INTRODUCTION: As populations are adopting a Western lifestyle, with high intake of dietary sugar and fat and low physical activity, the risk of developing Type 2 Diabetes is only increasing dramatically. Diabetes leads to drastic alterations within the body, primarily leading to neuropathies, nephropathies and retinopathies. As the prevalence of diabetes increases, it is important to understand the threat that it poses to the retina, and ultimately, vision. OBJECTIVE: We plan to compare the retina of diabetic patients with retinopathies to normal, healthy patients to understand the differences between them. We will be using a novel imaging technique, called Laser Speckle Flowgraphy, which provides the Mean Blur Rate, a value directly related to the blood flow velocity within the retina, specifically the optic nerve head. Using the calculated Mean Blur Rate, this study will quantify baseline blood flows in patients with diabetic retinopathies. This project aims to understand and differentiate the Mean Blur Rate of healthy patients and diabetic patients, including inter-patient and intra-patient comparisons, as well as changes in the Mean Blur Rate over time. The potential influence of treatment factors, such as intravitreal injection treatment or laser treatment, or demographic factors, such as age and race, on the Mean Blur Rate of diabetic retinopathy patients will also be evaluated. By understanding the difference in the retinas of diabetic patients and healthy patients, we can work towards preventing the loss of vision and function. METHODS: A total of 25 Type 2 diabetic patients with a diabetic retinopathy equaling 46 eyes were compared to 20 healthy patients, equaling 40 eyes. We collected the Mean Blur Rate for comparison between the two populations. Data was compared with correlation, t-test and ANOVA studies to find whether demographic or treatment variables influenced the Mean Blur Rate of diabetic retinopathy patients. RESULTS: We found a difference between the Mean Blur Rate, and thus blood flow, between the retina of diabetic and healthy patients. Diabetic patients tended to have a lower flow, presumably attributable the effects of hyperglycemia on blood circulation. Diabetic patients also have a significant difference in the Mean Blur Rate between both of their eyes, indicating that their hyperglycemia may affect both eyes differently (p<0). There was significant variability within both diabetic retinopathy patients and normal, healthy patients (p<0 for healthy patients and p<0.001 for diabetic patients). This is expected as blood circulation can be affected by a variety of factors other than disease status. We also found that the MBR of diabetics who were treated with intravitreal injections was on average higher than those who had not received intravitreal treatment. (p<0.05) CONCLUSION: Our study highlights how diabetic retinopathy impacts retinal blood flow, as well as showcases how Laser Speckle Flowgraphy can be used as a reliable method to measure and compare retinal blood velocities. Further studies are needed to understand how exactly diabetes affects blood circulation, although several theories are currently available. We also found a relation between previous intravitreal injection history and the blood flow velocity, but other studies have had mixed results on how exactly these injections alter the blood flow within the retina. Future studies can be conducted to better understand this relationship and uncover whether the effect on blood flow velocity is related to the drug used for the intravitreal injection or some other factor.

A endocrinologia reprodutiva do muriqui do sul B. arachnoides foi avaliada em quatro fêmeas adultas pela dosagem de metabólitos fecais de estrógenos e em quatro machos adultos e um macho subadulto pela dosagem de metabólitos de testosterona e glicocorticóides durante um período de onze meses em duas diferentes condições restritivas, ilha de 600m2, Curitiba (PPC) e viveiro (15,40x5,85x4,70m) Rio de Janeiro (CPRJ). As fêmeas apresentaram grande variação individual nas concentrações de estrógenos e progestinas fecais ao longo do período de estudo, três não apresentaram atividade ovariana no período de outubro-dezembro e apenas uma apresentou atividade durante todos os períodos amostrados. Mesmo com níveis baixos de esteróides as fêmeas apresentaram comportamento perceptivo e cópulas. Os machos do PPC apresentaram níveis significativamente mais altos de glicocorticóides e níveis significativamente mais baixos de testosterona do que os machos do CPRJ (p<0,05) apresentaram. O macho subadulto apresentou níveis significativamente mais baixos para metabólitos de testosterona. Nos machos as cópulas ocorreram próximo às elevações das concentrações de testosterona. Em três situações grandes elevações dos níveis de glicocorticóides fecais puderam ser relacionadas a situações estressantes. Nosso estudo comprovou a eficácia do método empregado para monitoramento reprodutivo bem como para avaliar situações estressantes. / The reproductive endocrinology of the southern muriqui (Brachyteles. Arachnoids) was evaluated through the dosage of fecal metabolites steroids for 04 adult females and fecal metabolites of testosterone and glucocorticoids for 04 adult males and 01 subadult male. The study was conducted over an eleven month period at two environmental conditions: a) an island of 600 m2, with natural vegetation, at Curitiba Zoo (PPC) and b) a large cage of 15,40X5,85X4,70m at Rio de Janeiro Primatological Centre (CPRJ). It was observed that females had large strogen interindividual variation and fecal progestins: three females did not show ovarian activity over a partial period of the study, while ovarian activity was observed for all sample periods for one female. Despite the detection of low levels of steroids, proceptive behaviour and copulations were observed. The PPC males showed significant levels of glicorticoids and testosteorne when compared to the CPRJ males (p<0.05). The subadult male exhibited the lowest level of testosterone metabolites and those differences were significant when compared to the adult males (p<0.05). For all males, copulations occurred when testosterone levels were highest and peaks of glucorticoids were linked to stressfull situations. This study have shown that the method used was effective for reproductive monitoring as well as for evaluating stressfull situations.

Background and Objective: According to national and regional treatment guidelines, metformin is the first choice and SGLT2-inhibitors may be added in case of insufficient effect of metformin or other comorbidities. SGLT2 inhibitors as add-on to metformin lowers HbA1c further 5-9 mmol/mol. The aim of this study was to map the effect of SGLT2 inhibitors on HbA1c at follow-up and map how many patients that remains on SGLT2 inhibitors with insufficient effect. Study design: A retrospective study in which patients with diabetes type 2 who received a prescription for SGLT2 inhibitors from Visby Norr or Visborg health care center during the period 2018-06-30 to 2020-06-30 was identified. HbA1c, kidney function and weight were registered in an Excel-file at insertion of the SGLT2 inhibitor and at the first follow-up after insertion. Setting: Visby Norr and Visborg health care centers in Gotland. Main outcomes measures: The change in HbA1c after insertion of SGLT2 inhibitors and the proportion of patients who had insufficient effect (HbA1c reduction &lt; 5 mmol/mol) at follow-up. Results: A total of 102 patients was included in the analyze. Following SGLT2 inhibitors was prescribed empagliflozin (91%) and dapagliflozin (9%). Mean follow up visit was within five months after insertion of the SGLT2 inhibitor. The mean decrease in HbA1c was 10 mmol/mol (95% confidence interval 7-13 mmol/mol). There were 21 individuals (21%) who achieved an HbA1c decrease &lt; 5 mmol/mol (mean decrease in this group was 3 mmol/mol), 61 (60%) achieved an HbA1c decrease &gt; 5 mmol/mol (average decrease in this group was 18 mmol/mol) and 20 subjects (19%) had increased HbA1c. Conclusion: In summary, the study shows that five months after insertion of SGLT2 inhibitor resulted in a decrease in HbA1c by 10 mmol/mol. At follow-up 40% of the population had an insufficient effect on HbA1c after insertion of the SGLT2-inhibitors.

Prenatal exposure to sex hormones has profound effects on neurodevelopment with lifelong implications for mental health. Fetal exposure to aberrant levels of sex hormones alters sexual dimorphism (i.e. degree of feminization or masculinization; sex differences in brain and behavior) and may contribute to the differential susceptibility of males and females to psychiatric risk and neurodevelopmental disorders, including autism. During fetal development, the in-utero environment is regulated by the placenta, a maternal-fetal endocrine structure that serves as a “gate-keeper” between the maternal and fetal circulatory systems. The placenta expresses high levels of aromatase, an enzyme that converts testosterone to estrogen, and it has been proposed that placental aromatase precludes the transfer of maternal testosterone to the fetus. However, this view does not account for individual differences in placental aromatase expression or maternal hormone levels that may account for altered neurobehavioral outcomes. Retinoic acid-related orphan receptor-alpha (RORA) has been identified as a transcription factor that regulates aromatase and as an autism candidate gene – yet the role of RORA in the placenta as a regulator of the prenatal hormonal environment has yet to be determined. The research presented in this thesis aimed to evaluate 1) the relationship between maternal and neonatal hormone concentrations, 2) whether placental aromatase/RORA influences the relationship between maternal and neonatal hormones concentrations, 3) the relationship between maternal sex hormones during pregnancy and neurobehavioral outcomes in the offspring, and 4) the relationship between placental aromatase/RORA and neurobehavioral outcomes in the offspring. Chapters 1 and 2 of this thesis provide a review of the literature pertaining to the sources of and neurodevelopmental consequences of fetal exposure to hormones and the methods used to address our research questions. Chapters 3, 4, and 5 of this thesis used in vivo and in vitro methods to investigate the role of placental aromatase and RORA in regulating fetal exposure to maternal hormones. Results from these studies indicate that maternal testosterone is a strong predictor of neonatal testosterone levels at birth and that aromatase and RORA expression in the human placenta subtly influence the relationship between maternal and neonatal testosterone and estradiol in a sex-dependent manner. Results from our studies using an in vitro approach call into question the widely proposed role of placental aromatase in converting maternal testosterone intro estradiol. Chapters 6 and 7 of this thesis aimed to determine whether variability in maternal testosterone and placental aromatase/RORA expression was associated with increased neurodevelopmental risk as a result of elevated fetal hormone exposure. For the first time in the literature, we report a direct association between elevated maternal testosterone and poorer childhood neurodevelopmental outcome in a sex-dependent manner. We also report that the effects of placental aromatase and RORA expression on childhood outcomes vary depending on the neurobehavioral domain being assessed. Taken together, these studies support the notion that fetal exposure to sex hormones, especially those of maternal origin, can affect neonatal hormone production as well as long-term child neurobehavior. The specific mechanisms by which the placenta regulates fetal exposure require further investigation.

BACKGROUND: Elevation of glucagon levels and increase in alpha-cell mass are associated with states of hyperglycemia in diabetes. However, little is known about the mechanisms that control glucagon secretion and alpha-cell mass expansion in normal or diabetogenic conditions. Glucagon is secreted during the fasting state, when glucose levels are low, to stimulate glycogenolysis and gluconeogenesis in the liver to increase the blood glucose level. Amino acids, also, stimulate-glucagon secretion and alpha-cell mass. Amino acids increase glucagon secretion via activation of mTORC1 in alpha-cells. A critical step for mTOR activation is the localization of mTORC1 to the lysosome where it meets Rheb for activation. Amino acids are unique in their ability to localize mTORC1 to the lysosomal membrane for activation through their interaction with a variety of amino acid sensors, such as Sestrin2, which modulates mTORC1 activity via its interaction with GATOR2. Integral to mTORC1’s localization is the Ragulator complex, more specifically, p18, which provides the essential scaffolding necessary for lysosomal docking. Amino acids sensors work upstream of mTORC1 and sense amino acid concentrations with different affinities and are specific to certain amino acids and relay this information to mTORC1. OBJECTIVE: To investigate the role that p18, a component of the Ragulator complex, and GATOR2, a component of an amino acid sensor complex, play in amino-acid dependent mTORC1 lysosomal localization and its effect on alpha-cell function and glucagon secretion. METHODS: Generation of Knockout mice for p18 and GATOR2 in alpha-cells were produced by crossing Glu-Cre mice with P18(flox/flox) and GATOR2(flox/flox). Blood glucose, glucagon, and insulin levels were evaluated during fed, fasting, and insulin-induced hypoglycemic conditions to evaluate glucagon secretion. Isolated islets were also exposed to media containing different glucose or nutrient concentrations to evaluate the effect on glucagon secretion. RESULTS: Our data shows that knockdown experiments in alpha-cells for p18 and GATOR2 have demonstrated the role of these proteins in amino acid dependent localization of mTORC1 to the lysosomal membrane. More specifically, our data demonstrate that animals with a knockdown for p18 or GATOR2 demonstrated decreased glucagon secretion during hypoglycemic conditions. Mice with a knockdown for p18 also demonstrate decreased glucagon secretion in the presence of glucagon secretion stimulators such as arginine and also demonstrated decreased insulin secretion. CONCLUSIONS: Loss of essential components of the amino acid signaling and lysosomal localization in the mTORC1 pathway results in impaired function of alpha-cells and glucagon secretion. Loss of p18 in alpha-cells potentially results in an inability of mTORC1 to dock and bind to the lysosomal membrane, whereas loss of GATOR2 potentially results in chronic inhibition of mTORC1 via GATOR1. Loss of each of these components results in the lost or impaired ability for mTORC1 to migrate and bind to the lysosomal membrane. / 2022-06-02T00:00:00Z

No description available.

Objective: To characterize current diabetes screening practices in the first trimester of pregnancy in the United States, evaluate patient characteristics and risk factors associated with early diabetes screening, and compare perinatal outcomes by early diabetes screening. Methods: This was a retrospective cohort study of US medical claims data from patients diagnosed with a viable intrauterine pregnancy who presented for care before 14 weeks of gestation without pre-existing pre-gestational diabetes from the IBM MarketScan® database for the period of January 1, 2016, to December 31, 2018. Univariate and multivariate analyses were used to evaluate clinical factors and perinatal outcomes. Results: There were 400,588 pregnancies identified as eligible for inclusion, with 18.0% of women receiving early screening for diabetes. Of those with laboratory order claims, 53.1% had hemoglobin A1c, 30.0% fasting glucose, and 16.9% oral glucose tolerance tests. Compared to women who did not have early diabetes screening, those that did were more likely to be older, obese, have a history of gestational diabetes, chronic hypertension, polycystic ovarian syndrome, hyperlipidemia, and a family history of diabetes. In adjusted logistic regression, history of gestational diabetes (aOR 3.99, 95% CI 3.73-4.26) had the strongest association with early diabetes screening. Early diabetes screening irrespective of the screening result was also associated with adverse perinatal outcomes including a higher rate of cesarean delivery, preterm delivery, gestational hypertension, pre-eclampsia, and gestational diabetes. Conclusion: First trimester early diabetes screening was mostly commonly performed by hemoglobin A1c evaluation, and women that underwent early diabetes screening regardless of the result were more likely to experience adverse perinatal outcomes.

No description available.

Reports have linked energy balance along with adipocyte derived leptin action to improved fertility. Recent evidence indicates that leptin hormone is present in breast milk and leptin receptors are well expressed in mammary epithelial cells. The hypothesis that insufficiency of leptin restraint in the hypothalamus may underlie infertility in rodents and the failure of lactating breast to express adequate amount of milk was tested. Female Sprague-Dawley rats were injected leptin through intracerebroventricular cannulation (ICVC) of the third ventricle. Female rats were mated with stud males and observed throughout gestation. Compared to the control groups, leptin treatment increased prolactin levels in the dams and increased milk transfer to pup. Hypothalamic mRNA leptin levels and brain size in the offspring from leptin treated dams were significantly higher than the control. These findings support the involvement of leptin in reproduction and could lead to better understanding of leptin transfer from dam to offspring.

Excessive alcohol consumption is a leading cause of death and disability globally and can lead to diseases such as alcoholic skeletal myopathy. Skeletal muscle is the largest organ in the human body and functions to regulate whole-body energy homeostasis. Additionally, skeletal muscle can function as an endocrine organ via secretion of myokines. Two myokines, myonectin and irisin, present a wide range of effects upon metabolism, inflammation, and tissue survival- signaling. We hypothesized that chronic alcohol consumption will result in reduced circulating myonectin and irisin levels. Mice were fed an ethanol-containing or control diet for 10 days or 6 weeks. Tissues and serum were collected from mice and immunoblotting was used to quantify myonectin and irisin levels. Our data demonstrated that neither a 10 day nor 6-week ethanol diet was effective in altering myonectin levels, whereas irisin was undetectable. Therefore, we conclude that these myokines are not affected by alcohol consumption.