Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Fator 1-alfa Nuclear de Hepatócito , Fator 4 Nuclear de Hepatócito , Adulto , Feminino , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Polipeptídeo Inibidor Gástrico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/genética , Pessoa de Meia-IdadeRESUMO
Growth differentiation factor-15 (GDF15) increases in circulation during pregnancy and has been implicated in food intake, weight loss, complications of pregnancy, and metabolic illness. We used a Gdf15 knockout mouse model (Gdf15-/- ) to assess the role of GDF15 in body weight regulation and food intake during pregnancy. We found that Gdf15-/- dams consumed a similar amount of food and gained comparable weight during the course of pregnancy compared to Gdf15+/+ dams. Insulin sensitivity on gestational day 16.5 was also similar between genotypes. In the postnatal period, litter size, and survival rates were similar between genotypes. There was a modest reduction in birth weight of Gdf15-/- pups, but this difference was no longer evident postnatal day 3.5 to 14.5. We observed no detectable differences in milk volume production or milk fat percentage. These data suggest that GDF15 is dispensable for changes in food intake, and body weight as well as insulin sensitivity during pregnancy in a mouse model.
RESUMO
"Implicit bias," also called "unconscious bias," refers to associations outside of conscious awareness that adversely affect one's perception of a person or group. Awareness of implicit bias has been increasing in the realm of diabetes care. Here, the authors highlight several types of unconscious bias on the part of clinicians and patients, including biases based on race, ethnicity, and obesity. They discuss how these biases can negatively affect patient-centered clinical interactions and diabetes care delivery, and they recommend implementation of evidence-based interventions and other health system policy approaches to reduce the potential impact of such biases in health care settings.
RESUMO
Lipids play a critical role in neonate development and breastmilk is the newborn's major source of lipids. Milk lipids directly influence the neonate plasma lipid profile. The milk lipidome is dynamic, influenced by maternal factors and related to the maternal plasma lipidome. The close inter-relationship between the maternal plasma, milk and neonate plasma lipidomes is critical to understanding maternal-child health and nutrition. In this exploratory study, lipidomes of blood and breast milk from Suffolk sheep and matched lamb blood (n = 13), were profiled on day 34 post birth by untargeted mass spectrometry. Comparative multivariate analysis of the three matrices identified distinct differences in lipids and class of lipids amongst them. Paired analysis identified 346 differential lipids (DL) and 31 correlated lipids (CL) in maternal plasma and milk, 340 DL and 32 CL in lamb plasma and milk and 295 DL and 16 CL in maternal plasma and lamb plasma. Conversion of phosphatidic acid to phosphatidyl inositol was the most active pathway in lamb plasma compared to maternal plasma. This exploratory study illustrates the partitioning of lipids across maternal plasma, milk and lamb plasma and the dynamic relationship between them, reiterating the need to study these three matrices as one biological system.
Assuntos
Lipidômica , Leite , Feminino , Animais , Ovinos , Humanos , Leite/metabolismo , Leite Humano/metabolismo , Estado Nutricional , Plasma , LipídeosRESUMO
Developmental exposure to endocrine disruptors like bisphenol A (BPA) are implicated in later-life metabolic dysfunction. Leveraging a unique sheep model of developmental programming, we conducted an exploratory analysis of the programming effects of BPA on the endocrine pancreas. Pregnant ewes were administered environmentally relevant doses of BPA during gestational days (GD) 30-90, and pancreata from female fetuses and adult offspring were analyzed. Prenatal BPA exposure induced a trend toward decreased islet insulin staining and ß-cell count, increased glucagon staining and α-cell count, and increased α-cell/ß-cell ratio. Findings were most consistent in fetal pancreata assessed at GD90 and in adult offspring exposed to the lowest BPA dose. While not assessed in fetuses, adult islet fibrosis was increased. Collectively, these data provide further evidence that early-life BPA exposure is a likely threat to human metabolic health. Future studies should corroborate these findings and decipher the molecular mechanisms of BPA's developmental endocrine toxicity.
