Background: Gestational diabetes mellitus (GDM) is an increasing problem world-wide. Lifestyle interventions and/or vitamin D supplementation might help prevent GDM in some women. Methods/design: Pregnant women at risk of GDM (BMI≥29 (kg/m²)) from 9 European countries will be invited to participate and consent obtained before 19+6 weeks of gestation. After giving informed consent, women without GDM will be included (based on IADPSG criteria: fasting glucose<5.1mmol; 1 hour glucose <10.0 mmol; 2 hour glucose <8.5 mmol) and randomized to one of the 8 intervention arms using a 2×(2×2) factorial design: (1) healthy eating (HE), 2) physical activity (PA), 3) HE+PA, 4) control, 5) HE+PA+vitamin D, 6) HE+PA+placebo, 7) vitamin D alone, 8) placebo alone), pre-stratified for each site. In total, 880 women will be included with 110 women allocated to each arm. Between entry and 35 weeks of gestation, women allocated to a lifestyle intervention will receive 5 face-to-face, and 4 telephone coaching sessions, based on the principles of motivational interviewing. The lifestyle intervention includes a discussion about the risks of GDM, a weight gain target <5kg and either 7 healthy eating ‘messages’ and/or 5 physical activity ‘messages’ depending on randomization. Fidelity is monitored by the use of a personal digital assistance (PDA) system. Participants randomized to the vitamin D intervention receive either 1600 IU vitamin D or placebo for daily intake until delivery. Data is collected at baseline measurement, at 24–28 weeks, 35–37 weeks of gestation and after delivery. Primary outcome measures are gestational weight gain, fasting glucose and insulin sensitivity, with a range of obstetric secondary outcome measures including birth weight. Discussion: DALI is a unique Europe-wide randomised controlled trial, which will gain insight into preventive measures against the development of GDM in overweight and obese women. Trial registration: ISRCTN70595832

In Type 1 diabetes, the insulin-producing β-cells within the pancreatic islets of Langerhans are destroyed. We showed previously that immunotherapy with Bacillus Calmette-Guerin (BCG) or complete Freund's adjuvant (CFA) of non-obese diabetic (NOD) mice can prevent disease process and pancreatic β-cell loss. This was associated with increased islet Regenerating (Reg) genes expression, and elevated IL-22-producing Th17 T-cells in the pancreas. We hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas. We therefore quantified the Reg1, Reg2, and Reg3δ (INGAP) mRNA expression in isolated pre-diabetic NOD islets treated with IL-22. We measured IL-22, and IL-22 receptor(R)-α mRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice. Our results showed: 1) Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro; 2) IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment; 3) a reduced expression of IL-22Rα following CFA treatment; 4) a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody; and 5) an increased islet β-cell DNA synthesis in vitro in the presence of IL-22. We conclude that IL-22 may contribute to the regeneration of β-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.

The purpose of this study was to examine the association between mental health status (i.e. depressed mood and pregnancy-related worries) and objectively measured physical activity levels in obese pregnant women from seven European countries. Baseline data from the vitamin D and lifestyle intervention for the prevention of gestational diabetes mellitus (DALI) study were used. Time spent in moderate-to-vigorous physical activity (MVPA) and sedentary behaviour was measured with accelerometers. Depressed mood was measured with the WHO well-being index (WHO-5) and pregnancy-related worries with the Cambridge Worry Scale (CWS). In addition, socio-demographic characteristics, lifestyle factors, and perceptions and attitude regarding weight management and physical activity were measured. Linear regression analyses were performed to assess the association of mental health status with MVPA and sedentary behaviour. A total of 98 obese pregnant women from Austria, Belgium, Ireland, Italy, Poland, Spain and the Netherlands were included. Women had a mean age of 31.6 ± 5.8 years, a pre-pregnancy BMI of 34.1 ± 4.3 kg/m2, and were on average 15.4 ± 2.8 weeks pregnant. WHO-5 scores indicative of depressed mood (<50) were reported by 27.1 % of the women and most frequently endorsed pregnancy-related worries pertained to own and the baby’s health. Women with good well-being spent 85 % more time in MVPA compared to women with a depressed mood (P = 0.03). No differences in MVPA levels were found for women with no, some, or many pregnancy worries. Depressed mood and pregnancy-related worries were not associated with sedentary behaviour. These findings suggest that in pregnant women who are obese, a depressed mood, but not pregnancy-related worries, may be associated with less physical activity. The combined risk of poor mental health and low physical activity levels makes women vulnerable for pregnancy complications. Whether a depressed mood may be a barrier for improving physical activity warrants further study.

Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP^+/+ mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter. There was a significant loss of HPAP-expressing β-cells in culture, but remaining HPAP⁺ cells lost insulin expression while gaining expression of the epithelial duct cell marker cytokeratin-19 (Ck19). Flow cytometry and recovery of β-cell subpopulations from whole pancreas vs. islets suggest that the HPAP⁺Ck19⁺ cells had derived from insulin-positive, glucose-transporter-2-low (Ins⁺Glut2^LO) cells, representing 3.5% of all insulin-expressing cells. The majority of these cells were found outside of islets within clusters of <5 β-cells. These insulin⁺Glut2^LO cells demonstrated a greater proliferation rate in vivo and in vitro as compared to insulin⁺Glut2⁺ cells at P7, were retained into adulthood, and a subset differentiated into endocrine, ductal, and neural lineages, illustrating substantial plasticity. Results were confirmed using RIPCre;ROSA- eYFP mice. Quantitative PCR data indicated these cells possess an immature β-cell phenotype. These Ins⁺Glut2^LO cells may represent a resident population of cells capable of forming new, functional β-cells, and which may be potentially exploited for regenerative therapies in the future.

Normal pregnancy is associated with increased insulin resistance as a metabolic adaptation to the nutritional demands of the placenta and fetus, and this is amplified in obese mothers. Insulin resistance is normally compensated for by an adaptive increase in pancreatic β-cell mass together with enhanced glucose-stimulated insulin release. Placentally-derived hormones and growth factors are central to the altered pancreatic morphology and function. A failure of β-cells to undergo adaptive change after the first trimester has been linked with gestational diabetes. In the pregnant mouse, an increase in β-cell replication contributes to a 2-3-fold increase in mass peaking in late gestation, depending on the proliferation of existing β-cells, the differentiation of resident progenitor β-cells, or islet cell transdifferentiation. Using mouse models and human studies placenta- and islet of Langerhans-derived molecules have been identified that are likely to contribute to the metabolic adaptations to pregnancy and whose physiology is altered in the obese, glucose-intolerant mother. Maternal obesity during pregnancy can create a pro-inflammatory environment that can disrupt the response of the β-cells to the endocrine signals of pregnancy and limit the adaptive changes in β-cell mass and function, resulting in an increased risk of gestational diabetes.