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Sample records for delaying insulin initiation

  1. Lessons learned from a pilot RCT of simultaneous versus delayed initiation of continuous glucose monitoring in children and adolescents with type 1 diabetes starting insulin pump therapy.

    PubMed

    Olivier, Patricia; Lawson, Margaret L; Huot, Celine; Richardson, Christine; Nakhla, Meranda; Romain, Judette

    2014-05-01

    Uncertainty remains about effectiveness of continuous glucose monitoring (CGM) in pediatric type 1 diabetes (T1D). Success with CGM is related to CGM adherence, which may relate to readiness to make the behavior changes required for effective use. We hypothesize that readiness for change will be greater at initiation of insulin pump therapy than in established pump users, and that this will predict CGM adherence. Our objective was to evaluate the feasibility of a randomized controlled trial (RCT) in children with established T1D comparing simultaneous pump and CGM initiation to standard pump therapy with delayed CGM initiation. We randomized participants to simultaneous pump and CGM initiation or to standard pump therapy with the option of adding CGM 4 months later. CGM adherence was tracked via web-based download and readiness for change assessed with the SOCRATES questionnaire. Of 41 eligible children, 20 agreed to participate; 15 subjects completed the study (7 males; baseline age 11.8 ± 4.0 years; T1D duration 2.7 ± 2.7 years; mean A1C 8.2 ± 0.8%). Six of 8 simultaneous group subjects used CGM > 60% of the time for 4 months compared to 1 of 7 delayed group subjects (P = .02). Using SOCRATES, we could assign 87-100% of subjects to a single motivation stage at baseline and 4 months. This pilot study demonstrates the feasibility of randomizing pump naïve children and adolescents with established T1D to simultaneous pump and CGM initiation versus standard pump therapy with delayed CGM initiation. Lessons from this pilot study were used to inform development of a full-scale multicenter RCT. PMID:24876616

  2. Empowering patients during insulin initiation: a real-world approach.

    PubMed

    LaSalle, James R

    2010-02-01

    Glycemic control is suboptimal in many patients with type 2 diabetes mellitus (T2DM). Despite documented benefits of insulin therapy, initiation of insulin is delayed in many cases because of the reluctance of patients and physicians to use this important treatment. A review of the literature revealed that educating patients about the role of insulin in managing T2DM and the advantages of using insulin analogs and insulin delivery devices may help alleviate some patients' concerns regarding insulin therapy. Compared with standard clinic-directed approaches, patient-driven algorithms that empower patients to initiate and titrate basal insulin therapy have been shown to improve glycemic control. Additional research is needed to confirm the importance of patient empowerment programs in T2DM management. PMID:20160245

  3. SBASI: Actuated pyrotechnic time delay initiator

    NASA Technical Reports Server (NTRS)

    Salter, S. J.; Lundberg, R. E.; Mcdougal, G. L.

    1975-01-01

    A precision pyrotechnic time delay initiator for missile staging was developed and tested. Incorporated in the assembly is a single bridgewire Apollo standard initiator (SBASI) for initiation, a through-bulkhead-initiator to provide isolation of the SBASI output from the delay, the pyrotechnic delay, and an output charge. An attempt was made to control both primary and secondary variables affecting functional performance of the delay initiator. Design and functional limit exploration was performed to establish tolerance levels on manufacturing and assembling operations. The test results demonstrate a 2% coefficient of variation at any one temperature and an overall 2.7% coefficient of variation throughout the temperature range of 30 to 120 F. Tests were conducted at simulated operational altitude from sea level to 200,000 feet.

  4. Initiating insulin therapy in type 2 diabetes: benefits of insulin analogs and insulin pens.

    PubMed

    Brunton, Stephen

    2008-08-01

    Despite the development of alternative therapies in recent years, insulin injections remain essential treatment for type 2 diabetes once oral therapy alone becomes inadequate. However, neither patients nor physicians are proactive enough with regard to starting insulin, despite the well-known benefits of early insulin initiation and aggressive dose titration. Barriers to starting insulin therapy are being overcome by developments in insulin and delivery device technology and are the subject of this review. A literature search spanning the last 25 years was carried out to identify publications addressing issues of insulin initiation, how insulin analogs can help overcome barriers to initiation, and the advantages of pen-type insulin delivery systems. Seventy-five publications were identified. These references illustrate that the drawbacks associated with regular exogenous human insulins (soluble and NPH) are improved with modern insulin analogs. The more rapid absorption of prandial insulin analogs compared with human insulin eliminates the need for an injection-meal-interval, increasing convenience, while basal analogs have no discernible peak in activity. Modern insulin delivery devices also have advantages over the traditional vial and syringe. Currently available insulin pens are either durable (insulin cartridge is replaceable; e.g., HumaPen, Eli Lilly [Indianapolis, IN]; NovoPen series, Novo Nordisk [Bagsvaerd, Denmark]) or disposable (prefilled; e.g., FlexPen, Novo Nordisk; SoloSTAR, sanofi-aventis [Paris, France]), with features to aid ease-of-use. These include a large dose selector, dial-up and dial-down facility, and audible clicks when selecting the dose. The potential for dosing errors is thus reduced with pen-type devices, with other benefits including a discreet appearance, ease of learning, and greater user confidence. Collectively, these features contribute to overwhelming patient preference when compared with vials and syringes. Despite the greater

  5. Primary care physician beliefs about insulin initiation in patients with type 2 diabetes

    PubMed Central

    Hayes, R P; Fitzgerald, J T; Jacober, S J

    2008-01-01

    tend to be more aggressive than primary care physicians (PCPs) with insulin initiation in patients with type 2 diabetes, and US physicians are more disposed to delay insulin than physicians in other countries. What's new This article confirms that US PCPs lack consensus on some beliefs about insulin initiation. Consensus was seen regarding insulin risk/benefits, positive patient experiences of insulin and patient fears about initiating insulin. No consensus was seen regarding insulin's metabolic effects, need for insulin, adequacy of self-monitoring blood glucose, time needed for training and potential for hypoglycaemia in elderly patients. Some PCPs have beliefs inconsistent with their diabetes treatment goals (HbA1c ≤ 7%). PMID:18393965

  6. Computational modeling and analysis of insulin induced eukaryotic translation initiation.

    PubMed

    Lequieu, Joshua; Chakrabarti, Anirikh; Nayak, Satyaprakash; Varner, Jeffrey D

    2011-11-01

    Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow. PMID:22102801

  7. A retrospective database analysis of insulin use patterns in insulin-naïve patients with type 2 diabetes initiating basal insulin or mixtures

    PubMed Central

    Bonafede, Machaon MK; Kalsekar, Anupama; Pawaskar, Manjiri; Ruiz, Kimberly M; Torres, Amelito M; Kelly, Karen R; Curkendall, Suellen M

    2010-01-01

    Objective: To describe insulin persistence among patients with type 2 diabetes initiating insulin therapy with basal insulin or insulin mixtures and determine factors associated with nonpersistence. Research design and methods: The Thomson Reuters MarketScan® databases were used to retrospectively analyze insulin-naïve patients with type 2 diabetes by initiating insulin therapy. Insulin use was described using a variety of measures. The persistence to insulin was described using both a gap-based measure and the number of claims measure. Results: Patients in the basal insulin cohort (N = 15,255) primarily used insulin analogs (88.1%) and vial and syringe (97%). Patients in the mixture cohort (N = 2,732) were more likely to initiate on human insulin mixtures (62.5%) and vial and syringe (68.1%). Average time between insulin refills was 80 and 71 days for basal and mixture initiators, respectively. Nearly, 75% of basal insulin initiators and 65% of insulin mixture initiators had a 90-day gap in insulin prescriptions. More than half of all the patients had at least one insulin prescription per quarter. Patients initiating with insulin analogs were more likely to be persistent compared with those initiating with human insulin across both cohorts and measures of persistence (P < 0.001). Conclusion: Persistence to insulin therapy is poorer than one would anticipate, but appears to be higher in users of insulin analogs and insulin mixtures. PMID:20622915

  8. Economic analysis of insulin initiation by pharmacists in a Canadian setting

    PubMed Central

    Brown, Stephen; Al Hamarneh, Yazid N.; Tsuyuki, Ross T.; Nehme, Kimberley; Sauriol, Luc

    2016-01-01

    Background: Conducted in Alberta, the RxING study examined the effect of a community pharmacist prescribing intervention on glycemic control in patients with uncontrolled type 2 diabetes mellitus (T2DM) using insulin glargine. The objective of this study was to assess the cost-effectiveness of pharmacists’ prescribing of insulin glargine as an early intervention in uncontrolled patients with T2DM vs usual clinical practice. Methods: The IMS CORE diabetes Markov model was used to project long-term clinical outcomes, costs and cost-effectiveness of interventions. The efficacy of insulin glargine, in terms of hemoglobin A1c reduction and hypoglycemia rates, was obtained from the RxING study. Health utility and cost data were found in Canadian publications. The base-case analyses examined the economic and clinical effects of having pharmacists initiate insulin therapy in patients with uncontrolled T2DM in comparison to a physician initiate it up to 3 years later. Results: Insulin initiation by pharmacists with uncontrolled T2DM patients is cost-effective. Having pharmacists prescribe insulin 1 year earlier than usual clinical practice resulted in an incremental cost savings of $805 (CDN$) and a gain of 0.048 QALYs per patient. Pharmacists prescribing insulin 2 years earlier resulted in an incremental cost savings of $624 (CDN$) per year and a gain of 0.075 quality-adjusted life-years (QALYs). Prescribing 3 years earlier allowed for a minor increase of $26 and a gain of 0.086 QALYs. Conclusion: Earlier initiation of insulin by pharmacists, in uncontrolled T2DM patients, resulted in cost savings and delays in the development of diabetes-related complications, leading to an improved quality of life and increased survival rates. PMID:27212963

  9. Effects of delayed gastric emptying on postprandial glucose kinetics, insulin sensitivity, and β-cell function

    PubMed Central

    Hinshaw, Ling; Schiavon, Michele; Mallad, Ashwini; Man, Chiara Dalla; Basu, Rita; Bharucha, Adil. E.; Cobelli, Claudio; Carter, Rickey E.; Basu, Ananda

    2014-01-01

    Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes. PMID:25074985

  10. Diabetes management: optimizing roles for nurses in insulin initiation.

    PubMed

    Levich, Bridget R

    2011-01-01

    Type 2 diabetes is a major public health concern. Screening and early diagnosis followed by prompt and aggressive treatment interventions can help control progression of diabetes and its complications. Nurses are often the first healthcare team members to interact with patients and are being called on to apply their specialized knowledge, training, and skills to educate and motivate patients with diabetes about insulin use and practical ways to achieve treatment goals. Clinical nurse specialists possess specific training and skills to provide this level of care, while staff or office-based nurses may be trained by physicians to fulfill a task-specific role. This manuscript reviews the benefits of intensive glycemic control in type 2 diabetes, therapeutic goals and guidelines, advances in insulin therapy, and contribution of nurses in overcoming barriers to insulin initiation and related aspects of diabetes care. Nurses are particularly well positioned to fill the gap and improve efficiency in diabetes-related healthcare by assisting patients with insulin initiation and other aspects of glycemic self-management. PMID:21468244

  11. A Real-World Study of the Effect of Timing of Insulin Initiation on Outcomes in Older Medicare Beneficiaries with Type 2 Diabetes Mellitus

    PubMed Central

    Bhattacharya, Rituparna; Zhou, Steve; Wei, Wenhui; Ajmera, Mayank; Sambamoorthi, Usha

    2016-01-01

    OBJECTIVES To compare clinical and economic outcomes of early insulin initiation with those of delayed initiation in older adults with type 2 diabetes mellitus (T2DM). DESIGN Retrospective cohort study. SETTING Humana Medicare Advantage health insurance plan. PARTICIPANTS Older (≥65) Medicare beneficiaries with T2DM. MEASUREMENTS Subjects were grouped according to number of classes of oral antidiabetes drugs (OADs) they had taken before initiation of insulin: one (early insulin initiators), two, or three or more (delayed insulin initiators). One-year follow-up outcomes included change in glycosylated hemoglobin (HbA1c), percentage of older adults with HbA1c less than 8.0%, hypoglycemic events, and total healthcare costs. RESULTS Overall, 14,669 individuals were included in the analysis. Baseline and 1-year follow-up HbA1c levels were available for 4,028 (27.5%) individuals. Insulin was initiated early in 32% and delayed in 20%. At follow-up, unadjusted reduction in HbA1c was 0.9 ± 3.7% for the group with one OAD, 0.7 ± 2.4% for those with two, and 0.5 ± 3.6% for those with three or more. Early insulin initiation was associated with significantly greater reduction in HbA1c (0.4%; adjusted P <.001), 30% greater likelihood of achieving HbA1c less than 8.0% (adjusted odds ratio = 1.30, 95% confidence interval = 1.18–1.43), and no significant differences in total costs or hypoglycemia events (11.5% of early initiators vs 10.2% of delayed initiators; P = .32). CONCLUSION This study suggests beneficial effects of early insulin initiation in older adults with T2DM who do not have adequate glycemic control, without increasing the risk of hypoglycemia or greater total direct healthcare costs. PMID:25955280

  12. Infantile-onset saccade initiation delay (congenital ocular motor apraxia).

    PubMed

    Salman, Michael S

    2015-05-01

    Infantile-onset saccade initiation delay, also known as congenital ocular motor apraxia, typically presents in early infancy with horizontal head thrusts once head control is achieved. Defective initiation of horizontal saccades and saccade hypometria with normal saccadic velocity are characteristic findings. Isolated impairment of vertical saccades is rare. Impaired smooth ocular pursuit may be seen. Other relatively common features include developmental delay, hypotonia, ataxia, or clumsiness. Brain MRI may be normal or show a diverse range of abnormalities, most commonly involving the cerebellum. Defective slow phases of the optokinetic response are commonly associated with brain MRI abnormalities. Isolated defect of vertical saccade initiation may indicate supratentorial brain abnormalities on MRI. Joubert syndrome, a developmental midbrain-hindbrain malformation, and ataxia telangiectasia are both commonly associated with defective volitional and reflexive saccade initiation, saccade hypometria, and head thrusts. Both horizontal and vertical saccades are impaired in these two disorders. PMID:25783597

  13. Charge Transfer Characteristics and Initiation Mechanisms of Long Delayed Sprites

    NASA Astrophysics Data System (ADS)

    Li, J.; Cummer, S. A.; Lyons, W. A.; Nelson, T. E.

    2007-12-01

    Simultaneous measurements of high altitude optical emissions and the magnetic field produced by sprite-associated lightning discharges enable a close examination of the link between low altitude lightning process and high altitude sprite process. In this work, we report results of the coordinated analysis of high speed (1000--10000 frames per second) sprite video and wideband (0.1 Hz to 30 kHz) magnetic field measurements made simultaneously at the Yucca Ridge Field Station and Duke University during the June through August 2005 campaign period. During the observation period, the high speed camera detected 83 sprite events in 67 TLE sequences, which are caused by the same number of +CGs. 46% of these sprite events are delayed more than 10 ms after the lightning return stroke. With the estimated lightning source current moment waveform, we computed the continuing current amplitude and total charge transfer characteristics of the long delayed sprites (>10 ms delay). Our calculation shows the total charge moment change of the long delayed sprites can vary from several hundred C km to more than ten thousand C km. All the long delayed sprites are related with intense continuing current bigger than 2 kA. This continuing current provides about 50% to 90% of the total charge transfer. However, a bigger continuing current does not necessarily mean a shorter time delay. This indicates that other processes also involved in the sprite initiation for long delayed sprites. In our observations, the sferic burst, a high frequency noise caused by intra-cloud activity, is always accompanied by a slow intensification in the lightning source current before the time of sprite initiation. Thus we used the lightning source current as an input and employed a 2-D FDTD model to numerically simulate the electric field at different altitudes and compare it with the breakdown field. Including the effect of the electron mobility dependence on electric field, the simulation results showed that

  14. Delayed improvement of insulin secretion after autologous islet transplantation in partially pancreatectomized patients.

    PubMed

    Jung, Hye Seung; Choi, Seong-Ho; Kim, Sung-Joo; Choi, Dong-Wook; Heo, Jin-Seok; Lee, Kyu Taek; Lee, Jong Kyun; Jang, Kee-Taek; Lee, Byung-Wan; Jee, Jae-Hwan; Noh, Jung-Hyun; Jeong, In Kyung; Yang, Tae-Young; Oh, Seung-Hoon; Ahn, You-Ran; Kim, Young-Seok; No, Heesung; Lee, Moon-Kyu; Kim, Kwang-Won

    2009-11-01

    The purpose of this study was to evaluate the effects of autologous islet transplantation (ITx) on glucose homeostasis and insulin secretory function after partial pancreatectomy (Px). Fourteen nondiabetic patients who underwent distal Px and autologous ITx for benign pancreatic tumors were enrolled in the study (Px + ITx group). Fourteen normal glucose-tolerant controls and 6 Px without ITx controls were recruited, and all groups were followed over a 24-month period. They performed the 75-g oral glucose tolerance test and the 1-mg glucagon stimulation test. Hemoglobin A(1c) was measured, and indices of insulin secretion were calculated. In the Px + ITx group, insulin secretion increased after a nadir at 6 months. Glucose tolerance, which had been abruptly impaired immediately after Px, recovered until 6 months and stabilized thereafter. As a result, differences in glucose intolerance emerged between the subjects in the Px group and those in the Px + ITx group at 24 months after Px. Characteristic variables in the better insulin secretory subjects in the Px + ITx group included younger age, less extensive pancreas resection, and a greater number of total islets. In summary, delayed amelioration of glucose intolerance was induced by autologous ITx after partial Px, even with a small number of islets. PMID:19604519

  15. A viral histone H4 suppresses insect insulin signal and delays host development.

    PubMed

    Kumar, Sunil; Gu, Xiaojun; Kim, Yonggyun

    2016-10-01

    Parasitization by an endoparasitoid wasp, Cotesia plutellae, alters host development of Plutella xylostella by extending larval period and preventing metamorphosis. Insulin signal plays a crucial role in mediating insect development and controlling blood sugar level in insects. In this study, three insulin-like peptide genes (PxILP1-3) were predicted from the genome of P. xylostella. However, only PxILP1 was confirmed to be expressed in P. xylostella. Starvation suppressed the expression level of PxILP1 and up-regulated plasma trehalose level. RNA interference against PxILP1 mimicked starvation effect and extended the larval period of P. xylostella. Parasitized larvae exhibited significantly lower levels of PxILP1 expression compared to nonparasitized larvae. Injection of wasp-symbiotic polydnavirus C. plutellae bracovirus (CpBV) also suppressed PxILP1 expression and extended the larval period. Injection of a viral segment (CpBV-S30) containing a viral histone H4 (CpBV-H4) also suppressed PxILP1 expression. Co-injection of CpBV-S30 and double-stranded RNA (dsCpBV-H4) specific to CpBV-H4 rescued the suppression of PxILP1 expression. Injection of CpBV-S30 significantly extended larval development. Co-injection of CpBV-S30 with dsCpBV-H4 rescued the delay of larval development. Injection of a bovine insulin to parasitized larvae prevented parasitoid development. These results indicate that parasitism of C. plutellae can down-regulate host insulin signaling with the help of parasitic factor CpBV-H4. PMID:27216029

  16. Insulin delays the progression of Drosophila cells through G2/M by activating the dTOR/dRaptor complex

    PubMed Central

    Wu, Mary Y W; Cully, Megan; Andersen, Ditte; Leevers, Sally J

    2007-01-01

    In Drosophila and mammals, insulin signalling can increase growth, progression through G1/S, cell size and tissue size. Here, we analyse the way insulin affects cell size and cell-cycle progression in two haemocyte-derived Drosophila cell lines. Surprisingly, we find that although insulin increases cell size, it slows the rate at which these cells increase in number. By using BrdU pulse-chase to label S-phase cells and follow their progression through the cell cycle, we show that insulin delays progression through G2/M, thereby slowing cell division. The ability of insulin to slow progression through G2/M is independent of its ability to stimulate progression through G1/S, so is not a consequence of feedback by the cell-cycle machinery to maintain cell-cycle length. Insulin's effects on progression through G2/M are mediated by dTOR/dRaptor signalling. Partially inhibiting dTOR/dRaptor signalling by dsRNAi or mild rapamycin treatment can increase cell number in cultured haemocytes and the Drosophila wing, respectively. Thus, insulin signalling can influence cell number depending on a balance between its ability to accelerate progression through G1/S and delay progression through G2/M. PMID:17183368

  17. Impact of patient attitudes and beliefs to insulin therapy upon initiation, and their attitudinal changes after initiation: the DAWN Japan study.

    PubMed

    Odawara, Masato; Ishii, Hitoshi; Tajima, Naoko; Iwamoto, Yasuhiko

    2016-01-01

    Objective As a part of the Diabetes Attitudes, Wishes and Needs (DAWN) Japan study, a multi-center, questionnaire-based survey conducted between 2004 and 2005, this analysis aimed to (1) explore patients' attitudes and beliefs contributing to their decision to start insulin therapy, and (2) assess the changes in their attitudes and beliefs after actual initiation. Methods Insulin-naive patients with type 2 diabetes who were recommended to start insulin therapy (n = 149) were invited to answer a 21-item questionnaire consisting of five clusters assessing their attitudes and beliefs toward insulin therapy. The questionnaire was administered twice: first upon insulin recommendation, and then 1 month after insulin initiation for those who started and 4 months after for those who did not. Results Of 130 patients included in the analysis, 74 patients (56.9%) started insulin therapy. 'Negative image of injections' and 'Positive image toward insulin therapy' were significantly associated with patient decision to start insulin therapy (odds ratios [95% CI]: 0.49 [0.32-0.76] and 2.58 [1.51-4.42], respectively). After insulin initiation, 'Negative image of injections', 'Positive image toward insulin therapy', 'Feelings of guilt regarding diabetes self-management', and 'Negative image toward insulin therapy' decreased significantly (P < 0.001 for all). 'Social/interpersonal effects' did not change after insulin initiation. Conclusions This study demonstrated that patients who started insulin therapy were less likely to have negative images of injections and more likely to have positive images toward insulin therapy. Starting insulin therapy did not deteriorate the patient's overall impression of therapy. The key limitation is the relatively small sample size (n = 130). The results suggest that education about the benefits of insulin therapy may help patients who are not ready to initiate insulin overcome their barrier to early insulin initiation and practical

  18. The Initial Assessment of Daily Insulin Dose in Chinese Newly Diagnosed Type 2 Diabetes

    PubMed Central

    Zhou, Huan; Xu, Hua; Chen, Xie; Teng, Xiangyu; Liu, Qianjing; Liu, Wei

    2016-01-01

    Background. It has been well accepted that insulin therapy is the ideal treatment for newly diagnosed diabetic patients. However, there was no study about assessment of the initial insulin dosage in new onset Chinese patients with type 2 diabetes. Research Design and Methods. 65 newly diagnosed patients with type 2 diabetes (39 males/26 females; HbA1c ≥ 11.80 ± 0.22%) were investigated. All patients had random hyperglycaemia (at 21.8 ± 3.9 mmol/L) on the first day of admission and received insulin infusion intravenously (5 U/per hour). When the blood glucose level dropped to around 10 mmol/L, patients were then transferred to continuous subcutaneous insulin infusion (CSII). The reduction of blood glucose levels in response to per unit of insulin (RBG/RI) was recorded. The target glucose level was achieved in about 3 days. The total daily insulin dose (TDD) and basal insulin dose (TBD) were calculated. Results. TDD was 45.97 ± 1.28 units and TBD was 19.00 ± 0.54 units. TBD was about 40% of the total daily insulin requirement. There was a negative correlation between the ratio of RBG/RI and TDD. Conclusions. TDD was correlated with blood glucose reduction in response to intravenous insulin infusion in Chinese new onset patients with type 2 diabetes. PMID:26697503

  19. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  20. Initial examination of priming tasks to decrease delay discounting.

    PubMed

    Sheffer, Christine E; Mackillop, James; Fernandez, Arislenia; Christensen, Darren; Bickel, Warren K; Johnson, Matthew W; Panissidi, Luana; Pittman, Jami; Franck, Christopher T; Williams, Jarrett; Mathew, Merlin

    2016-07-01

    Steep discounting of delayed rewards is linked with a variety of unhealthy behaviors that contribute to the major causes of preventable death and disease. Growing evidence suggests that decreases in delay discounting contribute to healthier preferences. This study sought to provide preliminary evidence for the viability of developing a brief priming task to reduce delay discounting in a large, diverse group of individuals. Participants (n=1,122) were randomized to one of three conditions: Future Focus (FF), Present Focus (PF), and Non-Temporal Focus (NTF) intended respectively to decrease, increase, or have no effect on delay discounting. Participants then completed the Monetary Choice Questionnaire, a brief assessment of delay discounting rate. Participants randomized to FF exhibited significantly lower discounting rates than those randomized to PF or NTF conditions. Race, Hispanic background, social self-monitoring, education, and cigarette smoking also accounted for a significant amount of variance in the discounting model. These findings provide support for the development of a brief priming intervention that might be examined in clinical or public health contexts to decrease discounting and support healthy choices. PMID:27179761

  1. Investigation of stability in a two-delay model of the ultradian oscillations in glucose-insulin regulation

    NASA Astrophysics Data System (ADS)

    Huard, B.; Easton, J. F.; Angelova, M.

    2015-09-01

    In this paper, a two-delay model for the ultradian oscillatory behaviour of the glucose-insulin regulation system is studied. Hill functions are introduced to model nonlinear physiological interactions within this system and ranges on parameters reproducing biological oscillations are determined on the basis of analytical and numerical considerations. Local and global stability are investigated and delay-dependent conditions are obtained through the construction of Lyapunov-Krasovskii functionals. The effect of Hill parameters on these conditions, as well as the boundary of the stability region in the delay domain, are established for the first time. Numerical simulations demonstrate that the model with Hill functions represents well the oscillatory behaviour of the system with the advantage of incorporating new meaningful parameters. The influence of the time delays on the period of oscillations and the sensitivity of the latter to model parameters, in particular glucose infusion, are investigated. The model can contribute to the better understanding and treatment of diabetes.

  2. Clinician Perspectives on Delaying Initiation of Antiretroviral Therapy for Clinically Eligible HIV-Infected Patients

    PubMed Central

    Valverde, Eduardo E.; Raiford, Jerris L.; Weiser, John; White, Becky L.; Skarbinski, Jacek

    2015-01-01

    Objectives: Guidelines for antiretroviral therapy (ART) initiation have evolved, but consistently note that adherence problems should be considered and addressed. Little is known regarding the reasons providers delay ART initiation in clinically eligible patients. Methods: In 2009, we surveyed a probability sample of HIV care providers in 582 outpatient facilities in the United States and Puerto Rico with an open-ended question about nonclinical reasons for delaying ART initiation in otherwise clinically eligible patients. Results: Very few providers (2%) reported never delaying ART. Reasons for delaying ART were concerns about patient adherence (68%), patient acceptance (60%), and structural barriers (33%). Provider and practice characteristics were associated with reasons for delaying ART. Conclusion: Reasons for delaying ART were consistent with clinical guidelines and were both patient level and structural. Providers may benefit from training and access to referrals for ancillary services to enhance their ability to monitor and address these issues with their patients. PMID:25394912

  3. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver.

    PubMed

    Shankar, T P; Drake, S; Solomon, S S

    1987-06-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t1/2) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers (P less than 0.001). Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance. PMID:3296781

  4. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

    SciTech Connect

    Shankar, T.P.; Drake, S.; Solomon, S.S.

    1987-06-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of /sup 125/I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance.

  5. A qualitative study on healthcare professionals’ perceived barriers to insulin initiation in a multi-ethnic population

    PubMed Central

    2012-01-01

    Background Nationwide surveys have shown that the prevalence of diabetes rates in Malaysia have almost doubled in the past ten years; yet diabetes control remains poor and insulin therapy is underutilized. This study aimed to explore healthcare professionals’ views on barriers to starting insulin therapy in people with type 2 diabetes. Methods Healthcare professionals consisting of general practitioners (n = 11), family medicine specialists (n = 10), medical officers (n = 8), government policy makers (n = 4), diabetes educators (n = 3) and endocrinologists (n = 2) were interviewed. A semi-structured topic guide was used to guide the interviews by trained facilitators. The interviews were transcribed verbatim and analysed using a thematic analysis approach. Results Insulin initiation was found to be affected by patient, healthcare professional and system factors. Patients’ barriers include culture-specific barriers such as the religious purity of insulin, preferred use of complementary medication and perceived lethality of insulin therapy. Healthcare professionals’ barriers include negative attitudes towards insulin therapy and the ‘legacy effect’ of old insulin guidelines; whilst system barriers highlight the lack of resources, language and communication challenges. Conclusions Tackling the issue of insulin initiation should not only happen during clinical consultations. It requires health education to emphasise the progressive nature of diabetes and the eventuality of insulin therapy at early stage of the illness. Healthcare professionals should be trained how to initiate insulin and communicate effectively with patients from various cultural and religious backgrounds. PMID:22469132

  6. The Effect of Initiating Pharmacologic Insulin on Serum Uric Acid Levels in Patients with Diabetes: A Matched Cohort Analysis

    PubMed Central

    MacFarlane, Lindsey A.; Liu, Chih-Chin; Solomon, Daniel H.

    2014-01-01

    Objectives Gout is a common inflammatory arthropathy associated with hyperuricemia. Substantial evidence links hyperuricemia to the metabolic syndrome and diabetes. Rising serum insulin levels correlate with an increase in serum uric acid (UA). The current study evaluated the effect of pharmacologic insulin on serum UA levels in patients with diabetes. Methods We conducted a retrospective analysis of previously collected data. The study cohort consisted of patients with both gout and diabetes who had initiated insulin therapy and a matched set of non-insulin users. The change in UA levels was calculated in both groups and compared. Potential confounders were assessed and adjusted for in a matched linear regression model. Results 23 patients met criteria for insulin initiators and were matched to 23 non-insulin users. In unadjusted analyses, patients started on insulin had a larger increase in UA (mean change 1.25 mg/dl, interquartile range, IQR: −0.7,2.3) in comparison to those not starting insulin (mean change 0.06 mg/dl, IQR: −1.1,0.9). After controlling for baseline UA and time between UA measurements, regression modeling showed that insulin use was significantly associated with an increase in UA ( = 1.25mg/dl, p value= 0.02). Conclusions Initiation of insulin among patients with diabetes was associated with a statistically significant increase in serum UA levels. This may affect the risk of gout flares and might suggest the potential for prophylactic therapy. PMID:25455681

  7. Electronic delay ignition module for single bridgewire Apollo standard initiator

    NASA Technical Reports Server (NTRS)

    Ward, R. D.

    1975-01-01

    An engineering model and a qualification model of the EDIM were constructed and tested to Scout flight qualification criteria. The qualification model incorporated design improvements resulting from the engineering model tests. Compatibility with single bridgewire Apollo standard initiator (SBASI) was proven by test firing forty-five (45) SBASI's with worst case voltage and temperature conditions. The EDIM was successfully qualified for Scout flight application with no failures during testing of the qualification unit. Included is a method of implementing the EDIM into Scout vehicle hardware and the ground support equipment necessary to check out the system.

  8. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  9. Body Composition and Epicardial Fat in Type 2 Diabetes Patients Following Insulin Detemir Versus Insulin Glargine Initiation.

    PubMed

    Elisha, B; Azar, M; Taleb, N; Bernard, S; Iacobellis, G; Rabasa-Lhoret, R

    2016-01-01

    The aim of the study was to compare body composition and epicardial fat thickness changes in insulin-naïve inadequately controlled patients with type 2 diabetes following basal insulin initiation with detemir vs. glargine. Six-month, open-label, interventional randomized pilot study was conducted. Dual-energy X-ray absorptiometry and echocardiography were used to estimate the body composition and epicardial fat thickness respectively. Thirty-six patients in the detemir group and 20 in the glargine group completed the study. Study groups baseline characteristics were comparable. At 6 months, for similar glycemic control, those on detemir significantly gained less total weight (0.6±2.5 vs. 4.2±4.1 kg, p=0.004), total fat mass (0.9±2.2 vs. 2.9±2.4 kg, p=0.02), and truncal fat mass (0.8±1.5 vs. 2.1±1.7 kg, p=0.02), with a loss in truncal lean mass (- 0.8±1.9 kg vs. 0.3±1.7 kg; p=0.02). EFT significantly decreased from baseline in both group (detemir - 1.7±0.52-mm, glargine - 1.1±1.6-mm; p<0.05, without significant difference inter-groups). Within the detemir group, epicardial fat thickness change correlated with truncal fat and total fat mass changes (r=0.65, p=0.06 and r=0.60, p=0.07). In conclusion, detemir resulted in less fat mass gain, a trend for a more pronounced epicardial fat thickness reduction when compared with glargine. PMID:26340704

  10. The Haiti Breast Cancer Initiative: Initial Findings and Analysis of Barriers-to-Care Delaying Patient Presentation

    PubMed Central

    Sharma, Ketan; Costas, Ainhoa; Damuse, Ruth; Hamiltong-Pierre, Jean; Pyda, Jordan; Ong, Cecilia T.; Shulman, Lawrence N.; Meara, John G.

    2013-01-01

    Background. In Haiti, breast cancer patients present at such advanced stages that even modern therapies offer modest survival benefit. Identifying the personal, sociocultural, and economic barriers-to-care delaying patient presentation is crucial to controlling disease. Methods. Patients presenting to the Hôpital Bon Sauveur in Cange were prospectively accrued. Delay was defined as 12 weeks or longer from initial sign/symptom discovery to presentation, as durations greater than this cutoff correlate with reduced survival. A matched case-control analysis with multivariate logistic regression was used to identify factors predicting delay. Results. Of N = 123 patients accrued, 90 (73%) reported symptom-presentation duration and formed the basis of this study: 52 patients presented within 12 weeks of symptoms, while 38 patients waited longer than 12 weeks. On logistic regression, lower education status (OR = 5.6, P = 0.03), failure to initially recognize mass as important (OR = 13.0, P < 0.01), and fear of treatment cost (OR = 8.3, P = 0.03) were shown to independently predict delayed patient presentation. Conclusion. To reduce stage at presentation, future interventions must educate patients on the recognition of initial breast cancer signs and symptoms and address cost concerns by providing care free of charge and/or advertising that existing care is already free. PMID:23840209

  11. Sulfate anion delays the self-assembly of human insulin by modifying the aggregation pathway.

    PubMed

    Owczarz, Marta; Arosio, Paolo

    2014-07-01

    The understanding of the molecular mechanisms underlying protein self-assembly and of their dependence on solvent composition has implications in a large number of biological and biotechnological systems. In this work, we characterize the aggregation process of human insulin at acidic pH in the presence of sulfate ions using a combination of Thioflavin T fluorescence, dynamic light scattering, size exclusion chromatography, Fourier transform infrared spectroscopy, and transmission electron microscopy. It is found that the increase of sulfate concentration inhibits the conversion of insulin molecules into aggregates by modifying the aggregation pathway. At low sulfate concentrations (0-5 mM) insulin forms amyloid fibrils following the nucleated polymerization mechanism commonly observed under acidic conditions in the presence of monovalent anions. When the sulfate concentration is increased above 5 mM, the sulfate anion induces the salting-out of ∼18-20% of insulin molecules into reversible amorphous aggregates, which retain a large content of α-helix structures. During time these aggregates undergo structure rearrangements into β-sheet structures, which are able to recruit monomers and bind to the Thioflavin T dye. The alternative aggregation mechanism observed at large sulfate concentrations is characterized by a larger activation energy and leads to more polymorphic structures with respect to the self-assembly in the presence of chloride ions. The system shown in this work represents a case where amorphous aggregates on pathway to the formation of structures with amyloid features could be detected and analyzed. PMID:24988354

  12. Sulfate Anion Delays the Self-Assembly of Human Insulin by Modifying the Aggregation Pathway

    PubMed Central

    Owczarz, Marta; Arosio, Paolo

    2014-01-01

    The understanding of the molecular mechanisms underlying protein self-assembly and of their dependence on solvent composition has implications in a large number of biological and biotechnological systems. In this work, we characterize the aggregation process of human insulin at acidic pH in the presence of sulfate ions using a combination of Thioflavin T fluorescence, dynamic light scattering, size exclusion chromatography, Fourier transform infrared spectroscopy, and transmission electron microscopy. It is found that the increase of sulfate concentration inhibits the conversion of insulin molecules into aggregates by modifying the aggregation pathway. At low sulfate concentrations (0–5 mM) insulin forms amyloid fibrils following the nucleated polymerization mechanism commonly observed under acidic conditions in the presence of monovalent anions. When the sulfate concentration is increased above 5 mM, the sulfate anion induces the salting-out of ∼18–20% of insulin molecules into reversible amorphous aggregates, which retain a large content of α-helix structures. During time these aggregates undergo structure rearrangements into β-sheet structures, which are able to recruit monomers and bind to the Thioflavin T dye. The alternative aggregation mechanism observed at large sulfate concentrations is characterized by a larger activation energy and leads to more polymorphic structures with respect to the self-assembly in the presence of chloride ions. The system shown in this work represents a case where amorphous aggregates on pathway to the formation of structures with amyloid features could be detected and analyzed. PMID:24988354

  13. Low-melting elemental metal or fusible alloy encapsulated polymerization initiator for delayed initiation

    SciTech Connect

    Hermes, Robert E.

    2015-12-22

    An encapsulated composition for polymerization includes an initiator composition for initiating a polymerization reaction, and a capsule prepared from an elemental metal or fusible alloy having a melting temperature from about 20.degree. C. to about 200.degree. C. A fluid for polymerization includes the encapsulated composition and a monomer. When the capsule melts or breaks open, the initiator is released.