Assuntos
Compostos Benzidrílicos , Ilhotas Pancreáticas , Fenóis , Efeitos Tardios da Exposição Pré-Natal , Animais , Compostos Benzidrílicos/toxicidade , Feminino , Fenóis/toxicidade , Gravidez , Ovinos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Disruptores Endócrinos/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Exposição Materna/efeitos adversos , Insulina/metabolismo , Feto/efeitos dos fármacos , Células Secretoras de Glucagon/efeitos dos fármacos , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologiaRESUMO
Obesity and metabolic diseases are rising among women of reproductive age, increasing offspring metabolic risk. Maternal nutritional interventions during lactation present an opportunity to modify offspring outcomes. We previously demonstrated in mice that adult male offspring have metabolic impairments and increased adipose tissue macrophages (ATM) when dams are fed high fat diet (HFD) during the postnatal lactation window (HFD PN). We sought to understand the effect of HFD during lactation on early-life inflammation. HFD PN offspring were evaluated at postnatal day 16 to 19 for tissue weight and gene expression. Profiling of adipose tissue and bone marrow immune cells was conducted through lipidomics, in vitro myeloid colony forming unit assays, and flow cytometry. HFD PN mice had more visceral gonadal white adipose tissue (GWAT) and subcutaneous fat. Adipose tissue RNA sequencing demonstrated enrichment of inflammation, chemotaxis, and fatty acid metabolism and concordant changes in GWAT lipidomics. Bone marrow (BM) of both HFD PN male and female offspring had increased monocytes (CD45+Ly6G-CD11b+CD115+) and B cells (CD45+Ly6G-CD11b-CD19+). Similarly, serum from HFD PN offspring enhanced in vitro BM myeloid colonies in a toll-like receptor 4-dependent manner. We identified that male HFD PN offspring had increased GWAT pro-inflammatory CD11c+ ATMs (CD45+CD64+). Maternal exposure to HFD alters milk lipids enhancing adiposity and myeloid inflammation even in early life. Future studies are needed to understand the mechanisms driving this pro-inflammatory state of both BM and ATMs, the causes of the sexually dimorphic phenotypes, and the feasibility of intervening in this window to improve metabolic health.
Assuntos
Dieta Hiperlipídica , Obesidade , Feminino , Masculino , Camundongos , Animais , Humanos , Dieta Hiperlipídica/efeitos adversos , Obesidade/etiologia , Lactação , Inflamação , Exposição Materna , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
The timing of food intake is a novel dietary component that impacts health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. The timing of eating may be an important factor to consider during critical periods, such as pregnancy. Nutrition during pregnancy, too, can have a lasting impact on offspring health. The timing of food intake has not been thoroughly investigated in models of pregnancy, despite evidence that interest in the practice exists. Therefore, using a mouse model, we tested body composition and glycemic health of gestational early TRF (eTRF) in male and female offspring from weaning to adulthood on a chow diet and after a high-fat, high-sucrose (HFHS) diet challenge. Body composition was similar between groups in both sexes from weaning to adulthood, with minor increases in food intake in eTRF females and slightly improved glucose tolerance in males while on a chow diet. However, after 10 weeks of HFHS, male eTRF offspring developed glucose intolerance. Further studies should assess the susceptibility of males, and apparent resilience of females, to gestational eTRF and assess mechanisms underlying these changes in adult males.
Assuntos
Intolerância à Glucose , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Masculino , Feminino , Humanos , Jejum Intermitente , Dieta Hiperlipídica , Composição CorporalRESUMO
Objective: The aim of this study was to develop priorities through stakeholder engagement to alleviate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the professional careers of women engaged in diabetes research, education, and care. Research Design and Methods: This study used concept mapping, a mixed-methods, multistep process, to generate a conceptual map of recommendations through the following steps: 1) identify stakeholders and develop the focus prompt, 2) generate ideas through brainstorming, 3) structure ideas through sorting and rating on priority and likelihood, 4) analyze the data and create a cluster map, and 5) interpret and use results. Results: Fifty-two participants completed the brainstorming phase, and 24 participated in sorting and rating. The final concept map included seven clusters. Those rated as highest priority were to ensure supportive workplace culture (µ = 4.43); promote practices to achieve gender parity in hiring, workload, and promotion (µ = 4.37); and increase funding opportunities and allow extensions (µ = 4.36). Conclusion: This study identified recommendations for institutions to better support women engaged in diabetes-related work to alleviate the long-term impact of the COVID-19 pandemic on their careers. Some areas were rated as high in priority and high in likelihood, such as ensuring a supportive workplace culture. In contrast, family-friendly benefits and policies were rated as high in priority but low in likelihood of being implemented; these may take more effort to address, including coordinated efforts within institutions (e.g., women's academic networks) and professional societies to promote standards and programs that advance gender equity in medicine.
