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Infants born to mothers with type 2 diabetes (T2D) and gestational diabetes (GDM) are at an increased risk of being overweight/obese. Modifiable lifestyle factors play a role in prevention of overweight and obesity. In 2017, the Canadian 24 h Movement Guidelines for the Early Years (CMG) were released. Alongside physical activity recommendations, sweetened beverage consumption (SBC) recommendations were also released by the American Academy of Pediatrics in 2017. The objective of this study was to determine the knowledge pregnant women with T2D and GDM have on the CMG and SBC recommendations, and to determine what factors affect this. A survey with questions regarding demographics, socioeconomic variables and the CMG and SBC recommendations was administered to pregnant women at Diabetes in Pregnancy clinics in Calgary, Alberta from July 2019 to January 2020. Surveys were analyzed utilizing the non-parametric Kruskall-Wallis Rank-Sum test, chi-square test and linear regression. A total of 79 respondents with T2D and GDM were collected. Respondents had the highest knowledge of SBC recommendations and the lowest knowledge of CMG recommendations. A bachelor's or higher degree was associated with significantly higher knowledge scores than a high-school education or less. In conclusion, pregnant women with T2D and GDM in this study had overall poor knowledge of the CMG and SBC recommendations, with less knowledge regarding the CMG. Level of education was found to be associated with knowledge regarding these recommendations. Future programs to improve education around infant and toddler physical activity and SBC recommendations may be beneficial for this patient population.
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Environmental and economic issues resulting from the unsustainable management of sewage sludge from wastewater have necessitated the development of eco-friendly sewage sludge disposal methods, whereas stormwater effluent contains tremendous amounts of pollutants. This study compares the feasibility and environmental impacts associated with incorporating biofilters with sludge-based activated carbon (SBAC) versus commercial activated carbon (CAC) for stormwater treatment. The results demonstrate that the construction and disposal life-cycle stages are the dominant contributors to several environmental impact categories, including resource scarcity, carcinogenic toxicity, terrestrial ecotoxicity, and ozone formation indicators. Across multiple impact categories, the incorporation of biofilters with SBAC can reduce the negative environmental impacts associated with biofilter construction and disposal by 40% over a 50-year analysis period. In contrast, the most significant improvement is on construction-dominant indicators, where the decreased need for biofilter reconstruction results in a higher reduction in environmental impacts. Economically, amending the biofilter with SBAC can increase profits by up to 66% due to extending its lifespan. This study shows that SBAC has similar performance as CAC for lowering the negative environmental impacts resulting from biofilter construction, while increasing the overall net profits of the system. However, converting sewage sludge to an effective sorbent (SBAC) and incorporating SBAC into a biofilter to capture pollutants from stormwater is an economically and environmentally sustainable solution available to practitioners to manage sewage sludge and stormwater effluent. This solution protects the environment in a cost efficient, sustainable manner.
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Poluentes Ambientais , Purificação da Água , Esgotos , Carvão Vegetal , Chuva , Abastecimento de Água , Custos e Análise de CustoRESUMO
During pregnancy, the mother develops insulin resistance to shunt nutrients to the growing fetus. As a result, the maternal islets of Langerhans undergo several changes to increase insulin secretion in order to maintain glucose homeostasis and prevent the development of gestational diabetes. These changes include an increase in ß-cell proliferation and ß-cell mass, upregulation of insulin synthesis and insulin content, enhanced cell-to-cell communication, and a lowering of the glucose threshold for insulin secretion, all of which resulting in an increase in glucose-stimulated insulin secretion. Emerging data suggests that a change in intracellular calcium dynamics occurs in the ß-cell during pregnancy as part of the adaptive process. Influx of calcium into ß-cells is crucial in the regulation of glucose-stimulated insulin secretion. Calcium fluxes into and out of the cytosol, endoplasmic reticulum, and mitochondria are also important in controlling ß-cell function and survival. Here, we review calcium dynamics in islets in response to pregnancy-induced changes in hormones and signaling molecules, and how these changes may enhance insulin secretion to stave off gestational diabetes.