  14. Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer

    PubMed Central

    Yoo, Tae-Kyung; Han, Wonshik; Moon, Hyeong-Gon; Kim, Jisun; Lee, Jun Woo; Kim, Min Kyoon; Lee, Eunshin; Kim, Jongjin; Noh, Dong-Young

    2016-01-01

    Purpose Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. Materials and Methods This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. Results A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. Conclusion Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer. PMID:26511801

  15. Gaze-Assisted User Intention Prediction for Initial Delay Reduction in Web Video Access

    PubMed Central

    Lee, Seungyup; Yoo, Juwan; Han, Gunhee

    2015-01-01

    Despite the remarkable improvement of hardware and network technology, the inevitable delay from a user's command action to a system response is still one of the most crucial influence factors in user experiences (UXs). Especially for a web video service, an initial delay from click action to video start has significant influences on the quality of experience (QoE). The initial delay of a system can be minimized by preparing execution based on predicted user's intention prior to actual command action. The introduction of the sequential and concurrent flow of resources in human cognition and behavior can significantly improve the accuracy and preparation time for intention prediction. This paper introduces a threaded interaction model and applies it to user intention prediction for initial delay reduction in web video access. The proposed technique consists of a candidate selection module, a decision module and a preparation module that prefetches and preloads the web video data before a user's click action. The candidate selection module selects candidates in the web page using proximity calculation around a cursor. Meanwhile, the decision module computes the possibility of actual click action based on the cursor-gaze relationship. The preparation activates the prefetching for the selected candidates when the click possibility exceeds a certain limit in the decision module. Experimental results show a 92% hit-ratio, 0.5-s initial delay on average and 1.5-s worst initial delay, which is much less than a user's tolerable limit in web video access, demonstrating significant improvement of accuracy and advance time in intention prediction by introducing the proposed threaded interaction model. PMID:26102494

  16. Universal Intervention Effects on Substance Use among Young Adults Mediated by Delayed Adolescent Substance Initiation

    ERIC Educational Resources Information Center

    Spoth, Richard; Trudeau, Linda; Guyll, Max; Shin, Chungyeol; Redmond, Cleve

    2009-01-01

    In this article, the authors examine whether delayed substance initiation during adolescence, achieved through universal family-focused interventions conducted in middle school, can reduce problematic substance use during young adulthood. Sixth-grade students enrolled in 33 rural midwestern schools and their families were randomly assigned to 3…

  17. Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups.

    PubMed

    Martinez, Bridget; Soñanez-Organis, José G; Viscarra, Jose A; Jaques, John T; MacKenzie, Duncan S; Crocker, Daniel E; Ortiz, Rudy M

    2016-03-15

    Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrβ-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late-fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrβ-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition. PMID:26739649

  18. Insulin-dependent diabetes impairs the inflammatory response and delays angiogenesis following Achilles tendon injury.

    PubMed

    Chbinou, Nadia; Frenette, Jérôme

    2004-05-01

    Although impaired wound healing associated with type 1 diabetes mellitus has been well studied in skin tissue, the influence of this metabolic disorder on tendon healing and recovery has not been extensively investigated. Because tendons are known to have limited repair potential, we studied the tendon-healing process by using a diabetic rat tendonitis model. We tested the hypothesis that diabetes influences the inflammatory response, cell proliferation, and angiogenesis in injured Achilles tendons. Diabetes was induced by injecting streptozotocin at 45 mg/kg body wt. Non-diabetic rats as well as diabetic and insulin-treated diabetic animals were then injected with collagenase. The accumulation of inflammatory cells was quantified in transversal sections of Achilles tendon by using immunohistochemical staining at days 0, 1, 3, 7, 14, and 28 posttrauma. The number of proliferative cells and the extent of neovascularization was also quantified in the paratenon and the core of the tendon at days 0, 3, 7, 14, and 28 posttrauma. Relative to nondiabetic and insulin-treated diabetic animals, the numbers of accumulated neutrophils and ED1(+) and ED2(+) macrophages in diabetic rats decreased by 46, 43, and 52%, respectively, in the first 3 days after injury compared with levels in nondiabetic and insulin-treated diabetic animals. The density of newly formed blood vessels decreased by 35 and 29% in the paratenon and the core of tendon, respectively, at days 3 and 7 after injury. Lastly, the concentration of proliferative cells decreased by 34% in the paratenon at day 7 posttrauma in injured tendons from diabetic rats relative to nondiabetic rats. These results indicate that alterations in inflammatory, angiogenic, and proliferative processes occurred in the diabetic state that might eventually perturb tendon healing and remodeling. PMID:14715491

  19. Human insulin-like growth factor II leader 2 mediates internal initiation of translation.

    PubMed Central

    Pedersen, Susanne K; Christiansen, Jan; Hansen, Thomas v O; Larsen, Martin R; Nielsen, Finn C

    2002-01-01

    Insulin-like growth factor II (IGF-II) is a fetal growth factor, which belongs to the family of insulin-like peptides. During fetal life, the IGF-II gene generates three mRNAs with different 5' untranslated regions (UTRs), but identical coding regions and 3' UTRs. We have shown previously that IGF-II leader 3 mRNA translation is regulated by a rapamycin-sensitive pathway, whereas leader 4 mRNA is constitutively translated, but so far the significance of leader 2 mRNA has been unclear. Here, we show that leader 2 mRNA is translated efficiently in an eIF4E-independent manner. In a bicistronic vector system, the 411 nt leader 2 was capable of internal initiation via a phylogenetically conserved internal ribosome entry site (IRES), located in the 3' half of the leader. The IRES is composed of an approx. 120 nt ribosome recruitment element, followed by an 80 nt spacer region, which is scanned by the ribosomal pre-initiation complex. Since cap-dependent translation is down-regulated during cell division, leader 2 might facilitate a continuous IGF-II production in rapidly dividing cells during development. PMID:11903044

  20. Delay in initiating adjuvant radiotherapy following breast conservation surgery and its impact on survival

    SciTech Connect

    Hershman, Dawn L. . E-mail: dlh23@columbia.edu; Wang Xiaoyan; McBride, Russell

    2006-08-01

    Purpose: Delays in the diagnosis of breast cancer are associated with advanced stage and poor survival, but the importance of the time interval between lumpectomy and initiation of radiation therapy (RT) has not been well studied. We investigated factors that influence the time interval between lumpectomy and RT, and the association between that interval and survival. Patients and Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database on women aged 65 years and older, diagnosed with Stages I-II breast cancer, between 1991 and 1999. Among patients who did not receive chemotherapy, we studied factors associated with the time interval between lumpectomy and the initiation of RT, and the association of delay with survival, using linear regression and Cox proportional hazards modeling. Results: Among 24,833 women with who underwent lumpectomy, 13,907 (56%) underwent RT. Among those receiving RT, 97% started treatment within 3 months; older age, black race, advanced stage, more comorbidities, and being unmarried were associated with longer time intervals between surgery and RT. There was no benefit to earlier initiation of RT; however, delays >3 months were associated with higher overall mortality (hazard ratio, 1.92; 95% confidence interval, 1.64-2.24) and cancer-specific mortality (hazard ratio, 3.84; 95% confidence interval 3.01-4.91). Conclusions: Reassuringly, early initiation of RT was not associated with survival. Although delays of >3 months are uncommon, they are associated with poor survival. Whether this association is causal or due to confounding factors, such as poor health behaviors, is unknown; until it is better understood, efforts should be made to initiate RT in a timely fashion.

  1. Mouse intracerebral hemorrhage models produce different degrees of initial and delayed damage, axonal sprouting, and recovery.

    PubMed

    Barratt, Harriet E; Lanman, Tyler A; Carmichael, S Thomas

    2014-09-01

    The mechanisms of delayed damage and recovery after intracerebral hemorrhage (ICH) remain poorly defined. Two rodent models of ICH are commonly used: injection of the enzyme collagenase (cICH) and injection of autologous blood (bICH). In mice, we compared the effects of these two models on initial and delayed tissue damage, motor system connections, and behavioral recovery. There is no difference in lesion size between models. Injection of autologous blood causes greater mass effect and early mortality. However, cICH produces greater edema, inflammation, and cell death. Injection of the enzyme collagenase causes greater loss of cortical connections and secondary shrinkage of the striatum. Intracerebral hemorrhage occurs within the motor system connections of the striatum. Mapping of the projections of the forelimb motor area shows a significant sprouting in motor cortex projections only in cICH. Both models of ICH produce deficits in forelimb motor control. Behavioral recovery occurs by 5 weeks in cICH and 9 weeks in bICH. In summary, cICH and bICH differ in almost every facet of initial and delayed stroke pathophysiology, with cICH producing greater initial and secondary tissue damage and greater motor system axonal sprouting than bICH. Motor recovery occurs in both models, suggesting that motor system axonal sprouting in cICH is not causally associated with recovery. PMID:24917041

  2. Aberrant Accumulation of Undifferentiated Myeloid Cells in the Adipose Tissue of CCR2-Deficient Mice Delays Improvements in Insulin Sensitivity

    PubMed Central

    Gutierrez, Dario A.; Kennedy, Arion; Orr, Jeb S.; Anderson, Emily K.; Webb, Corey D.; Gerrald, William K.; Hasty, Alyssa H.