RESUMO
Insulin secretion from ß-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the ß-cell is altered after metabolic stress, such as high-fat diet or the ß-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in ß-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either specifically within the pancreas (GcgΔPanc) or the intestine (GcgΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both α- and ß-cell hyperplasia and reactivation of Gcg in the intestine normalized ß- but not α-cell mass, whereas pancreatic reactivation normalized both ß- and α-cell mass. GcgNull and GcgΔIntest mice maintained higher ß-cell mass after treatment with STZ compared with control and GcgΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of ß-cell mass in the GcgNull mice compensated for decreased individual ß-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes.NEW & NOTEWORTHY We examined the role of Gcg on ß-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased ß-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized ß-cell mass and glucose-stimulated insulin secretion. Increased ß-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes.
Assuntos
Diabetes Mellitus Experimental , Células Secretoras de Glucagon , Hiperglicemia , Camundongos , Animais , Proglucagon/genética , Proglucagon/metabolismo , Estreptozocina , Insulina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucose/farmacologia , Camundongos Knockout , Células Secretoras de Glucagon/metabolismo , Glicemia/metabolismoRESUMO
Background: Health care trainees lack opportunities to practice breast assessment and clinical skills with patients, making breast models significant for hands-on training. Insufficient training leads to low competence across practitioners in breast health areas of practice, including clinical lactation. The aim of this review was to describe types of breast models used to teach clinical skills of the breast across breast health areas. The secondary aims were to describe education interventions that included each model and identify whether multiple skin tones were available in models. Methods: Authors conducted a scoping review to identify which types of breast models are used to teach clinical skills across breast health areas of practice and determine gaps in literature regarding how clinical lactation skills are taught. The literature search was conducted in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, MedLine, and ProQuest. Inclusion criteria were students/professionals engaging in breast model simulation. Eighteen studies were reviewed. Authors extracted data on participants, breast health area, breast model, intervention, evaluation, general outcomes, skin tone, and research design. Results: The most common skill area was clinical breast exam (n = 7), while least was breastfeeding education (n = 1). Most models were commercial (n = 12). Zero studies described skin tone. Generally, breast model simulations were correlated with increased clinical skills and confidence regardless of model used. Conclusions: Despite demonstrated gain of skills, this review reveals inconsistent use of breast models and evaluation, exclusion of diverse skin tones, and lack of breast models reported to teach clinical lactation skills.
Assuntos
Aleitamento Materno , Competência Clínica , Feminino , Humanos , Atenção à SaúdeRESUMO
Background: Dietary interventions are first-line therapies for the prevention and management of many chronic diseases, yet primary care physicians prescribe these interventions infrequently. Objectives: This study investigates primary care physicians' current knowledge and opinions regarding the delivery of dietary interventions. This work aims to identify modifiable barriers to prescribing dietary interventions to prevent and treat diet-related diseases. Methods: We designed and fielded an anonymous, cross-sectional survey of faculty and resident physicians across the Internal Medicine, Family Medicine, and Pediatrics departments in three academic and community hospitals in lower Michigan. Data were collected between January 15 and April 15, 2019. Self-rated knowledge and attitudes were measured on a 5-point Likert scale. Objective scores were calculated for each question as percentage answered correctly among all respondents. Objective knowledge scores were compared based on participants' years in practice. Results: Response rate was 23% (356 responses). The sample was 62.3% female and 75.3% non-Hispanic White, and 56.7% were age 40 or younger. Average objective knowledge score was 70.3% (±17.2) correct. Mean self-rated knowledge score was 2.51 (±0.96) on a scale of 1(Poor) - 5(Excellent). Overall agreement with a statement of importance of dietary interventions was 3.99 (±0.40) on a scale of 1 (strongly disagree) to 5 (strongly agree). A majority (91.7%) of respondents indicated they would like more opportunities to learn about the evidence supporting dietary interventions. Conclusions: Physicians desire to incorporate dietary interventions into their practice. Findings encourage the development of educational strategies to support dietary intervention use among primary care physicians.
RESUMO
Maternal health and diet can have important consequences for offspring nutrition and metabolic health. During lactation, signals are communicated from the mother to the infant through milk via macronutrients, hormones, and bioactive molecules. In this study we designed experiments to probe the mother-milk-infant triad in the condition of normal maternal health and upon exposure to high fat diet (HFD) with or without concurrent metformin exposure. We examined maternal characteristics, milk composition and offspring metabolic parameters on postnatal day 16, prior to offspring weaning. We found that lactational HFD increased maternal adipose tissue weight, mammary gland adipocyte size, and altered milk lipid composition causing a higher amount of omega-6 (n6) long chain fatty acids and lower omega-3 (n3). Offspring of HFD dams were heavier with more body fat during suckling. Metformin (Met) exposure decreased maternal blood glucose and several milk amino acids. Offspring of met dams were smaller during suckling. Gene expression in the lactating mammary glands was impacted to a greater extent by metformin than HFD, but both metformin and HFD altered genes related to muscle contraction, indicating that these genes may be more susceptible to lactational stressors. Our study demonstrates the impact of common maternal exposures during lactation on milk composition, mammary gland function and offspring growth with metformin having little capacity to rescue the offspring from the effects of a maternal HFD during lactation.
Assuntos
Glândulas Mamárias Humanas , Metformina , Animais , Gorduras na Dieta/análise , Gorduras na Dieta/metabolismo , Feminino , Humanos , Lactação/metabolismo , Metformina/farmacologia , Leite/metabolismoRESUMO
BACKGROUND: Compared to the exhaustive study of transgenerational programming of obesity and diabetes through exposures in the prenatal period, postnatal programming mechanisms are understudied, including the potential role of breast milk composition linking maternal metabolic status (body mass index and diabetes) and offspring growth, metabolic health and future disease risk. METHODS: This narrative review will principally focus on four emergent bioactive compounds [microRNA's (miRNA), lipokines/signalling lipids, small molecules/metabolites and fructose] that, until recently were not known to exist in breast milk. The objective of this narrative review is to integrate evidence across multiple fields of study that demonstrate the importance of these compositional elements of breast milk during lactation and the subsequent effect of breast milk components on the health of the infant. RESULTS: Current knowledge on the presence of miRNA's, lipokines/signalling lipids, small molecules/metabolites and fructose in breast milk and their associations with infant outcomes is compelling, but far from resolved. Two themes emerge: (1) maternal metabolic phenotypes are associated with these bioactives and (2) though existing in milk at low concentrations, they are also associated with offspring growth and body composition. CONCLUSION: Breast milk research is gaining momentum though we must remain focused on understanding how non-nutritive bioactive components are affected by the maternal phenotype, how they subsequently impact infant outcomes. Though early, there is evidence to suggest fructose is associated with fat mass in the 1st months of life whereas 12,13 diHOME (brown fat activator) and betaine are negatively associated with early adiposity and growth.
Assuntos
MicroRNAs , Aleitamento Materno , Feminino , Frutose , Humanos , Lipídeos , Leite Humano/metabolismo , Mães , Obesidade/metabolismo , GravidezRESUMO
BACKGROUND: Whether current dietary guidelines are appropriate for pregnancy and lactation has not been well studied. Many women of reproductive age are not meeting recommendations for dietary components such as fat, added sugar, and fiber. OBJECTIVES: To assess associations between maternal dietary components during pregnancy and lactation and infant growth and adiposity at 6 mo of age. METHODS: Mother-infant dyads (n = 349) from the prospective, observational Mothers and Infants Linked for Healthy Growth study were included (100% fully breastfed for 1 mo; 75% to 6 mo). Daily intake of fat, fiber, and added sugar was obtained using the National Cancer Institute Diet History Questionnaire II during the third trimester of pregnancy and at 1 and 3 mo postpartum. Furthermore, intakes were categorized as meeting/exceeding 2015-2020 Dietary Guidelines for Americans. Multiple linear regression models adjusted for numerous potential confounders tested relations between dietary components and infant adiposity (via DXA) and growth parameters. Regression coefficients (ß) for continuous variables were expressed per SD to allow for comparison of effect sizes. RESULTS: Maternal intake of total fat and saturated fat was positively associated with infant percent body fat (%BF) (ß: 0.84 per SD, P = 0.04; ß: 0.96 per SD, P = 0.01, respectively). Added sugar intake was positively associated with infant weight-for-length z score (ß: 0.16 per SD, P = 0.02), and excessive added sugar intake was positively associated with %BF at 6 mo (ß: 0.75 per SD, P = 0.05). CONCLUSIONS: In a predominantly fully breastfeeding cohort of women, maternal intake of fat and added sugar during pregnancy and lactation were associated with small increases in infant adiposity and relative weight at 6 mo. Additional research is needed to determine if these relations persist later in infancy and if such elevations in adiposity are important for long-term obesity risk.