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Diabetes Gestacional , Ilhotas Pancreáticas , Cálcio , Feminino , Glucose/farmacologia , Humanos , Insulina , GravidezRESUMO
This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.
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Adipogenia , Tecido Adiposo/metabolismo , Fatores de Risco Cardiometabólico , Doenças Metabólicas/metabolismo , Adipócitos/ultraestrutura , Tecido Adiposo/embriologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Tamanho Celular , Dieta Hiperlipídica , Feminino , Frutose/farmacologia , Hiperlipidemias/genética , Insulina/sangue , Lipidômica , Masculino , Doenças Metabólicas/patologia , Camundongos , Gravidez , Receptores para Leptina/genética , Células-Tronco , Triglicerídeos/sangueRESUMO
Autotaxin (ATX) is a lysophospholipase D that is the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from a conditioned medium of melanoma cells, later it was discovered to play a critical role in vascular and neuronal development. ATX has also been implicated in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as neurological diseases such as multiple sclerosis, Alzheimer's disease, and neuropathic pain. As ATX and LPA levels are increased upon neuronal injury, a selective ATX inhibitor could provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.
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Pancreatic islets adapt to insulin resistance of pregnancy by up regulating ß-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/-), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects ß-cell development, to understand ß-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from ß-cells. Here, we found that ß-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed ß-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr+/-) versus ß-cell-specific Prlr reduction (ßPrlR+/-), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/- mice in comparison to the ßPrlR+/- mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/- mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant ßPrlR+/- mice. These observations suggest that down regulation of prolactin action during pregnancy in non-ß-cells secondarily and negatively affect ß-cell gene expression, and increased ß-cell susceptibility to external insults.
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Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Complicações na Gravidez/patologia , Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Animais , Glicemia/análise , Glicemia/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout , Gravidez , Complicações na Gravidez/genética , Receptores da Prolactina/genéticaRESUMO
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.
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COVID-19/epidemiologia , COVID-19/prevenção & controle , Diabetes Mellitus Tipo 1/epidemiologia , Cetoacidose Diabética/epidemiologia , SARS-CoV-2 , Adolescente , Alberta/epidemiologia , Automonitorização da Glicemia/estatística & dados numéricos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Cetoacidose Diabética/diagnóstico , Feminino , Humanos , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Masculino , Pandemias , Estudos RetrospectivosRESUMO
Therapeutic payload delivery to the central nervous system (CNS) remains a major challenge in gene therapy. Recent studies using function-driven evolution of adeno-associated virus (AAV) vectors have successfully identified engineered capsids with improved blood-brain barrier (BBB) penetration and CNS tropism in mouse. However, these strategies require transgenic animals and thus are limited to rodents. To address this issue, we developed a directed evolution approach based on recovery of capsid library RNA transcribed from CNS-restricted promoters. This RNA-driven screen platform, termed TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA), was tested in the mouse with AAV9 peptide display libraries and showed rapid emergence of dominant sequences. Ten individual variants were characterized and showed up to 400-fold higher brain transduction over AAV9 following systemic administration. Our results demonstrate that the TRACER platform allows rapid selection of AAV capsids with robust BBB penetration and CNS tropism in non-transgenic animals.
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Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ß-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ß-cell mass. Prolactin also prevents ß-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ß-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ß-cell proliferation/apoptosis (thus ß-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ß-cells had minimal effect on ß-cell proliferation and glucose-stimulated insulin secretion but protected ß-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ß-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ß-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ß-cell survival.
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Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Proteínas de Membrana/fisiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Cálcio/metabolismo , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Diabetes Mellitus Experimental/genética , Feminino , Insulina/biossíntese , Insulina/genética , Secreção de Insulina/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Transdução de Sinais/genética , Resposta a Proteínas não Dobradas/genética , Regulação para CimaRESUMO
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.
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Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Prebióticos/administração & dosagem , Centros Médicos Acadêmicos , Adolescente , Glicemia/análise , Canadá , Criança , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/microbiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Permeabilidade/efeitos dos fármacos , Projetos Piloto , Prognóstico , Valores de Referência , Resultado do TratamentoRESUMO
The Salmonella Syst-OMICS consortium is sequencing 4,500 Salmonella genomes and building an analysis pipeline for the study of Salmonella genome evolution, antibiotic resistance and virulence genes. Metadata, including phenotypic as well as genomic data, for isolates of the collection are provided through the Salmonella Foodborne Syst-OMICS database (SalFoS), at https://salfos.ibis.ulaval.ca/. Here, we present our strategy and the analysis of the first 3,377 genomes. Our data will be used to draw potential links between strains found in fresh produce, humans, animals and the environment. The ultimate goals are to understand how Salmonella evolves over time, improve the accuracy of diagnostic methods, develop control methods in the field, and identify prognostic markers for evidence-based decisions in epidemiology and surveillance.
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In type 1 diabetes, restoration of normoglycemia can be achieved if the autoimmune attack on beta cells ceases and insulin requirement is met by the residual beta cells. We hypothesize that an adjunctive therapy that reduces insulin demand by increasing insulin sensitivity will improve the efficacy of an immunotherapy in reversing diabetes. We tested the gut microbiota-modulating prebiotic, oligofructose (OFS), as the adjunctive therapy. We treated non-obese diabetic mice with an immunotherapy, monoclonal anti-CD3 antibody (aCD3), with or without concurrent dietary supplement of OFS. After 8 weeks of OFS supplement, the group that received both aCD3 and OFS (aCD3 + OFS) had a higher diabetes remission rate than the group that received aCD3 alone. The aCD3 + OFS group had higher insulin sensitivity accompanied by reduced lymphocytic infiltrate into the pancreatic islets, higher beta-cell proliferation rate, higher pancreatic insulin content, and secreted more insulin in response to glucose. The addition of OFS also caused a change in gut microbiota, with a higher level of Bifidobacterium and lower Clostridium leptum. Hence, our results suggest that OFS can potentially be an effective therapeutic adjunct in the treatment of type 1 diabetes by improving insulin sensitivity and beta-cell function, leading to improved glycemic control.
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Diabetes Mellitus Experimental/tratamento farmacológico , Oligossacarídeos/uso terapêutico , Animais , Complexo CD3/imunologia , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Experimental/patologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Camundongos Endogâmicos NOD , Oligossacarídeos/farmacologiaRESUMO
Nutritional counseling for children with obesity is an important component of management. This randomized controlled trial was conducted to compare change in body mass index (BMI) z score after 6 months. Children 8 to 16 years with a BMI greater than the 85th percentile were randomized to standard of care nutrition counseling versus intervention with standard nutrition counseling including portion control tool training for the family. Measures were completed at baseline, 3 months, and 6 months. Fifty-one children were randomized to control and 48 to intervention. Mean age was 11 years (SD = 2.2). Mean BMI z score was 2.7 (SD = 0.4). Forty-five percent were male (n = 45). Follow-up at 6 months was 73.7% (73/99). Although no differences were seen between the groups, there was a significant decrease in BMI z score between baseline and 6 months within each group.
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To determine if physical activity is linked to cardiovascular biomarkers in preschool children at risk, we need information on these biomarkers in healthy normal-weight children. In this population, multi-level modelling analyses found no correlation between accelerometer recorded physical activity and fasting lipids, adiponectin, or insulin sensitivity. Exploratory analyses found positive correlations between adiponectin and time spent in light physical activity, and between triglyceride and time spent in sedentary behaviour; these findings need to be confirmed in longitudinal prospective studies.
