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Here, we evaluated the feasibility of non-prodrug PEG-drug conjugates to decrease the accumulation of drugs within the placental tissues. The results showed that PEG was biocompatible with the human placenta with no alteration of the basal rate of proliferation or apoptosis in term placental explants. No significant changes in the released levels of lactate dehydrogenase and the human chorionic gonadotropin were observed after PEG treatment. The cellular uptake studies revealed that conjugating Cy5.5 and haloperidol to PEG significantly reduced (by up to ∼40-fold) their uptake by the placenta. These findings highlight the viability of novel non-prodrug polymer-drug conjugates to avoid the accumulation of drugs within the placenta.

Sickle cell anemia (SCA) is characterized by decreased red blood cell (RBC) deformability due to polymerization of deoxygenated hemoglobin, leading to abnormal mechanical properties of RBC, increased cellular adhesion, and microcirculatory obstruction. Prior work has demonstrated that NO• influences RBC hydration and deformability and is produced at a basal rate that increases under shear stress in normal RBC. Nevertheless, the origin and physiological relevance of nitric oxide (NO•) production and scavenging in RBC remains unclear. We aimed to assess the basal and shear-mediated production of NO• in RBC from SCA patients and control (CTRL) subjects. RBCs loaded with a fluorescent NO• detector, DAF-FM (4-Amino-5-methylamino- 2',7'-difluorofluorescein diacetate), were imaged in microflow channels over 30-min without shear stress, followed by a 30-min period under 0.5Pa shear stress. We utilized non-specific nitric oxide synthase (NOS) blockade and carbon monoxide (CO) saturation of hemoglobin to assess the contribution of NOS and hemoglobin, respectively, to NO• production. Quantification of DAF-FM fluorescence intensity in individual RBC showed an increase in NO• in SCA RBC at the start of the basal period; however, both SCA and CTRL RBC increased NO• by a similar quantity under shear. A subpopulation of sickle-shaped RBC exhibited lower basal NO• production compared to discoid RBC from SCA group, and under shear became more circular in the direction of shear when compared to discoid RBC from SCA and CTRL, which elongated. Both CO and NOS inhibition caused a decrease in basal NO• production. Shear-mediated NO• production was decreased by CO in all RBC, but was decreased by NOS blockade only in SCA. In conclusion, total NO• production is increased and shear-mediated NO• production is preserved in SCA RBC in a NOS-dependent manner. Sickle shaped RBC with inclusions have higher NO• production and they become more circular rather than elongated with shear.

Objective: Pump-treated children with type 1 diabetes (T1DM) have widely differing basal insulin (BI) infusion profiles for specific periods of the day. The pattern of BI requirements depends on the timing and magnitude of cortisol and growth hormone secretion within each age group. In adolescents and young adults, a decreased insulin sensitivity is seen, particularly in the early morning (dawn phenomenon) and to a lesser extent, in the late afternoon (dusk phenomenon). Different approaches exist for the inititation of basal rates. However, there is a lack of evidence-based recommendation, especially in young children. Usually the basal rates are set equally throughout day and night or the day is divided into tertiles. The aim of this study was to analyze the change of the initial, equally distributed, BI rates over the first year of standard insulin pump therapy. Methods: A total of 154 patients with T1DM, aged between 0 and 18 years, (n=5). Distribution of hourly basal rates at the initiation of the pump and at the end of first year were evaluated. Results: Median (range) age and diabetes duration was 14.46 (1.91-26.15) and 7.89 (1.16-17.15) years, respectively. Forty-four percent were male, 56% were female. Mean total insulin dose/kg in the whole cohort at the initiation and after one year of pump therapy was 0.86 +/- 0.23 U/kg and 0.78 +/- 0.19 U/kg, respectively and differed significantly between each age group (p

A new insulin patch pump for continuous subcutaneous insulin infusion was developed. The pump is composed of reusable and disposable parts and operates with a stepping motor. This pump was compared to a patch pump and a durable pump regarding basal rate and bolus accuracy. Using a microgravimetric method, boluses of 0.2 U, 1 U and 7 U, and a basal rate of 1 U/h were tested. For all pumps, bolus accuracy was higher when larger volumes were delivered. While median deviations were similar for all pumps, there were differences in the precision of individual boluses and when regarding basal rate delivery divided into 1-h windows.

The ability to account with precision for the quantitative variation in the basal rate of metabolism (BMR) at the species level is explored in four groups of endotherms: arvicoline rodents, ducks, melaphagid honeyeaters, and phyllostomid bats. An effective analysis requires the inclusion of the factors that distinguish species and their responses to the conditions they encounter in the environment. These factors are implemented by changes in body composition and are responsible for the non-conformity of species to a scaling curve. Two concerns may limit an analysis. The factors correlated with energy expenditure often correlate with each other, which usually prevents them from being included together in an analysis, thereby preventing a complete analysis, implying the presence of factors other than mass. Many of the relevant factors, such as food habits and an island residence, are qualitative, which complicates their inclusion in a quantitative analysis, a difficulty that is solved by ANCOVA. The precision of an analysis, based on an inclusive equation, can be determined by comparing its estimates with measurements of the performance of species. Without this comparison, the effectiveness of an analysis cannot be determined, which then simply becomes a suggestion. A proposed standard for a precise estimate is for it to be within 10% of the measured rate.

For people with type 1 diabetes and some with type 2 diabetes, the problem of insulin titration, i.e. finding an adequate basal rate of insulin, is a complex and time-consuming task. This paper proposes a simple model-free algorithm and a procedure for fast initial titration in people with type 1 diabetes (T1D). A modified proportional-integral-derivative (PID) controller (i) updates the estimated insulin basal rate, and (ii) administers micro-boli of insulin every 5 minutes using glucose measurements from a continuous glucose monitor (CGM). A bolus calculator mitigates the effect of meals and reduces postprandial peaks. We evaluate the performance of our system qualitatively and numerically using a virtual clinic of 1,000 T1D patients with a broad inter-patient variability representative of a real population of people with T1D. We let the titration phase run for three consecutive days, followed by a three-day test phase using the newly computed basal insulin infusion rate. The proposed algorithm is able to provide a safe titration and individualized treatment for people with T1D.

Background: Pump-treated patients with type 1 diabetes have widely differing basal insulin infusion profiles. We analyzed consequences of such heterogeneity for glycemic control under fasting conditions. Methods: Data from 339 adult patients with type 1 diabetes on insulin pump therapy undergoing a 24-hour fast (basal rate test) were retrospectively analyzed. Hourly programmed basal insulin infusion rates and plasma glucose concentrations as well as their proportions within, below, or above arbitrarily defined target ranges were assessed for specific periods of the day (eg, 1-7 hours, “dawn” period, 16-19 hours, “dusk” period, reference period 20-1 hours/10-14 hours), by tertiles of a predefined “dawn” index (mean basal insulin infusion rate during the “dawn” divided by the reference periods). Results: The “dawn” index varied interindividually from 0.7 to 4.4. Basal insulin infusion profiles exhibited substantial differences ( P = .011), especially overnight. Despite higher insulin infusion rates at 4 and 6.45 hours, patients with the most pronounced “dawn” phenomenon exhibited higher plasma glucose concentrations at those time points ( P < .012). Patients with a marked “dawn” phenomenon exhibited a lower probability for low (7.2 mmol/L) during the dawn period (all P values Conclusions: We observe substantial interindividual heterogeneity in the “dawn” phenomenon. However, widely different empirically derived basal insulin infusion profiles appear appropriate for individual patients, as indicated by similar plasma glucose concentrations, mainly in the target range, during a 24-hour fasting period.

Glucagon’s effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg−1·min−1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg−1·min−1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg−1·min−1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg−1·min−1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Background: Optimizing programmed basal rates and carbohydrate ratios may improve the performance of the artificial pancreas. We tested, in a diabetes camp, the efficacy of a learning algorithm tha...

Evidence suggests that patients with type 1 diabetes (T1D) performing aerobic exercise with their insulin pump connected (pump on) vs pump disconnected (pump off) have an increased risk of hypoglycemia. It has not been examined whether this risk remains during high-intensity exercise. This study compared the effects of pump on (50% basal insulin at exercise onset) vs pump off (0% basal insulin at exercise onset) on glucose concentrations during intermittent high-intensity exercise in adults with T1D and on patients' own perspective of their glycemia.Twelve adults with T1D using insulin pump therapy completed two 40-min intermittent high-intensity exercise bouts. Insulin adjustments included: 1) pump set to 50% of usual basal rate (pump on) or 2) pump suspended (pump off) during exercise, in random order. Blood glucose was recorded every 10 min during exercise and, after providing subjects with an initial reference glucose value before exercise, participants were asked to estimate their glucose during exercise.Glucose levels were higher in pump off (8.1±1.3 mmol/L) vs pump on (7.4±2.1 mmol/L) at exercise start (p0.05), but were similar by the end of exercise (p=0.9). During exercise, hypoglycemia incidence did not differ between conditions (1 of 12 for both). However, the percentage of time in hypoglycemia at 12 h after exercise was 5±8% vs 1±2% for pump on vs pump off, respectively (p=0.3). Participants were better able to estimate their own glucose during pump on vs pump off (rPump on vs pump off at exercise onset showed no significant differences in blood glucose concentrations during 40 min of intermittent high-intensity exercise.

Background: Various studies have evaluated the safety and efficacy of using insulin pumps during Ramadan; some of them demonstrated favorable outcomes in reducing hypoglycemia and hyperglycemia. However, there is no consensus on the recommendations for basal insulin adjustments and the utilization of technical features of insulin pumps to improve glycemic control. Objectives: We aimed to investigate the effects of different insulin pump settings on time in range in patients with type 1 diabetes during Ramadan. Methods: In this randomized pilot study, 30 patients classified to have low to moderate risk for fasting were assigned to either a control group to receive basal insulin adjustments only or an intervention group to use the temporary basal rate and extended bolus features in addition to the basal insulin modifications. The percentage of time spent at different glucose ranges was measured by continuous glucose monitoring. Results: The percentage of time spent within target (70-180 mg/dL) increased significantly in the intervention group from 63.0 ± 10.7 to 76 ± 16.2% (mean difference, 27% points; P < .001). The percentage of time spent in hyperglycemia level 1 (>180 mg/dL) and level 2 (>250 mg/dL) met the criterion of significance, indicating that the intervention group spent less time in hyperglycemia. However, there was no significant difference in the percentage of time spent in hypoglycemia ranges. Conclusions: Incorporating technological approaches of pump therapy with clinical practice guidelines could improve glycemic control during Ramadan.

Laminin-γ1 is required for early embryonic development; however, the need for laminin-γ1 synthesis in adulthood is unknown. A global and inducible mouse model of laminin-γ1 deficiency was generated to address this question. Genetic ablation of the Lamc1 gene in adult mice was rapidly lethal. Despite global Lamc1 gene deletion in tamoxifen-induced mutant mice, there was minimal change in total cardiac, pulmonary, hepatic or renal laminin protein. In contrast, laminin-γ1 was significantly depleted in the small intestines, which showed crypt hyperplasia and dissociation of villous epithelium from adjacent mesenchyme. We conclude that the physiologic requirement for laminin-γ1 synthesis in adult mice is dependent on a tissue-specific basal rate of laminin-γ1 turnover that results in rapid depletion of laminin-γ1 in the intestine.