Assuntos
Adiposidade , Açúcares , Tecido Adiposo , Ingestão de Alimentos , Feminino , Humanos , Lactente , Obesidade , Gravidez , Estudos ProspectivosRESUMO
The newly established CD3FLAG-mIR transgenic mouse model on a C57Bl/6 background has a FLAG tag on the mouse Insulin Receptor (mIR), specifically on T cells, as the FLAG-tagged mIR gene was engineered behind CD3 promoter and enhancer. The IR is a chemotactic molecule for insulin and the Flag-tagged mIR T cells in the BL/6-CD3FLAGmIR transgenic mice can migrate into the pancreas, as shown by immunofluorescent staining. While the transgenic mice do not become diabetic, there are phenotypic and metabolic changes in the islets. The transgenic islets become enlarged and disorganized by 15 weeks and those phenotypes continue out to 35 weeks of age. We examined the islets by RT-PCR for cell markers, ER stress markers, beta cell proliferation markers, and cytokines, as well as measuring serum insulin and insulin content in the pancreas at 15, 25, and 35 weeks of age. In transgenic mice, insulin in serum was increased at 15 weeks of age and glucose intolerance developed by 25 weeks of age. Passage of transgenic spleen cells into C57Bl/6 RAG-/- mice resulted in enlarged and disorganized islets with T infiltration by 4 to 5 weeks post-transfer, replicating the transgenic mouse studies. Therefore, migration of non-antigen-specific T cells into islets has ramifications for islet organization and function.
Assuntos
Secreção de Insulina , Células Secretoras de Insulina/patologia , Pancreatite/genética , Receptor de Insulina/genética , Linfócitos T/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Estresse do Retículo Endoplasmático , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pancreatite/metabolismo , Pancreatite/patologia , Receptor de Insulina/metabolismo , Linfócitos T/fisiologia , TransgenesRESUMO
Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic ß cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/patologia , Pâncreas/imunologia , Receptor de Insulina/metabolismo , Linfócitos T/imunologia , Adolescente , Adulto , Animais , Movimento Celular , Criança , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Risco , Adulto JovemRESUMO
Maternal metabolic disease and diet during pregnancy and lactation have important implications for the programming of offspring metabolic disease. In addition, high-fat diets during pregnancy and lactation can predispose the offspring to non-alcoholic fatty liver disease (NAFLD), a rising health threat in the U.S. We developed a model of maternal high-fat feeding exclusively during the lactation period. We previously showed that offspring from dams, given lactational high-fat diet (HFD), are predisposed to obesity, glucose intolerance, and inflammation. In separate experiments, we also showed that lactational metformin treatment can decrease offspring metabolic risk. The purpose of these studies was to understand the programming implications of lactational HFD on offspring metabolic liver disease risk. Dams were fed a 60% lard-based HFD from the day of delivery through the 21-day lactation period. A subset of dams was also given metformin as a co-treatment. Starting at weaning, the offspring were fed normal fat diet until 3 months of age; at which point, a subset was challenged with an additional HFD stressor. Lactational HFD led male offspring to develop hepatic insulin resistance. The post-weaning HFD challenge led male offspring to progress to NAFLD with more severe outcomes in the lactational HFD-challenged offspring. Co-administration of metformin to lactating dams on HFD partially rescued the offspring liver metabolic defects in males. Lactational HFD or post-weaning HFD had no impact on female offspring who maintained a normal insulin sensitivity and liver phenotype. These findings indicate that HFD, during the lactation period, programs the adult offspring to NAFLD risk in a sexually dimorphic manner. In addition, early life intervention with metformin via maternal exposure may prevent some of the liver programming caused by maternal HFD.
RESUMO
The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood.
Assuntos
Glicemia/metabolismo , Dieta Hiperlipídica , Intolerância à Glucose/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Exposição Materna , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Animais Recém-Nascidos , Peso ao Nascer , Feminino , Células Secretoras de Insulina/patologia , Tamanho da Ninhada de Vivíparos , Masculino , Camundongos , Tamanho do Órgão , GravidezRESUMO
Maternal low-protein diet (LP) throughout gestation affects pancreatic ß-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for ß-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal ß-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with ß-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient ß-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes.
Assuntos
Dieta Hiperlipídica , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Dieta com Restrição de Proteínas , Feminino , Teste de Tolerância a Glucose , Secreção de Insulina/fisiologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , GravidezRESUMO
Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30-90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance.