During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the G alpha(q)-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the G alpha(i)-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.

https://escholarship.org/content/qt57p1w163/qt57p1w163.pdf?t=qag5o5

Serotonin regulates pancreatic beta cell mass during pregnancy.

Purpose of reviewTo examine the roles of the placental and pituitary hormones in the control of maternal metabolism and fetal growth.Recent findingsIn addition to promoting growth of maternal tissues, placental growth hormone (GH-V) induces maternal insulin resistance and thereby facilitates the mob

Placental hormones and the control of maternal metabolism and fetal growth.

Neocortical projection neurons, which segregate into six
cortical layers according to their birthdate, have diverse
morphologies, axonal projections and molecular profiles,
yet they share a common cortical regional identity and
glutamatergic neurotransmission phenotype. Here we demonstrate
that distinct genetic programs operate at different
stages of corticogenesis to specify the properties shared
by all neocortical neurons. Ngn1 and Ngn2 are required to
specify the cortical (regional), glutamatergic (neurotransmitter)
and laminar (temporal) characters of early-born
(lower-layer) neurons, while simultaneously repressing an
alternative subcortical, GABAergic neuronal phenotype.
Subsequently, later-born (upper-layer) cortical neurons
are specified in an Ngn-independent manner, requiring
instead the synergistic activities of Pax6 and Tlx, which
also control a binary choice between cortical/glutamatergic
and subcortical/GABAergic fates. Our study thus reveals an
unanticipated heterogeneity in the genetic mechanisms
specifying the identity of neocortical projection neurons.

Sequential phases of cortical specificationinvolve Neurogenin-dependentand -independent pathways

Background: Child and adolescent overweight and obesity has increased globally, and can be associated with significant short- and longterm health consequences This is an update of a Cochrane Review published first in 2003, and updated previously in 2009 However, the update has now been split into six reviews addressing different childhood obesity treatments at different ages Objectives: To assess the effects of diet, physical activity and behavioural interventions (behaviour-changing interventions) for the treatment of overweight or obese children aged 6 to 11 years Search methods: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as trial registers ClinicalTrialsgov and RsdI1401 Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from th 2 / 499 ICTRP Search Portal We checked references of studies and systematic reviews We did not apply any language restrictions The date of the last search was July 2016 for all databases Selection criteria: We selected randomised controlled trials (RCTs) of diet, physical activity, and behavioural interventions (behaviour-changing interventions) for treating overweight or obese children aged 6 to 11 years, with a minimum of six months' follow-up We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity Data collection and analysis Two review authors independently screened references, extracted data, assessed risk of bias, and evaluated the quality of the evidence using the GRADE instrument We contacted study authors for additional information We carried out metaanalyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions Main results: We included 70 RCTs with a total of 8461 participants randomised to either the intervention or control groups The number of participants per trial ranged from 16 to 686 Fifty-five trials compared a behaviour-changing intervention with no treatment/usual care control and 15 evaluated the effectiveness of adding an additional component to a behaviour-changing intervention Sixty-four trials were parallel RCTs, and four were cluster RCTs Sixty-four trials were multicomponent, two were diet only and four were physical activity only interventions Ten trials had more than two arms The overall quality of the evidence was low or very low and 62 trials had a high risk of bias for at least one criterion Total duration of trials ranged from six months to three years The median age of participants was 10 years old and the median BMI z score was 22 Primary analyses demonstrated that behaviour-changing interventions compared to no treatment/usual care control at longest follow-up reduced BMI, BMI z score and weight Mean difference (MD) in BMI was -053 kg/m2 (95% confidence interval (CI) -082 to -024); P < 000001; 24 trials; 2785 participants; low-quality evidence MD in BMI z score was -006 units (95% CI -010 to -002); P = 0001; 37 trials; 4019 participants; low-quality evidence and MD in weight was -145 kg (95% CI -188 to -102); P < 000001; 17 trials; 1774 participants; low-quality evidence Thirty-one trials reported on serious adverse events, with 29 trials reporting zero occurrences RR 057 (95% CI 017 to 193); P = 037; 4/2105 participants in the behaviour-changing intervention groups compared with 7/1991 participants in the comparator groups) Few trials reported health-related quality of life or behaviour change outcomes, and none of the analyses demonstrated a substantial difference in these outcomes between intervention and control In two trials reporting on minutes per day of TV viewing, a small reduction of 66 minutes per day (95% CI -1288 to -031), P = 004; 2 trials; 55 participants) was found in favour of the intervention No trials reported on all-cause mortality, morbidity or socioeconomic effects, and few trials reported on participant views; none of which could be meta-analysed As the meta-analyses revealed substantial heterogeneity, we conducted subgroup analyses to examine the impact of type of comparator, type of intervention, risk of attrition bias, setting, duration of post-intervention follow-up period, parental involvement and baseline BMI z score No subgroup effects were shown for any of the subgroups on any of the outcomes Some data indicated that a reduction in BMI immediately post-intervention was no longer evident at follow-up at less than six months, which has to be investigated in further trials Authors' conclusions: Multi-component behaviour-changing interventions that incorporate diet, physical activity and behaviour change may be beneficial in achieving small, short-term reductions in BMI, BMI z score and weight in children aged 6 to 11 years The evidence suggests a very low occurrence of adverse events The quality of the evidence was low or very low The heterogeneity observed across all outcomes was not explained by subgrouping Further research is required of behaviourchanging interventions in lower income countries and in children from different ethnic groups; also on the impact of behaviour-changing interventions on health-related quality of life and comorbidities The sustainability of reduction in BMI/BMI z score and weight is a key consideration and there is a need for longer-term follow-up and further research on the most appropriate forms of post-intervention maintenance in order to ensure intervention benefits are sustained over the longer term