Background V-Go is a wearable, patch-like, 24-h insulin delivery device that delivers both a continuous preset basal rate and on-demand bolus dosing. The aim of this study was to observe glycemic control, insulin dosing, and hypoglycemia risk in patients switched to V-Go in a real-world setting. The primary objective was to compare change in mean hemoglobin A1c (HbA1c) from baseline to the end of V-Go use. Methods This prospective, open-label, multicenter study recruited patients with type 2 diabetes (T2D) and suboptimal glycemic control (HbA1c ≥ 7%) across 28 centers. Efficacy analyses were conducted for all patients with a post-baseline HbA1c and results stratified based on prior antihyperglycemic medication therapies. Insulin dosing was at the discretion of the health care provider and the protocol did not mandate glycemic targets. Treatment satisfaction surveys were utilized to gain patient feedback on the use of V-Go. Results One hundred eighty-eight patients were enrolled in the study, among whom 140 patients had a valid post-baseline HbA1c and were included in the primary efficacy analysis. Use of V-Go resulted in a change of − 0.64%; (P = 0.003) in HbA1c from baseline, and in those prescribed insulin, the total daily dose of insulin was decreased by 12 units/day (P

Background: Twenty-four hour fasting periods are being used to scrutinize basal insulin infusion rates for pump-treated patients with type 1 diabetes. Methods: Data from 339 consecutive in-patients with adult type 1 diabetes on insulin pump therapy undergoing a 24-hour fast as a basal rate test were retrospectively analyzed. Hourly programmed basal insulin infusion rates and plasma glucose concentrations within, below, or above arbitrarily defined target ranges were assessed for periods of the day of special interest (eg, 01:00-07:00 am, “dawn” period, 04:00-07:00 pm, and “dusk” period). Statistics: χ2-tests, paired t-tests were used. Results: Basal rates (mean: 0.90 ± 0.02 IU/h) showed circadian variations with peaks corresponding to “dawn” (1.07 ± 0.02 IU/h from 01:00 to 07:00 am) and, less prominently, “dusk” (0.95 ± 0.02 IU/h from 03:00 to 07:00 pm). Individual mean plasma glucose concentrations averaged 6.6 ± 0.1 mmol/L, with 53.1% in the predefined “strict” (4.4-7.2 mmol/L) target range. Interestingly, during the “dawn” period, plasma glucose was significantly higher (by 0.5 ± 0.1 mmol/L [95% confidence interval: 0.3-0.8 mmol/L; P < .0001]) and the odds ratio for hypoglycemia was significantly lower compared to the reference period. Interpretation: Twenty-four hour fasting periods as basal rate tests frequently unravel periods with inappropriate basal insulin infusion rates potentially responsible for fasting hyper- or hypoglycemia. Notably, the higher basal insulin infusion rate found during the “dawn” period seems to be justified and may need to be accentuated.

BACKGROUND: The adult hippocampal dentate is comprised of both developmentally-generated dentate granule cells (dDGCs) and adult-generated dentate granule cells (aDGCs), which play distinct roles in hippocampal information processing and network function. EtOH exposure throughout gestation in mouse impairs the neurogenic response to enriched environment (EE) in adulthood, although the basal rate of adult neurogenesis under standard housing (SH) is unaffected. Here, we tested whether the production and/or survival of either dDGCs or aDGCs are selectively impaired following exposure of mice to EtOH vapors during early postnatal development (human 3(rd) trimester-equivalent), and whether this exposure paradigm leads to impairment of EE-mediated dentate neurogenesis in adulthood. METHODS: All experiments were performed using NestinCreER(T2):tdTomato bitransgenic mice, which harbor a tamoxifen-inducible tdTomato (tdTom) reporter for indelible labeling of newborn hippocampal DGCs. We exposed all mice to EtOH vapor or room air (Control) for 4 hours (hr) per day from postnatal day (PND) 3 through PND 15. This paradigm resulted in a mean daily post-exposure blood EtOH concentration (BEC) of ~160 mg/dl. One cohort of neonatal mice received a single injection of tamoxifen at PND 2 and was sacrificed at either PND 16 or PND 50 to assess the impact of EtOH exposure on the production and long-term survival of dDGCs born during the early postnatal period. A second cohort of mice received daily injections of tamoxifen at PND 35-39 to label aDGCs, and was exposed to SH or EE for 6 weeks prior to sacrifice. RESULTS: Early postnatal EtOH exposure had no statistically significant effect on the production or survival of tdTom(+) dDGCs, as assessed at PND 16 or PND 50. Early postnatal EtOH exposure also had no effect on the number of tdTom+ aDGCs under SH conditions. Furthermore, early postnatal EtOH exposure had no significant impact on the adult neurogenic response to EE. CONCLUSIONS: Both early postnatal dentate neurogenesis and adult dentate neurogenesis, as well as the adult neurogenic response to EE, are surprisingly resistant to early postnatal EtOH vapor exposure in mice.

In this case report we present a 28-year-old woman with type 1 diabetes mellitus on a ketogenic diet for 5 months, using a personal insulin pump in an unusual way. The patient was admitted to the Department of Internal Medicine and Diabetology due to vomiting and diarrhea that had lasted for several days. On a daily basis, she used personal insulin pump for only several hours a day (a 5-hour basal rate of 0.6 units/hour of fast-acting insulin) in order to avoid dawn phenom­enon, without any prandial insulin, and she used continuous glucose monitoring for 24 hours a day for glycemia control. Additionally she was taking 30 units of long acting insulin analog before sleep. The patient was unwilling to change her treatment method and she was discharged from the hospital against medical advice. Due to the increase in popularity of ketogenic diet, there is a need for large studies assessing its safety and efficacy. Moreover, our case draws attention to the fact that patients can use modern technologies, which are developed to improve the glycemic control, in un­conventional ways.

Background/aim Prevention of hypoglycemia remains a major challenge in diabetic management, despite the introduction of modern insulin pumps in daily clinical practice. The Low Glucose Suspend (LGS) and the newer Predictive Low Glucose Management (PLGM) systems incorporated in the Medtronic insulin pumps have shown promising results in prevention of hypoglycemia. Our aim was to evaluate the effect of the 2 systems relative to the frequency of clinically significant hypoglycemia in Type 1 diabetes (T1DM). In addition, we investigated the events preceding clinically significant hypoglycemia episodes. Methods A cross-sectional study was conducted in 30 T1DM patients using the MiniMed 640G vs. 30 using the MiniMed Veo sensor-augmented insulin pump. All data was recorded during patients’ normal daily activity and living conditions. The patients were matched for age and duration of diabetes. Results PLGM use was associated with lower incidence of clinically significant hypoglycemia (1.9±1.4 vs. 3.6±1.9 episodes per week), along with reduced exposure to hypoglycemia. The data indicated that both pump systems are effective in preventing severe hypoglycemic episodes. In both groups the most common events preceding hypoglycemic episodes included adjustment of hyperglycemia, basal rate increase and miscalculation of carbohydrates. Conclusions The results indicated that the use of the Minimed 640G pump system can help reduce the frequency of clinically significant hypoglycemia. Management of hyperglycemia must be addressed in diabetes education programs in order to encourage proper adjustment of high blood glucose levels. Future studies would be useful in exploring the details of the events preceding hypoglycemia episodes in insulin pump users.

We investigated the pharmacodynamics (PD) and pharmacokinetics (PK) of BioChaperone insulin Lispro (BCLIS), faster insulin aspart (FIA) and insulin aspart (ASP) in patients with type 1 diabetes using an insulin pump. In this randomized, double-blind, three-way crossover glucose clamp study, 43 patients received a bolus dose of each insulin (0.15 U/kg) in addition to a basal rate (0.01 U/kg/h), delivered via an insulin pump. With BCLIS, the AUC-GIR,0-60 minutes (primary endpoint) was improved compared to ASP (least square means ratio, 1.63; 95% CI, 1.44-1.88; P < 0.0001) and was similar compared to FIA (least square means ratio, 1.06; 95% CI, 0.94-1.18; P = 0.4609). BCLIS showed faster-on PD (tearly0.5GIRmax ) than ASP and faster-off PD (tlate0.5GIRmax ) than both FIA and ASP. BCLIS also demonstrated significantly higher early exposure (AUCins, 0-60 minutes) and lower late exposure (AUCins,120-600 minutes) than both other insulins. In patients with type 1 diabetes using an insulin pump, BCLIS better mimics prandial insulin secretion and action than ASP and shows a faster off-PD than FIA.

Glucagon-containing α-cells potently regulate glucose homeostasis, but the developmental biology of α-cells in adults remains poorly understood. Although glucagon receptor antagonists (GRAs) have great potential as antidiabetic therapies, murine and human studies have raised concerns that GRAs might cause uncontrolled α-cell growth. Surprisingly, previous rodent GRA studies were only performed in young mice, implying that the potential impact of GRAs to drive α-cell expansion in adult patients is unclear. We assessed adaptive α-cell turnover and adaptive proliferation, administering a novel GRA (JNJ-46207382) to both young and aged mice. Basal α-cell proliferation rapidly declined soon after birth and continued to drop to very low levels in aged mice. GRA drove a 2.4-fold increase in α-cell proliferation in young mice. In contrast, GRA-induced α-cell proliferation was severely reduced in aged mice, although still present at 3.2-fold the very low basal rate of aged controls. To interrogate the lineage of GRA-induced α-cells, we sequentially administered thymidine analogs and quantified their incorporation into α-cells. Similar to previous studies of β-cells, α-cells only divided once in both basal and stimulated conditions. Lack of contribution from highly proliferative “transit-amplifying” cells supports a model whereby α-cells expand by self-renewal and not via specialized progenitors.

Diabetes is a widespread civilization disease. It manifests with an elevated blood glucose level. In the long-term, elevated blood glucose level continuously damages organs. In the short-term, hypo- and hyperglycemia are acute complications. Insulin lowers blood glucose level by promoting its utilization. At basal rate, insulin pump delivers insulin to subcutaneous tissue to control blood glucose level. In addition, patient doses insulin boluses in accordance with estimated carbohydrate content of consumed meal. Control algorithm of the pump considers the boluses, when calculating the basal rate. In our previous work, we have proposed a parallel-architecture for the next-generation of glucose monitoring - SmartCGMS. It unifies the source-code base and the glucose-monitoring-and-control paradigm across real, simulated and prototyped devices. As the development continues, especially towards the pump-control algorithms, we face a problem of reducing the SmartCGMS requirements when considering a low-power hardware. In this paper, we present the modifications that lead to a reduced number of threads, while implementing the closed-loop feedback between a glucose sensor and insulin pump to conduct FDA accepted in-silico pre-clinical trials.

The current paradigm in the field of mammalian iron biology states that body iron levels are determined by dietary iron absorption, not by iron excretion. Iron absorption is a highly regulated process influenced by iron levels and other factors. Iron excretion is believed to occur at a basal rate irrespective of iron levels and is associated with processes such as turnover of intestinal epithelium, blood loss, and exfoliation of dead skin. Here we explore iron excretion in a mouse model of iron excess due to inherited transferrin deficiency. Iron excess in this model is attributed to impaired regulation of iron absorption leading to excessive dietary iron uptake. Pharmacological correction of transferrin deficiency not only normalized iron absorption rates and halted progression of iron excess but also reversed body iron excess. Transferrin treatment did not alter the half-life of 59Fe in mutant mice. 59Fe-based studies indicated that most iron was excreted via the gastrointestinal tract and suggested that iron-loaded mutant mice had increased rates of iron excretion. Direct measurement of urinary iron levels agreed with 59Fe-based predictions that urinary iron levels were increased in untreated mutant mice. Fecal ferritin levels were also increased in mutant mice relative to wild-type mice. Overall, these data suggest that mice have a significant capacity for iron excretion. We propose that further investigation into iron excretion is warranted in this and other models of perturbed iron homeostasis, as pharmacological targeting of iron excretion may represent a novel means of treatment for diseases of iron excess.

Resumo O objetivo deste trabalho foi avaliar o efeito do período de periparto sobre os parâmetros clínicos e hematológicos de cabras adultas. Utilizou-se animais da raça Saanen e Parda Alpina, sendo 24 nos tempos: T-15 (quinze dias antes do parto), T0 (imediatamente após o parto), T2 (dois dias após o parto), T5 (cinco dias após o parto), T10 (dez dias após o parto), T15 (quinze dias após o parto) e T30 (trinta dias após o parto) e 10 animais como grupo controle (Mesma raça, não gestantes e não lactantes). Como principais achados físicos, observou-se que a frequência cardíaca (FC) dos animais é normalmente mais elevada no pré-parto e parto, caindo ao longo do tempo de lactação. A frequência respiratória (FR) dos animais avaliados é mais elevada em relação aos animais controle, com o pico acontecendo no T-15. Na avaliação das principais observações no hemograma, observam-se valores mais baixos para hemoglobina no T-15 em relação ao grupo controle, e uma redução da toda série vermelha no T15. Houve uma elevação do número de leucócitos por neutrofilia com linfopenia em T0 e a leucocitose com neutrofilia se manteve ao longo da fase observacional. Valores de proteínas mais baixos foram observados em T-15 e T0, aumentando posteriormente. A variável fibrinogênio apresentou o maior valor em T0. Conclui-se que os parâmetros físicos e hematimétricos são úteis para detecção das variações que ocorrem no periparto. Tais achados, associados ao leucograma de estresse e aumento da taxa metabólica basal, encontrado nesta mesma fase, corroboram com o momento de fragilidade fisiológica na qual a cabra se encontra. Assim, cuidados no manejo relacionados ao conforto térmico e atendimento às exigências nutricionais são fundamentais a fim de se evitar mais desequilíbrios orgânicos decorrentes de fatores externos que podem vir a comprometer a saúde do caprino e posterior desempenho produtivo. Abstract The aim of this research was to evaluate the effects of the peripartum period in the clinical and hematological parameters of adult goats. The research used animals of Saanen and Alpine Brown breed at the following times: T-15 (fifteen days before partum), T0 (immediately after partum), T2 (two days after partum), T5 (five days after partum), T10 (ten days after partum), T15 (fifteen days after partum) and T30 (thirty days after partum). A group of 10 adult goats, of the same breed, non-pregnant and non-lactating comprised the control group. The main physical find was higher heart rate (HR) at pre-parturition and at delivery time, with a decrease of the values through the time. The respiratory (RR) rate of the evaluated group was higher than that of the control group, with the pic at T-15. The main alteration revealed in the complete blood count was lower values of hemoglobin at T-15, when compared to the control group. It was observed a leukocytosis by neutrophil increasing with lymphopenia at T0 and leukocytosis with neutrophil increasing in the early lactation period. The protein values were lower at T-15 and T0, but they were increased by the lactation time. The fibrinogen presented higher values in T0. As conclusion of this assay, the physical and hematological parameters were useful to detect the variation that occurs in the periparturition period of dairy goats. Those findings, associated to the stress leucogram and the increase in the metabolic basal rate in this period, confirm the physiological susceptibility of the goats in early lactation. Management of temperature and of nutritional needs is imperative to keep these animals without organic unbalance, and to avoid health problems and productive failures.

BACKGROUND Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. METHODS We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c ≤ 80 mmol/mol [9.5%], fasting C-peptide

Background: Patients experience moderate-high intensity postoperative pain after cesarean section (CS). The aim of this study was to investigate the optimal concentrations of ropivacaine and sufentanil for use in controlling pain after CS.Methods: One hundred and seventy-four women undergoing elective CS were randomly allocated to four groups. Epidural analgesia was administered with 0.1% ropivacaine in the R1 group, 0.15% ropivacaine in the R2 group, a combination of 0.1% ropivacaine and 0.5 μg/ml of sufentanil in the R1S group, and a combination of 0.15% ropivacaine and 0.5 μg/ml of sufentanil in the R2S group (at a basal rate of 4 ml/h, bolus dose of 4 ml/20 min as needed). Pain scores (numerical rating scale [NRS]: 0–10 cm) at rest (NRS-R), during movement (NRS-M), and when massaging the uterus (NRS-U) were documented at 6 and 24 h. We also recorded patient satisfaction scores, time to first flatus, motor deficits, and adverse drug reactions.Results: NRS (NRS-R, NRS-M, NRS-U) scores in the R2S group (2 [1–3], 4 [3–5], 6 [5–6], respectively) were lower than in the R1 group (3 [3–4], 5 [4–6], 7 [6–8], respectively) (p < 0.001, p < 0.05, p < 0.01, respectively) at 6 h; and patient satisfaction (9 [8–10]) was improved compared to the R1 group (8 [6–8]) (p < 0.01). The time to first flatus (18.7 ± 11.8 h) was reduced relative to the R1 group (25.9 ± 12.0 h) (p < 0.05). The time to first ambulation was not delayed (p > 0.05). However, the incidence of pruritus (4 [9.3%]) was increased compared to the R2 group (0 [0]) (p < 0.05) at 6 h, and the incidence of numbness (23 [53.5%], 23 [53.5%]) was increased compared to the R1 group (10 [23.3%], 10 [23.3%]) (all p < 0.01) at both 6 and 24 h.Conclusions: Although we observed a higher incidence of pruritus and numbness, co-administration of 0.15% ropivacaine and 0.5 μg/ml of sufentanil administered epidurally optimized pain relief after CS, with treated subjects exhibiting lower NRS scores, shorter time to first flatus, and higher patient-satisfaction scores.

Background: Basal rate profiles in patients with type 1 diabetes on insulin pump therapy are subject to enormous inter-individual heterogeneity. Tools to predict basal rates based on clinical characteristics may facilitate insulin pump therapy. Methods: Data from 339 consecutive in-patients with adult type 1 diabetes on insulin pump therapy were collected. Basal rate tests were performed over 24 hours. A mathematical algorithm to predict individual basal rate profiles was generated by relating the individual insulin demand to selected clinical characteristics in an exploratory cohort of 170 patients. The predicted insulin pump profiles were validated in a confirmatory cohort of 169 patients. Findings: Basal rates (0.27 ± 0.01 IU.d−1.kg−1) showed circadian variations with peaks corresponding to the “dawn” and “dusk” phenomena. Age, gender, duration of pump treatment, body-mass-index, HbA1c, and triacylglycerol concentrations largely predicted the individual basal insulin demand per day (IU/d; exploratory vs prospective cohorts: r2 = 0.518, P Interpretation: Clinical characteristics predict 52% of the variation in individual basal rate profiles, including their diurnal fluctuations. The multivariate regression model can be used to initiate or optimize insulin pump treatment in patients with type 1 diabetes.

Aging is associated with alterations in skeletal muscle autophagy, potentially affecting both muscle mass and quality in a negative manner. Strength training with protein supplementation has been reported to improve both muscle mass and quality in frail elderly individuals, but whether improvements are accompanied by alterations in protein quality control is not known. To address this issue, we investigated protein degradation markers in skeletal muscle biopsies (m. vastus lateralis) from twenty-four frail elderly men and women (86 ± 7 yr) after acute and chronic (10 weeks) strength training with protein supplementation (ST + PRO) or protein supplementation alone (PRO). Acute increases in mRNA expression of genes related to the ubiquitin proteasome system (MuRF-1, MUSA1), autophagy (ATG7, LC3, p62), and mitochondrial fission (DRP1) were observed after the first, but not after the last training session in ST + PRO. Acute changes in gene expression were accompanied by changes in protein levels of both LC3-I and LC3-II. Hence, the acute training-induced activation of proteasomal degradation and autophagy seems to depend on training status, with activation in the untrained, but not trained state. The ten-week training intervention did not affect basal levels of autophagy mRNAs and proteins, and neither markers of the ubiquitin-proteasome system. This suggests that a relatively short period of strength training may not be sufficient to increase the basal rate of protein degradation in frail elderly.

Background and objectives The hybrid artificial pancreas regulates glucose levels in people with type 1 diabetes. It delivers (i) insulin boluses at meal times based on the meals’ carbohydrate content and the carbohydrate ratios (CRs) and (ii) insulin basal, between meals and at night, continuously modulated around individual-specific programmed basal rate. The CRs and programmed basal rate significantly vary between individuals and within the same individual with type 1 diabetes, and using suboptimal values in the hybrid artificial pancreas may degrade glucose control. We propose a reinforcement learning algorithm to adaptively optimize CRs and programmed basal rate to improve the performance of the hybrid artificial pancreas. Methods The proposed reinforcement learning algorithm was designed using the Q-learning approach. The algorithm learns the optimal actions (CRs and programmed basal rate) by applying them to the individual's state (previous day's glucose levels and insulin delivery) based on an exploration and exploitation trade-off. First, outcomes from our simulator were compared to those of a clinical study in 23 individuals with type 1 diabetes and have yielded similar results. Second, the learning algorithm was tested using the simulator with two scenarios. Scenario 1 has fixed meal sizes and ingestion times and scenario 2 has a more realistic eating behavior with random meal sizes, ingestion times, and carbohydrate counting errors. Results After about five weeks, the reinforcement learning algorithm improved the percentage of time spent in target range from 67% to 86.7% in scenario 1 and 65.5% to 86% in scenario 2. The percentage of time spent below 4.0 mmol/L decreased from 9% to 0.9% in scenario 1 and 9.5% to 1.1% in scenario 2. Conclusions Results indicate that the proposed algorithm has the potential to improve glucose control in people with type 1 diabetes using the hybrid artificial pancreas. The proposed algorithm is a key in making the hybrid artificial pancreas adaptive for the long-term real life outpatient studies.

OBJECTIVE Exercising while fasted with type 1 diabetes facilitates weight loss; however, the best strategy to maintain glucose stability remains unclear. RESEARCH DESIGN AND METHODS Fifteen adults on continuous subcutaneous insulin infusion completed three sessions of fasted walking (120 min at 45% VO2max) in a randomized crossover design: 50% basal rate reduction, set 90 min pre-exercise (−90min50%BRR); usual basal rate with carbohydrate intake of 0.3 g/kg/h (CHO-only); and combined 50% basal rate reduction set at exercise onset with carbohydrate intake of 0.3 g/kg/h (Combo). RESULTS Combo had a smaller change in glucose (5 ± 47 mg/dL) versus CHO-only (−49 ± 61 mg/dL, P = 0.03) or −90min50%BRR (−34 ± 45 mg/dL). The −90min50%BRR strategy produced higher β-hydroxybutyrate levels (0.4 ± 0.3 vs. 0.1 ± 0.1 mmol/L) and greater fat oxidation (0.51 ± 0.2 vs. 0.39 ± 0.1 g/min) than CHO-only (both P < 0.05). CONCLUSIONS All strategies examined produced stable glycemia for fasted exercise, but a 50% basal rate reduction, set 90 min pre-exercise, eliminates carbohydrate needs and enhances fat oxidation better than carbohydrate feeding with or without a basal rate reduction set at exercise onset.

Ca2+ release by inositol trisphosphate receptors (IP3Rs) regulates diverse physiological processes in many cell types. Notably, agonist-stimulated Ca2+ signaling involving IP3Rs can modulate ER export rates through activation of the Ca2+-dependent adaptor ALG-2. It is unknown, however, whether IP3Rs and ALG-2 regulate ER export rates at steady state. Here we report that partial depletion of IP3Rs from normal rat kidney (NRK) epithelial cells caused a marked increase of ER export of the transmembrane cargo VSV-G. Depletion of IP3R-3, the major IP3R isoform in NRK cells, had a larger impact on secretion than the other extant isoform, IP3R-l. Under standard growth conditions, spontaneous cytosolic Ca2+ oscillations usually occurred simultaneously in successive groups of contiguous cells, generating intercellular Ca2+ waves (ICWs) that moved across the monolayer. Unexpectedly, IP3R-3-depleted cells exhibited increased cell participation in this spontaneous signaling. IP3R-3-depleted cells also exhibited increased agonist-dependent Ca2+ signaling, suggesting a general potentiation of the remaining IP3R channels. Increased spontaneous signaling was accompanied by increased ALG-2 and decreased peflin at ER exit sites (ERES), resulting in increased targeting of COPII coat to ERES. Furthermore, the increased secretion rate associated with IP3R depletion required ALG-2. Unexpectedly, IP3R depletion also resulted in partial depletion of ER luminal Ca2+ stores, though this phenomenon was not involved in the secretion change. We conclude that in NRK cells, IP3Rs regulate spontaneous Ca2+ signaling that helps determine the basal secretion rate by modulating COPII targeting to ERES. Furthermore, the IP3R channel density and/or isoform composition significantly impacts this phenomenon.

The amount of oral carbohydrate (CHO) needed to prevent hypoglycemia during prolonged fasted exercise in CSII is unclear. We assessed CHO intake needs during 3 different basal rate strategies during prolonged fasted exercise in active patients with T1D. Individuals with T1D on CSII (n=15) completed three 120-min treadmill exercise (∼45% of VO2peak) visits in a randomized crossover design. Strategies included: A) no basal rate reduction (BRR) and a dextrose intake of 0.3 g/kg/hr when BG was Glycemia was higher in C compared to A or B by 105 min of exercise (P < 0.05). The drop in blood glucose during exercise was greater in A (-2.7 ± 3.4 mmol/L) than in B (-1.9 ± 2.5 mmol/L) or C (0.3 ± 2.6 mmol/L). Total CHO intake was 38.0 ± 18.8 g, 0.8 ± 3.1 g, and 29.5 ± 16.2 g, for A, B and C, respectively. Compared to A, B had lower RER (0.83 ± 0.04 vs. 0.79 ± 0.04), higher ketones (0.1 ± 0.1 vs. 0.4 ± 0.3 mmol/L), greater net loss of calories (709.2 ± 217.4 vs. 859.7 ± 239.6 kcal) and greater fat oxidation rate (0.39 ± 0.1 vs. 0.51 ± 0.2 g/min) (all P < 0.05). A BRR, set 90 min prior to exercise is associated with good glycemic control and an increased rate of lipid oxidation compared to CHO feeding alone or combined BRR and CHO feeding approach at exercise onset. Disclosure S.M. McGaugh: None. R. Pooni: None. D. Zaharieva: Speaker’s Bureau; Self; Ascensia Diabetes Care, Insulet Corporation, Medtronic. N.C. D’Souza: None. T. Vienneau: Employee; Self; Insulet Corporation. Stock/Shareholder; Self; Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation. M. Riddell: Advisory Panel; Self; Zucara Therapeutics Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Funding Insulet Corporation

Bile acids are endogenous amphiphilic steroids from the metabolites of cholesterol. Studies showed that they might contribute to the pathogenesis of cardiopathy in cholestatic liver diseases. Chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) is associated with colon cancer, gallstones, and gastrointestinal disorders. However, little information is available regarding their cardiac effects. Here, we reported that CDCA (100 μM) and DCA (100 μM) significantly increased the left ventricular developed pressure of the isolated rat hearts to 122.3 ± 5.6% and 145.1 ± 13.7%, and the maximal rate of the pressure development rising and descending (± dP/dtmax) to 103.4 ± 17.6% and 124.4 ± 37.7% of the basal levels, respectively. They decreased the heart rate and prolonged the RR, QRS, and QT intervals of Langendorff-perfused hearts in a concentration-dependent manner. Moreover, CDCA and DCA increased the developed tension of left ventricular muscle and the cytosolic Ca2+ concentrations in left ventricular myocytes; these functions positively coordinated with their inotropic effects on hearts. Additionally, CDCA (150 μM) and DCA (100 μM) decreased the sinoatrial node beating rate to 80.6 ± 3.0% and 79.7 ± 0.9% of the basal rate (334.2 ± 10.7 bpm), respectively. These results were consistent with their chronotropic effects. In conclusion, CDCA and DCA induced positive inotropic effects by elevating the Ca2+ in left ventricular myocytes. They exerted negative chronotropic effects by lowering the pace of the sinoatrial node in rat heart. These results indicated that the potential role of bile acids in cardiopathy related to cholestasis.