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Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Exercício Físico , Adiponectina/sangue , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Peso Corporal , Criança , Pré-Escolar , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Pais , Fatores de Risco , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The gut microbiome is increasingly recognized as a contributor to disease states. Patients with type 1 diabetes (DM1) have distinct gut microbiota in comparison to non-diabetic individuals, and it has been linked to changes in intestinal permeability, inflammation and insulin resistance. Prebiotics are non-digestible carbohydrates that alter gut microbiota and could potentially improve glycemic control in children with DM1. This pilot study aims to determine the feasibility of a 12-week dietary intervention with prebiotics in children with DM1. METHODS/DESIGN: This pilot study is a single-centre, randomized, double-blind, placebo-controlled trial in children aged 8 to 17 years with DM1 for at least one year. Participants will be randomized to receive either placebo (maltodextrin 3.3 g orally/day) or prebiotics (oligofructose-enriched inulin 8 g orally/day; Synergy1, Beneo, Mannheim, Germany). Measures to be assessed at baseline, 3 months and 6 months include: anthropometric measures, insulin doses/regimens, frequency of diabetic ketoacidosis, frequency of severe hypoglycemia, average number of episodes of hypoglycemia per week, serum C-peptide, HbA1c, serum inflammatory markers (IL-6, IFN-gamma, TNF-alpha, and IL-10), GLP-1 and GLP-2, intestinal permeability using urine assessment after ingestion of lactulose, mannitol and 3-O-methylglucose, and stool sample collection for gut microbiota profiling. DISCUSSION: This is a novel pilot study designed to test feasibility for a fully powered study. We hypothesize that consumption of prebiotics will alter gut microbiota and intestinal permeability, leading to improved glycemic control. Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for DM1 that may improve glycemic control by changes in gut microbiota, gut permeability and inflammation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02442544 . Registered on 10 March 2015.
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Glicemia/metabolismo , Diabetes Mellitus Tipo 1/terapia , Microbioma Gastrointestinal , Intestinos/microbiologia , Inulina/administração & dosagem , Oligossacarídeos/administração & dosagem , Prebióticos/administração & dosagem , Adolescente , Fatores Etários , Alberta , Biomarcadores/sangue , Criança , Protocolos Clínicos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/microbiologia , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Humanos , Mucosa Intestinal/metabolismo , Inulina/efeitos adversos , Masculino , Oligossacarídeos/efeitos adversos , Permeabilidade , Projetos Piloto , Prebióticos/efeitos adversos , Projetos de Pesquisa , Fatores de Tempo , Resultado do TratamentoRESUMO
Type 1 diabetes is caused by autoimmune destruction of ß-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune-mediated ß-cell loss, residual ß-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost ß-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate ß-cell proliferation and up-regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms. Here, we test the hypothesis that PRL can improve the efficacy of an immune modulator, the anticluster of differentiation 3 monoclonal antibody (aCD3), in inducing diabetes remission by up-regulating ß-cell mass and function. Diabetic nonobese diabetic (NOD) mice were treated with a 5-day course of aCD3 with or without a concurrent 3-week course of PRL. We found that a higher proportion of diabetic mice treated with the aCD3 and PRL combined therapy achieved diabetes reversal than those treated with aCD3 alone. The aCD3 and PRL combined group had a higher ß-cell proliferation rate, an increased ß-cell fraction, larger islets, higher pancreatic insulin content, and greater glucose-stimulated insulin release. Lineage-tracing analysis found minimal contribution of ß-cell neogenesis to the formation of new ß-cells. Although we did not detect a significant difference in the number or proliferative capacity of T cells, we observed a higher proportion of insulitis-free islets in the aCD3 and PRL group. These results suggest that combining a growth factor with an immunotherapy may be an effective treatment paradigm for autoimmune diabetes.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Fatores Imunológicos/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Muromonab-CD3/uso terapêutico , Prolactina/uso terapêutico , Animais , Crescimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Terapia Combinada , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Implantes de Medicamento , Feminino , Hipoglicemiantes/administração & dosagem , Insulina/biossíntese , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Estimativa de Kaplan-Meier , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Prolactina/administração & dosagem , Prolactina/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Indução de Remissão , Proteína Vermelha FluorescenteRESUMO
Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy.