Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1 knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1 population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1 in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1, expression of the man-made, ligand-independent ACVR1 mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1 knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.

Objective To evaluate the effectiveness of an exercise programme for pregnant women who were overweight or obese and at risk for gestational diabetes mellitus (GDM).Design Randomised controlled trial.Setting Hospitals and midwifery practices in the Netherlands.Population Pregnant women who were overweight or obese and at risk for GDM between 2007 and 2011.Methods Normal care was compared with an exercise training programme during pregnancy. The training consisted of aerobic and strength exercises, and was aimed at improving maternal fasting blood glucose, insulin sensitivity, and birthweight. Linear regression analyses were performed to determine the effects.Main outcome measures Maternal outcome measures were fasting blood glucose (mmol/l), fasting insulin (pmol/l) and HbA1c (%), body weight (kg), body mass index (kg/m 2 ), and daily physical activity (minute/week). Offspring outcome measures were birthweight and fetal growth.Results A total of 121 women were randomly allocated to either a control (n = 59) or an intervention (n = 62) group. Intention-totreat analysis showed that the exercise programme did not reduce maternal fasting blood glucose levels nor insulin sensitivity. Also, no effect was found on birthweight.Conclusions The exercise intervention performed over the second and third trimester of pregnancy had no effects on fasting blood glucose, insulin sensitivity, and birthweight, most probably because of low compliance. The high prevalence of women at risk for GDM calls for further research on possible interventions that can prevent GDM, and other types of interventions to engage this target group in physical activity and exercise.

Background: Pregnancy is a period in the life of women that is often associated with decreased daily physical activity and/or exercise. However, maintaining adequate levels of daily physical activity during pregnancy is important for mother and child. Studies suggest that moderate daily physical activity and exercise during pregnancy are associated with reductions in the risk of gestational diabetes mellitus (GDM). However, at present, physical activity is not routinely advised to pregnant women at risk for gestational diabetes in the Netherlands. In FitFor2-study we aim to assess whether an exercise program can improve insulin sensitivity and fasting plasma glucose levels of women at high risk for gestational diabetes, assuming that this will lower their risk of gestational diabetes.

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Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose–raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose–raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide–based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.