To assess the relationship of body composition measures and basal metabolic rate (BMR) with gastrointestinal hormones in weight regain 5 years after gastric bypass. A total of 42 patients were divided into two groups: with and without weight regain 5 years after gastric bypass. Hormone assessments were performed after a fasting period and at 30, 60, and 120 min after the standard meal intake. Patients with no weight regain had significantly lower visceral fat (VF), lower fat body mass (FBM), and lower fat percentage (%F) in relation to the other group. In the group without weight regain, at baseline, glucose-dependent insulinotropic polypeptide (GIP) showed a negative correlation with weight and BMI and a positive correlation with BMR, skeletal muscle mass (SMM), and fat-free mass (FFM). After the standard meal, the following results were found: a negative correlation with %F, a positive correlation of glucagon-like peptide-1 (GLP-1) with FFM, and a positive correlation of GLP-2 and PYY with BMR, SMM, and FFM. In the group with weight regain, at baseline, GIP, PYY, and GLP-1 showed a negative correlation with %F. After the standard meal, PYY and GLP-1 showed a negative correlation with VF, FBM, and %F. On the other hand, GLP-2 negatively correlated with VF and FBM. It is possible to conclude that there is a different relationship of concentrations of PYY, GIP, GLP-1, and GLP-2 with body composition and BMR in patients with and without weight regain in the late gastric bypass postoperative period.

Tight glycemic control is important to mitigate diabetes complications but is difficult to achieve because of the increased risk of hypoglycemia. With the recent advances in the management of type 1 diabetes (T1D), the use of continuous glucose monitors and sensor-augmented pumps have benefited both the patients with T1D and their caregivers. This chapter presents the current state of predictive low glucose suspend (PLGS) systems and their clinical use in various clinical trials and real-world settings. The primary goal of these algorithms is to prevent or reduce hypoglycemia and to decrease the burden of diabetes care. The systems use a continuous glucose monitor that communicates with an algorithm that suspends insulin delivery based on the current glucose level and rate of change, with slightly different rules for the resumption of insulin delivery. The use of most of these systems was associated with a reduction in hypoglycemic events without consequent hyperglycemia. With the development of automated insulin delivery systems, the PLGS algorithm was built into the hybrid closed-loop controllers that adjust basal rate delivery and/or correct hyperglycemia to improve hemoglobin A1c.

Aims: To determine the effects of the dipeptidyl peptidase-4 inhibitor, sitagliptin, ongastric emptying (GE) of a high-carbohydrate meal and associated glycaemic and blood pressure (BP) responses in type 2 diabetes mellitus (T2DM). Materials and Methods: Fourteen patients with T2DM (nine men, five women; age67.8 ± 1.5 years; body mass index 31.2 ± 0.9 kg/m2; T2DM duration: 4.2 ± 0.9 years; glycated haemoglobin: 46 ± 1.8 mmol/mol [6.4% ± 0.2%]), managed by diet and/or metformin, underwent concurrent measurements of GE, BP and plasma glucose for240 minutes after ingestion of a radio labelled mashed potato meal after receiving sitagliptin (100 mg) or placebo in randomized, double-blind, crossover fashion on2 consecutive days Results: Sitagliptin reduced postprandial plasma glucose (P< .005) without affecting GE (P= .88). The magnitude of the glucose-lowering effect (change in incremental area under the curve 0–240 min from placebo to sitagliptin) was related to GE (kcal/min)on placebo (r= 0.68,P= .008) There was a comparable fall in systolic BP (P= .80) following the meal, with no difference between the 2 days Conclusions: In T2DM, while sitagliptin has no effect on either GE or postprandial BP, its ability to lower postprandial glucose are dependent on the basal rate of GE usc Refereed/Peer-reviewed

Accuracy of insulin pump basal rate delivery, if tested according to the standard IEC 60601-2-24 for infusion pumps, shall be presented as a trumpet curve. This way of graphical presentation is common; however, it is often misunderstood and misinterpreted by people. It is often assumed that a trumpet curve shows the error rate as a function of time, thus implying an increasing accuracy in the course of time. On the contrary, the horizontal axis of a trumpet curve shows increasingly long observation windows. In addition, trumpet curves display only extreme values, that is, those windows with minimal and maximal deviation, which might not be representative for the total deviation. This commentary provides information regarding the calculations and the interpretation of trumpet curves and proposes alternative approaches.

Aim To evaluate the PAQ ® (CeQur SA, Horw, Switzerland), a wearable 3‐day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes. Method Adults with Type 2 diabetes with HbA1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single‐arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA1c, seven‐point self‐monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects. Results A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m2, Type 2 diabetes duration 17 ± 8 years, HbA1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA1c –16 ± 9 mmol/mol (95% CI –20, –12) or –1.5 ± 0.9% (95% CI –1.8, –1.1) P, What's new? As Type 2 diabetes mellitus progresses, basal‐bolus insulin is required to achieve glycaemic targets; however, because of barriers associated with multiple daily injections (MDI), many people with Type 2 diabetes do not reach their goal.Randomized controlled trials evaluating continuous subcutaneous insulin infusion (CSII) via pumps vs MDI in people with Type 2 diabetes have shown that CSII achieves better glycaemic control and treatment satisfaction scores than MDI, but use is limited because of cost and complexity.The PAQ, a simple wearable CSII device provides freedom from daily injections.Results suggest the PAQ device achieves improved glycaemic control and treatment satisfaction scores among people with Type 2 diabetes. The PAQ device may be a viable alternative to MDI.