in MZ twins with diabetes compared with their non-diabetic co-twins. Differences for members of the miR-15 family (miR-15b and miR-16) were the most statistically significant, and these miRNAs were predicted to influence insulin signalling. Indeed, miR-15b and miR-16 levels were associated with levels of key insulin signalling proteins, miR-15b was associated with the insulin receptor in non-diabetic twins and knockdown of miR-15b/miR-16 in myocytes changed the levels of insulin signalling proteins. LBW in twins and undernutrition during pregnancy in rats were, in contrast to overt type 2 diabetes, associated with increased expression of miR-15b and/or miR-16. Elevated glucose and insulin suppressed miR-16 expression in vitro. CONCLUSIONS: Type 2 diabetes is associated with non-genetic downregulation of several miRNAs in skeletal muscle including miR-15b and miR-16, potentially targeting insulin signalling. The paradoxical findings in twins with overt diabetes and twins at increased risk of the disease underscore the complexity of the regulation of muscle insulin signalling in glucose homeostasis.JB-J was supported by a grant from the Danish PhD School for Molecular Metabolism. The study was supported by grants from the Danish Medical Research Council, the Danish Strategic Research Council. The Novo Nordisk Foundation, the Danish Ministry of Science, Technology and Innovation. DSF-T was supported by the Biotechnology and Biological Sciences Research Council project grant BB/F-15364/1. SEO is a British Heart Foundation Senior Fellow (FS/09/029/27902).This is the final version of the article. It was first published by Springer at http://link.springer.com/article/10.1007%2Fs00125-014-3434-

Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations

ObjectiveWomen with a history of gestational diabetes mellitus (GDM) have an exceptionally high risk for type 2 diabetes (T2D). Yet, little is known about genetic determinants for T2D in this population. We examined the association of a genetic risk score (GRS) with risk of T2D in two independent populations of women with a history of GDM and how this association might be modified by non-genetic determinants for T2D.Research design and methodsThis cohort study included 2434 white women with a history of GDM from the Nurses’ Health Study II (NHSII, n=1884) and the Danish National Birth Cohort (DNBC, n=550). A GRS for T2D was calculated using 59 candidate single nucleotide polymorphisms for T2D identified from genome-wide association studies in European populations. An alternate healthy eating index (AHEI) score was derived to reflect dietary quality after the pregnancy affected by GDM.ResultsWomen on average were followed for 21 years in NHSII and 13 years in DNBC, during which 446 (23.7%) and 155 (28.2%) developed T2D, respectively. The GRS was generally positively associated with T2D risk in both cohorts. In the pooled analysis, the relative risks (RRs) for increasing quartiles of GRS were 1.00, 0.97, 1.25 and 1.19 (p trend=0.02). In both cohorts, the association appeared to be stronger among women with poorer (AHEI <median) than better dietary quality (AHEI ≥median), although the interaction was not significant. For example, in NHSII, the RRs across increasing quartiles of GRS were 1.00, 0.99, 1.51 and 1.29 (p trend=0.06) among women with poorer dietary quality and 1.00, 0.83, 0.81 and 0.94 (p trend=0.79) among women with better dietary quality (p interaction=0.11).ConclusionsAmong white women with a history of GDM, higher GRS for T2D was associated with an increased risk of T2D

Genetic, non-genetic and epigenetic risk determinants in developmental programming of type 2 diabetes.

Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both pre- as well as postnatal non-genetic factors, and it remains unknown to which extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared to non-genetic and epigenetic risk determinants and disease mechanisms. This article is protected by copyright. All rights reserved