/pdf/diet-physical-activity-and-behavioural-interventions-for-the-2rqinkqyld.pdf

Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from the age of 6 to 11 years

Inadequate β-cell mass can lead to insulin insufficiency and diabetes. During times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by increasing cell size and by changing the balance between β-cell proliferation and apoptosis. In this paper, we review recent advances in our understanding of the mechanisms that control the adaptive expansion of β-cell mass, focusing on the islet's response to pregnancy, a physiological state of insulin resistance. Functional characterization of factors controlling both β-cell proliferation and survival might not only lead to the development of successful therapeutic strategies to enhance the response of the β-cell to increased metabolic loads, but also improve islet transplantation regimens.

/pdf/expansion-of-b-cell-mass-in-response-to-pregnancy-m33823d70m.pdf

Expansion of β-cell mass in response to pregnancy

Increased islet mass is an adaptive mechanism that occurs to combat insulin resistance during pregnancy. Prolactin (PRL) can enhance β-cell proliferation and insulin secretion in vitro, yet whether it is PRL or other pregnancy-related factors that mediate these adaptive changes during pregnancy is unknown. The objective of this study was to determine whether prolactin receptor (Prlr) is required for normal maternal glucose homeostasis during pregnancy. An ip glucose tolerance test was performed on timed-pregnant Prlr+/+ and heterozygous null Prlr+/− mice on d 0, 15, and 18 of pregnancy. Compared with Prlr+/+ mice, Prlr+/− mice had impaired glucose clearance, decreased glucose-stimulated insulin release, higher nonfasted blood glucose, and lower insulin levels during but not before pregnancy. There was no difference in their insulin tolerance. Prlr+/+ mice show a significant incremental increase in islet density and β-cell number and mass throughout pregnancy, which was attenuated in the Prlr+/− mice. Prlr...

/pdf/prolactin-receptor-is-required-for-normal-glucose-2hp9vtwyc5.pdf

Prolactin Receptor Is Required for Normal Glucose Homeostasis and Modulation of β-Cell Mass during Pregnancy

Context Patients with type 1 diabetes (T1D) have lower microbiota diversity and distinct gut microbial profiles that have been linked to changes in intestinal permeability. Prebiotics are nondigestible carbohydrates that alter gut microbiota and could potentially improve glycemic control and reduce intestinal permeability and thereby insulin sensitivity. Objective To determine the effect of prebiotics on glycemic control, gut microbiota, and intestinal permeability in children with T1D. Design A randomized, placebo-controlled trial in children 8 to 17 years of age with T1D using placebo or prebiotic oligofructose-enriched inulin for 12 weeks. Baseline, 3-month, and 6-month assessments included HbA1c, C-peptide, gut microbiota, intestinal permeability, frequency of diabetic ketoacidosis (DKA), and severe hypoglycemia. Results Forty-three subjects were randomized and 38 completed the study. The groups were similar at baseline: prebiotic (N = 17), age 12.5 years (SD of 2.8), HbA1c 8.02% (SD of 0.82); placebo (N = 21), age 12.0 years (SD of 2.6), HbA1c 8.08% (SD of 0.91). No significant differences were found in the frequency of DKA or severe hypoglycemia. At 3-months, C-peptide was significantly higher (P = 0.029) in the group who received prebiotics, which was accompanied by a modest improvement in intestinal permeability (P = 0.076). There was a significant increase in the relative abundance of Bifidobacterium within the prebiotic group at 3 months that was no longer present after the 3-month washout. The placebo group had significantly higher relative abundance of Streptococcus, Roseburia inulinivorans, Terrisporobacter, and Faecalitalea compared with the prebiotic group at 3 months. Conclusion Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for T1D that may improve glycemic control. Further larger-scale trials are needed.

Effect of Prebiotic on Microbiota, Intestinal Permeability, and Glycemic Control in Children With Type 1 Diabetes

Proneural genes encode evolutionarily conserved basic-helix-loop-helix transcription factors. In Drosophila, proneural genes are required and sufficient to confer a neural identity onto naive ectodermal cells, inducing delamination and subsequent neuronal differentiation. In vertebrates, proneural genes are expressed in cells that already have a neural identity, but they are still required and sufficient to initiate neurogenesis. In all organisms, proneural genes control neurogenesis by regulating Notch-mediated lateral inhibition and initiating the expression of downstream differentiation genes. The general mode of proneural gene function has thus been elucidated. However, the regulatory mechanisms that spatially and temporally control proneural gene function are only beginning to be deciphered. Understanding how proneural gene function is regulated is essential, as aberrant proneural gene expression has recently been linked to a variety of human diseases-ranging from cancer to neuropsychiatric illnesses and diabetes. Recent insights into proneural gene function in development and disease are highlighted herein.

Proneural bHLH genes in development and disease.

OBJECTIVE: The COVID-19 pandemic has led to significant public health measures that have resulted in decreased acute pediatric care utilization. We evaluated whether the rate of severe presentations of new onset type 1 diabetes (DM1), such as, diabetic ketoacidosis (DKA) has changed since the COVID-19 public health measures were enacted. RESEARCH DESIGN AND METHODS: A retrospective chart review of children less than 18 years of age presenting with new onset DM1 during the pandemic period of March 17, 2020 to August 31, 2020 was conducted at two tertiary care pediatric hospitals in Alberta, Canada. Rates of DKA and severe DKA were compared to the same time period in the year 2019 (pre-pandemic control). RESULTS: The number of children presenting with newly diagnosed DM1 was similar during the pandemic year of 2020 compared with 2019 (107 children in 2020 vs. 114 in 2019). The frequency of DKA at DM1 onset was significantly higher in the pandemic period (68.2% vs 45.6%; p < 0.001) and incidence of severe DKA was also higher (27.1% in 2020 vs 13.2% in 2019; p = 0.01). CONCLUSIONS: There was a significant increase in DKA and severe DKA in children presenting with new onset DM1 during the COVID-19 pandemic period. This emphasizes the need for educating health care professionals and families to be aware of the symptoms of hyperglycemia and the importance of early diagnosis and treatment even during public health measures for COVID-19.

Diabetic ketoacidosis at type 1 diabetes diagnosis in children during the COVID-19 pandemic.

Pregnancy-induced increase in β-cell proliferation requires intact prolactin receptors, an increase involving up-regulation of Jak2, IRS-2, Akt, and p21 expression and suppression of menin/p18 pathways.

/pdf/participation-of-akt-menin-and-p21-in-pregnancy-induced-b-2gic22ed8p.pdf

Carol Huang

Papers

Prolactin Receptor Is Required for Normal Glucose Homeostasis and Modulation of β-Cell Mass during Pregnancy

Effect of Prebiotic on Microbiota, Intestinal Permeability, and Glycemic Control in Children With Type 1 Diabetes

Proneural bHLH genes in development and disease.

Diabetic ketoacidosis at type 1 diabetes diagnosis in children during the COVID-19 pandemic.

Participation of Akt, Menin, and p21 in Pregnancy-Induced β-Cell Proliferation