    2011-01-01

    OBJECTIVE Mice with CCR2 deficiency are protected from insulin resistance but only after long periods of high-fat diet (HFD) feeding, despite the virtual absence of circulating inflammatory monocytes. We performed a time course study in mice with hematopoietic and global CCR2 deficiency to determine adipose tissue–specific mechanisms for the delayed impact of CCR2 deficiency on insulin resistance. RESEARCH DESIGN AND METHODS Mice with global or hematopoietic CCR2 deficiency (CCR2−/− and BM-CCR2−/−, respectively) and wild-type controls (CCR2+/+ and BM-CCR2+/+, respectively) were placed on an HFD for 6, 12, and 20 weeks. Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed. RESULTS Flow cytometry analysis showed that two different populations of F4/80+ myeloid cells (CD11bloF4/80lo and CD11bhiF4/80hi) accumulated in the adipose tissue of CCR2−/− and BM-CCR2−/− mice after 6 and 12 weeks of HFD feeding, whereas only the CD11bhiF4/80hi population was detected in the CCR2+/+ and BM-CCR2+/+ controls. After 20 weeks of HFD feeding, the CD11bloF4/80lo cells were no longer present in the adipose tissue of CCR2−/− mice, and only then were improvements in adipose tissue inflammation detected. Gene expression and histological analysis of the CD11bloF4/80lo cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11bloF4/80lo cells are transiently found in wild-type mice, but CCR2 deficiency leads to the aberrant accumulation of these cells in adipose tissue. CONCLUSIONS The discovery of this novel adipose tissue monocytic cell population provides advances toward understanding the pleiotropic role of CCR2 in monocyte/macrophage accumulation and regulation of adipose tissue inflammation. PMID:21926275

  3. Failure to initiate early insulin therapy – A risk factor for diabetic retinopathy in insulin users with Type 2 diabetes mellitus: Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS, Report number 35)

    PubMed Central

    Gupta, Aditi; Delhiwala, Kushal S; Raman, Rajiv P G; Sharma, Tarun; Srinivasan, Sangeetha; Kulothungan, Vaitheeswaran

    2016-01-01

    Context: Insulin users have been reported to have a higher incidence of diabetic retinopathy (DR). Aim: The aim was to elucidate the factors associated with DR among insulin users, especially association between duration, prior to initiating insulin for Type 2 diabetes mellitus (DM) and developing DR. Materials and Methods: Retrospective cross-sectional observational study included 1414 subjects having Type 2 DM. Insulin users were defined as subjects using insulin for glycemic control, and insulin nonusers as those either not using any antidiabetic treatment or using diet control or oral medications. The duration before initiating insulin after diagnosis was calculated by subtracting the duration of insulin usage from the duration of DM. DR was clinically graded using Klein's classification. SPSS (version 9.0) was used for statistical analysis. Results: Insulin users had more incidence of DR (52.9% vs. 16.3%, P < 0.0001) and sight threatening DR (19.1% vs. 2.4%, P < 0.0001) in comparison to insulin nonusers. Among insulin users, longer duration of DM (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00–1.25, P = 0.044) and abdominal obesity (OR 1.15, 95% CI 1.02–1.29, P = 0.021) was associated with DR. The presence of DR was significantly associated with longer duration (≥5 years) prior to initiating insulin therapy, overall (38.0% vs. 62.0%, P = 0.013), and in subjects with suboptimal glycemic control (32.5% vs. 67.5%, P = 0.022). Conclusions: The presence of DR is significantly associated with longer duration of diabetes (>5 years) and sub-optimal glycemic control (glycosylated hemoglobin <7.0%). Among insulin users, abdominal obesity was found to be a significant predictor of DR; DR is associated with longer duration prior to initiating insulin therapy in Type 2 DM subjects with suboptimal glycemic control. PMID:27488152

  4. Initial tsunami source estimation by inversion with an intelligent selection of model parameters and time delays

    NASA Astrophysics Data System (ADS)

    Mulia, Iyan E.; Asano, Toshiyuki

    2016-01-01

    We propose a method for accurately estimating the initial tsunami source. Our technique is independent of the earthquake parameters, because we only use recorded tsunami waveforms and an auxiliary basis function, instead of a fault model. We first use the measured waveforms to roughly identify the source area using backward propagated travel times, and then infer the initial sea surface deformation through inversion analysis. A computational intelligence approach based on a genetic algorithm combined with a pattern search was used to select appropriate least squares model parameters and time delays. The proposed method significantly reduced the number of parameters and suppressed the negative effect of regularization schemes that decreased the plausibility of the model. Furthermore, the stochastic approach for deriving the time delays is a more flexible strategy for simulating actual phenomena that occur in nature. The selected parameters and time delays increased the accuracy, and the model's ability to reveal the underlying physics associated with the tsunami-generating processes. In this paper, we applied the method to the 2011 Tohoku-Oki tsunami event and examined its effectiveness by comparing the results to those using the conventional method.

  5. Appropriateness and delay to initiate therapy in ventilator-associated pneumonia.

    PubMed

    Luna, C M; Aruj, P; Niederman, M S; Garzón, J; Violi, D; Prignoni, A; Ríos, F; Baquero, S; Gando, S

    2006-01-01

    Inappropriate therapy (IT) and delayed initiation of appropriate therapy (DIAT) result in inadequate therapy in patients with ventilator-associated pneumonia (VAP). The aim of the current study was to assess the impact of DIAT in VAP. A total of 76 mechanically ventilated patients with bacteriologically confirmed VAP were prospectively evaluated in the intensive care unit of six hospitals in Buenos Aires, Argentina. Appropriate therapy was defined as coverage of all the identified pathogens by the antimicrobial therapy administered at the time of VAP clinical diagnosis. The clinical pulmonary infection score was measured during the 3 days before, at the onset and during the days which followed the onset of VAP. A total of 24 patients received adequate therapy; mortality was 29.2%. The remaining 52 patients received either IT (n = 16) or DIAT (n = 36); the mortality was 63.5% combined, and 75.0 and 58.3% for IT and DIAT, respectively (statistically significant compared with adequate therapy). Inappropriate therapy and delayed initiation of appropriate therapy increased the mortality of ventilator-associated pneumonia. Patients with inappropriate therapy and/or delayed initiation of appropriate therapy had a more gradual increase in clinical pulmonary infection score than those receiving adequate therapy, and this increase was found to occur prior to the time of the clinical diagnosis. In conclusion, these findings might provide the rationale for a trial of earlier initiation of therapy, based on clinical grounds in an effort to improve the outcome of patients with ventilator-associated pneumonia. PMID:16387949

  6. Diapause Formation and Downregulation of Insulin-Like Signaling via DAF-16/FOXO Delays Axonal Degeneration and Neuronal Loss

    PubMed Central

    Calixto, Andrea; Jara, Juan S.; Court, Felipe A.

    2012-01-01

    Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO–dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment. PMID:23300463

  7. Basal insulin persistence, associated factors, and outcomes after treatment initiation among people with type 2 diabetes mellitus in the US.

    PubMed

    Perez-Nieves, Magaly; Kabul, Samaneh; Desai, Urvi; Ivanova, Jasmina I; Kirson, Noam Y; Cummings, Alice Kate; Birnbaum, Howard G; Duan, Ran; Cao, Dachuang; Hadjiyianni, Irene

    2016-04-01

    Objective To assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in the US. Research design and methods People aged ≥18 years diagnosed with T2DM initiating basal insulin between April 2006 and March 2012 (index date), no prior insulin use, and continuous insurance coverage for 6 months before (baseline) and 24 months after index date (follow-up period) were selected using de-identified administrative claims data in the US. Based on whether there were ≥30 day gaps in basal insulin use in the first year post-index, patients were classified as continuers (no gap), interrupters (≥1 prescription after gap), and discontinuers (no prescription after gap). Main outcome measures Factors associated with persistence - assessed using multinomial logistic regression model; annual healthcare resource use and costs during follow-up period - compared separately between continuers and interrupters, and continuers and discontinuers. Results Of the 19,110 people included in the sample (mean age: 59 years, ∼60% male), 20% continued to use basal insulin, 62% had ≥1 interruption, and 18% discontinued therapy in the year after initiation. Older age, multiple antihyperglycemic drug use, and injectable antihyperglycemic use during baseline were associated with significantly higher likelihoods of continuing basal insulin. Relative to interrupters and discontinuers, continuers had fewer emergency department visits, shorter hospital stays, and lower medical costs (continuers: $10,890, interrupters: $13,674, discontinuers: $13,021), but higher pharmacy costs (continuers: $7449, interrupters: $5239, discontinuers: $4857) in the first year post-index (p < 0.05 for all comparisons). Total healthcare costs were similar across the three cohorts. Findings for the second year post-index were similar. Conclusions The majority of people in this study interrupted or discontinued basal insulin

  8. Reasons for delaying or engaging in early sexual initiation among adolescents in Nigeria

    PubMed Central

    Ankomah, Augustine; Mamman-Daura, Fatima; Omoregie, Godpower; Anyanti, Jennifer

    2011-01-01

    Background Annually, over 1 million births in Nigeria are to teenage mothers. Many of these pregnancies are unwanted and these mothers are also exposed to the risk of human immunodeficiency virus (HIV) infection. Sexual abstinence is a critical preventative health strategy. Several quantitative studies in Nigeria have identified the correlates and determinants of early sex, yet few have explored in depth the underlying reasons for early sex. This paper explores both the key factors that motivate some unmarried young people to engage in early sex and reasons why some delay. Methods This qualitative study was based on data from 30 focus group discussions held with unmarried 14- to 19-year-olds in four geographically and culturally dispersed Nigerian states. Focus groups were stratified by sexual experience to capture variations among different subgroups. Results Several reasons for early premarital sex were identified. The “push” factors included situations where parents exposed young female adolescents to street trading. “Pull” factors, particularly for males, included the pervasive viewing of locally produced movies, peer pressure and, for females, transactional sex (where adolescent girls exchange sex for gifts, cash, or other favors). Also noted were overtly coercive factors, including rape. There were also myths and misconceptions that “justified” early sexual initiation. Reasons cited for delay included religious injunction against premarital sex; disease prevention (especially HIV/acquired immunodeficiency syndrome); fear of pregnancy, and linked to this, the fear of dropping out of school; and, for females, the fear of bringing shame to the family, which could lead to their inability to get a “good” husband in the future. Conclusion The differences observed between sexually active and abstinent adolescents were that the latter were more confident, had greater determination, and, most important, deployed refusal skills to delay first sex

  9. Insulin stimulates muscle protein synthesis in neonates during endotoxemia despite repression of translation initiation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle protein synthesis is reduced in neonatal pigs in response to endotoxemia. To examine the role of insulin in this response, neonatal pigs were infused with endotoxin (LPS, 0 and 10 µg•kg(-1)•h(-1)), whereas glucose and amino acids were maintained at fasting levels and insulin was clam...

  10. Angiotensin II inhibits insulin-stimulated phosphorylation of eukaryotic initiation factor 4E-binding protein-1 in proximal tubular epithelial cells.

    PubMed Central

    Senthil, D; Faulkner, J L; Choudhury, G G; Abboud, H E; Kasinath, B S

    2001-01-01

    Interaction between angiotensin II, which binds a G-protein-coupled receptor, and insulin, a ligand for receptor tyrosine kinase, was examined in renal proximal tubular epithelial cells. Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) which follows the release of the factor from a heterodimeric complex by phosphorylation of its binding protein, 4E-BP1. Angiotensin II (1 nM) or insulin (1 nM) individually stimulated 4E-BP1 phosphorylation. However, pre-incubation with angiotensin II abrogated insulin-induced phosphorylation of 4E-BP1, resulting in persistent binding to eIF4E. Although angiotensin II and insulin individually activated phosphoinositide 3-kinase and extracellular signal-regulated kinase (ERK)-1/-2-type mitogen-activated protein (MAP) kinase, pre-incubation with angiotensin II abolished insulin-induced stimulation of these kinases, suggesting more proximal events in insulin signalling may be intercepted. Pretreatment with angiotensin II markedly inhibited insulin-stimulated tyrosine phosphorylation of insulin-receptor beta-chain and insulin-receptor substrate 1. Losartan prevented angiotensin II inhibition of insulin-induced ERK-1/-2-type MAP kinase activation and 4E-BP1 phosphorylation, suggesting mediation of the effect of angiotensin II by its type 1 receptor. Insulin-stimulated de novo protein synthesis was also abolished by pre-incubation with angiotensin II. These data show that angiotensin II inhibits 4E-BP1 phosphorylation and stimulation of protein synthesis induced by insulin by interfering with proximal events in insulin signalling. Our data provide a mechanistic basis for insulin insensitivity induced by angiotensin II. PMID:11695995

  11. Can community retail pharmacist and diabetes expert support facilitate insulin initiation by family physicians? Results of the AIM@GP randomized controlled trial

    PubMed Central

    2013-01-01

    Background Limited evidence exists on the effectiveness of external diabetes support provided by diabetes specialists and community retail pharmacists to facilitate insulin-prescribing in family practice. Methods A stratified, parallel group, randomized control study was conducted in 15 sites across Canada. Family physicians received insulin initiation/titration education, a physician-specific ‘report card’ on the characteristics of their type 2 diabetes (T2DM) population, and a registry of insulin-eligible patients at a workshop. Intervention physicians in addition received: (1) diabetes specialist/educator consultation support (active diabetes specialist/educator consultation support for 2 months [the educator initiated contact every 2 weeks] and passive consultation support for 10 months [family physician initiated as needed]); and (2) community retail pharmacist support (option to refer patients to the pharmacist(s) for a 1-hour insulin-initiation session). The primary outcome was the insulin prescribing rate (IPR) per physician defined as the number of insulin starts of insulin-eligible patients during the 12-month strategy. Results Consenting, eligible physicians (n = 151) participated with 15 specialist sites and 107 community pharmacists providing the intervention. Most physicians were male (74%), and had an average of 81 patients with T2DM. Few (9%) routinely initiated patients on insulin. Physicians were randomly allocated to usual care (n = 78) or the intervention (n = 73). Intervention physicians had a mean (SE) IPR of 2.28 (0.27) compared to 2.29 (0.25) for control physicians, with an estimated adjusted RR (95% CI) of 0.99 (0.80 to 1.24), p = 0.96. Conclusions An insulin support program utilizing diabetes experts and community retail pharmacists to enhance insulin prescribing in family practice was not successful. Too few physicians are appropriately intensifying diabetes management through insulin initiation, and aggressive

  12. Increasing Patient Acceptance and Adherence Toward Insulin.

    PubMed

    Riddle, Matthew; Peters, Anne; Funnell, Martha

    2016-10-01

    Because of the progressive nature of type 2 diabetes mellitus (T2DM), the majority of patients will need insulin to achieve and maintain glycemic control. By maintaining glycemic control, patients will avoid acute osmotic symptoms of hyperglycemia, instability in plasma glucose (PG) over time, and prevent or delay the development of diabetes complications without adversely affecting quality of life. Despite recommendations for initiating insulin therapy, both patient and health system barriers stand in the way. To develop confidence in individualizing patient therapy and maximize outcomes for patients with T2DM, healthcare practitioners (HCPs) were updated on recommendations and clinical evidence supporting when to initiate insulin therapy, strategies for overcoming provider and patient barriers for initiating insulin therapy, and the safety and efficacy of current and emerging insulin therapy and delivery technology for patients with T2DM. PMID:27109558

  13. Update on a Quality Initiative to Standardize Perioperative Care for Continuous Subcutaneous Insulin Infusion Therapy

    PubMed Central

    Mackey, Patricia A.; Thompson, Bithika M.; Boyle, Mary E.; Apsey, Heidi A.; Seifert, Karen M.; Schlinkert, Richard T.; Stearns, Joshua D.; Cook, Curtiss B.

    2015-01-01

    Objective: The objective of the analysis was to review the effectiveness of a care process model (CPM) developed to guide management of patients on insulin pump therapy undergoing elective surgical procedures. Methods: Electronic medical records were reviewed to assess the impact of the CPM on documentation of insulin pump status, glucose monitoring, and safety during the perioperative phase of care. Post-CPM care was compared with management provided before CPM implementation. Results: We reviewed 45 cases on insulin pump therapy in the pre-CPM cohort and 106 in the post-CPM cohort. Demographic characteristics, categories of surgery, and perioperative times were not significantly different between the 2 groups. Recommended hemoglobin A1c monitoring occurred in 73% of cases in the pre-CPM cohort but improved to 94% in the post-CPM group (P < .01). There was a higher frequency of documentation of the insulin pump during the preoperative, intraoperative, and postanesthesia care unit segments of care in the post- vs pre-CPM periods (all P < .01). The number of cases with intraoperative glucose monitoring increased (57% pre-CPM vs 81% post-CPM; P < .01). Glycemic control was comparable between the 2 CPM periods. Hypoglycemia was rare, with only 3 episodes in the pre-CPM group and 4 in the post-CPM. No adverse events associated with perioperative insulin pump use were observed. Conclusions: This analysis adds to previous data on use of insulin pump therapy during the perioperative period. Some processes require additional attention, but data continue to indicate that a standardized approach to care can lead to a successful and safe transition of insulin pump therapy throughout the perioperative period. PMID:26092687

  14. Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation?

    PubMed Central

    2012-01-01

    Background There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. Methods/design We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will

  15. Disordered Eating Behaviors in Youth with Type 1 Diabetes: Prospective Pilot Assessment Following Initiation of Insulin Pump Therapy

    PubMed Central

    Markowitz, Jessica T.; Alleyn, Cielo A.; Phillips, Roxanne; Muir, Andrew; Young-Hyman, Deborah

    2013-01-01

    Abstract Background There is risk for disordered eating behaviors in type 1 diabetes, especially related to insulin manipulation. Implementation of insulin pump therapy may encourage either normalization of eating behaviors or a greater focus on food intake due to renewed emphasis on carbohydrate counting. There is need for prospective studies to assess disordered eating behaviors upon implementation of pump therapy using diabetes-specific measurement tools. Subjects and Methods In a multicenter pilot study, 43 youth with type 1 diabetes, 10–17 years old, were assessed prior to pump initiation and after 1 and 6 months of pump therapy. Youth completed the Diabetes-specific Eating Problems Survey-Revised (DEPS-R), a validated measure of risk for both diabetes-specific and general disordered eating behaviors. Results Youth (45% female), 13.3 years old with diabetes for 2.1 years, had a mean hemoglobin A1c of 8.3±1.3% (68±14.5 mmol/mol) at baseline. DEPS-R scores decreased over time (P=0.01). Overall rate of high risk for eating disorders was low. Overweight/obese youth endorsed more disordered eating behaviors than normal-weight participants. DEPS-R scores were correlated with z-score for body mass index at all three time points and with hemoglobin A1c after 1 and 6 months. Hemoglobin A1c did not change significantly over the 6 months and was higher in overweight/obese compared with normal-weight participants. Conclusions Initiation of insulin pump therapy was associated with diminished endorsement of disordered eating behaviors in youth with type 1 diabetes. Longer follow-up studies are needed to assess the impact of insulin pump therapy on glycemic control, weight status, and disordered eating behaviors in this vulnerable population. PMID:23550556

  16. The effects of peer-play level on initiations and responses of preschool children with delayed play skills.

    PubMed

    Tanta, Kari J; Deitz, Jean C; White, Owen; Billingsley, Felix

    2005-01-01

    The potential impact of peer-play opportunities on the overall development of young children has been well-documented in the social development, occupational therapy, and special education literature. However, the effect of peer characteristics on the manifestation and facilitation of specific types of play roles and behaviors has received little attention. This topic is of key importance to occupational therapists who are striving to develop interventions that enhance the development of social participation and play in preschool children. The purpose of this study was to examine the differences in initiation and response exhibited by preschool-aged children with social-play delays when participating in free-play dyads with peers of differing developmental levels. A single-subject alternating treatments design was replicated across five preschool-aged children with developmental play delays. Each child was paired with one peer who had lower developmental play skills and one peer who had higher developmental play skills. The arranged dyads were given the opportunity to play together in a specially designed playroom at their school. Their interactions were videotaped and later coded. All five children generally showed more initiation and response to initiation during play with higher-level peers, although one participant showed less differentiation for initiation than the other four children. An occupational therapist working with a preschool child with play delays and wanting to facilitate the child's initiation and response in play situations should consider pairing the child with play delays with a child who has higher play skills. PMID:16124210

  17. Durations and Delays in Care Seeking, Diagnosis and Treatment Initiation in Uncomplicated Pulmonary Tuberculosis Patients in Mumbai, India

    PubMed Central

    Mistry, Nerges; Rangan, Sheela; Dholakia, Yatin; Lobo, Eunice; Shah, Shimoni; Patil, Akshaya

    2016-01-01

    Background Timely diagnosis and treatment initiation are critical to reduce the chain of transmission of Tuberculosis (TB) in places like Mumbai, where almost 60% of the inhabitants reside in overcrowded slums. This study documents the pathway from the onset of symptoms suggestive of TB to initiation of TB treatment and examines factors responsible for delay among uncomplicated pulmonary TB patients in Mumbai. Methods A population-based retrospective survey was conducted in the slums of 15 high TB burden administrative wards to identify 153 self-reported TB patients. Subsequently in-depth interviews of 76 consenting patients that fit the inclusion criteria were undertaken using an open-ended interview schedule. Mean total, first care seeking, diagnosis and treatment initiation duration and delays were computed for new and retreatment patients. Patients showing defined delays were divided into outliers and non-outliers for all three delays using the median values. Results The mean duration for the total pathway was 65 days with 29% of patients being outliers. Importantly the mean duration of first care seeking was similar in new (24 days) and retreatment patients (25 days). Diagnostic duration contributed to 55% of the total pathway largely in new patients. Treatment initiation was noted to be the least among the three durations with mean duration in retreatment patients twice that of new patients. Significantly more female patients experienced diagnostic delay. Major shift of patients from the private to public sector and non-allopaths to allopaths was observed, particularly for treatment initiation. Conclusion Achieving positive behavioural changes in providers (especially non-allopaths) and patients needs to be considered in TB control strategies. Specific attention is required in counselling of TB patients so that timely care seeking is effected at the time of relapse. Prioritizing improvement of environmental health in vulnerable locations and provision of

  18. Initiating or Switching to Biphasic Insulin Aspart 30/70 Therapy in Subjects with Type 2 Diabetes Mellitus. An Observational Study

    PubMed Central

    Breum, Leif; Almdal, Thomas; Eiken, Pia; Lund, Per; Christiansen, Erik; on behalf of the Danish BIAsp Study Group

    2008-01-01

    OBJECTIVE: To investigate tolerability and glycemic control over 26 weeks in patients with type 2 diabetes (T2D) who initiated insulin with, or switched to, biphasic insulin aspart 30/70 (BIAsp 30) in routine clinical care. METHODS: This was a non-randomized, non-interventional, open-label, observational study involving patients under the care of approximately 150 insulin-prescribing physicians in Denmark. All patients enrolled were prescribed BIAsp 30 in routine care. Starting dose, dose titration and injection frequency were determined individually by each physician. Information on serious adverse drug reactions (SADR), glycemic parameters and hypoglycemic events were obtained from patients’ notes, patients’ diaries and recall, and transferred to case report forms by physicians at baseline (during 4 weeks prior to BIAsp 30 therapy) and after 12 and 26 weeks of treatment. RESULTS: 421 subjects were recruited and 392 provided safety data. The age (mean ± SD) was 62.0 ± 11.4 years, body mass index (BMI) 30.4 ± 6.4 kg/m2, duration of diabetes 9.1 ± 8.1 years and HbA1c (%) 9.4 ± 1.7. 199 subjects were prior insulin users and 193 were insulin-naïve patients. Four patients reported a SADR (3 hypoglycemia, 1 severe hypoglycemia). HbA1c was significantly reduced after 26 weeks of BIAsp 30 therapy: prior insulin users -1.2%, insulin-naïve patients -2.2% (both p < 0.001). 28% and 41% of patients, respectively, reached target HbA1c < 7%. Overall the hypoglycemia rate was lower for insulin-naïve patients than for prior insulin users: 5.0 vs. 6.6 episodes/patient-year (p < 0.05). CONCLUSION: Initiating insulin with, or switching insulin to, BIAsp 30 in routine care was safe and effective in patients with T2D. PMID:19099087

  19. Inoculation against Forgetting: Advantages of Immediate versus Delayed Initial Testing Due to Superior Verbatim Accessibility

    ERIC Educational Resources Information Center

    Pansky, Ainat

    2012-01-01

    In this study, potential benefits of early memory testing were examined in terms of "inoculating" eyewitness memory against forgetting. As predicted by fuzzy trace theory (e.g., Reyna & Titcomb, 1997), a larger testing advantage in the delayed recall of event details was expected after immediate testing than after delayed testing because of the…

  20. Delays before Diagnosis and Initiation of Treatment in Patients Presenting to Mental Health Services with Bipolar Disorder

    PubMed Central

    Patel, Rashmi; Shetty, Hitesh; Jackson, Richard; Broadbent, Matthew; Stewart, Robert; Boydell, Jane; McGuire, Philip; Taylor, Matthew

    2015-01-01

    Background Bipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare. Method Retrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay). Results The median diagnostic delay was 62 days (interquartile range: 17–243) and median treatment delay was 31 days (4–122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18–3.06) and treatment delay (4.40, 3.63–5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33–0.41) and substance misuse disorders (0.44, 0.31–0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay. Conclusions Some individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify

  1. Evolving strategies for insulin delivery and therapy.

    PubMed

    Cefalu, William T

    2004-01-01

    It has now been conclusively proven that adequate control of blood glucose delays or prevents the progression of diabetic complications. In order to achieve the suggested targets for glycaemic control necessary to reduce the incidence of diabetic complications, it has been established that a more intensive insulin regimen requiring multiple insulin injections is required for patients with type 1 diabetes mellitus. For patients with type 2 diabetes, oral antidiabetic therapy is generally used initially, but given the natural history of type 2 diabetes and the need to achieve improved glycaemic control, earlier use of insulin has been promoted. However, the use of insulin in more intensive regimens for the patient with type 1 diabetes or for earlier treatment of the patient with type 2 diabetes is not routine. Many factors are responsible for this observation. Nevertheless, available device options such as insulin pens or insulin pumps are routinely available for implementation of intensive insulin therapy. However, a major limitation for advancing to intensive insulin therapy is that the only viable way to administer insulin is through injection. Delivery options that use dermal, nasal and oral approaches have been explored. The oral approach may include gastrointestinal, buccal or pulmonary uptake. Recent evidence shows that delivery of insulin via the oral cavity with uptake occurring in the pulmonary alveoli may be the most viable clinical option in the future. PMID:15161324

  2. Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates

    PubMed Central

    2005-01-01

    The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARγ (peroxisome-proliferator-activated receptor γ) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified (‘free’) fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARγ ligands and by hyperinsulinaemia as being responsible for a major insulin-resistant condition. PMID:15810879

  3. Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates.

    PubMed

    Sevillano, Julio; López-Pérez, Inmaculada C; Herrera, Emilio; Del Pilar Ramos, María; Bocos, Carlos

    2005-08-01

    The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARgamma (peroxisome-proliferator-activated receptor gamma) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified ('free') fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARgamma ligands and by hyperinsulinaemia as being responsible for a major insulin-resistant condition. PMID:15810879

  4. Plasmapheresis in the initial treatment of insulin-dependent diabetes mellitus in children.

    PubMed Central

    Ludvigsson, J; Heding, L; Liedén, G; Marner, B; Lernmark, A

    1983-01-01

    Several factors indicate that autoimmune mechanisms may play a part in the aetiology of insulin-dependent diabetes mellitus. At the onset of the disease in 10 children (aged 11-16 years) plasmapheresis was performed four times over one to two weeks. Seventeen age-matched children with the same clinical features served as controls. The C-peptide concentrations at onset were the same in the two groups, but after one month the children treated with plasmapheresis had significantly higher values. This difference became even more pronounced after three, nine, and 18 months, both during fasting and at the maximum response to a standardised meal. The study group also had a significantly more stable metabolism, longer partial remission, and no higher insulin requirement. Of the 10 treated children islet-cell cytoplasmic antibodies were present in seven before plasmapheresis and in nine during treatment. The antibodies remained detectable in five and six out of nine patients at one and six months respectively after plasmapheresis. Although the mechanisms are obscure, plasmapheresis performed at the onset of insulin-dependent diabetes mellitus may help to preserve beta-cell function. PMID:6401518

  5. Plasmapheresis in the initial treatment of insulin-dependent diabetes mellitus in children.

    PubMed

    Ludvigsson, J; Heding, L; Liedén, G; Marner, B; Lernmark, A

    1983-01-15

    Several factors indicate that autoimmune mechanisms may play a part in the aetiology of insulin-dependent diabetes mellitus. At the onset of the disease in 10 children (aged 11-16 years) plasmapheresis was performed four times over one to two weeks. Seventeen age-matched children with the same clinical features served as controls. The C-peptide concentrations at onset were the same in the two groups, but after one month the children treated with plasmapheresis had significantly higher values. This difference became even more pronounced after three, nine, and 18 months, both during fasting and at the maximum response to a standardised meal. The study group also had a significantly more stable metabolism, longer partial remission, and no higher insulin requirement. Of the 10 treated children islet-cell cytoplasmic antibodies were present in seven before plasmapheresis and in nine during treatment. The antibodies remained detectable in five and six out of nine patients at one and six months respectively after plasmapheresis. Although the mechanisms are obscure, plasmapheresis performed at the onset of insulin-dependent diabetes mellitus may help to preserve beta-cell function. PMID:6401518

  6. Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption

    PubMed Central

    Bowman, Thomas A.; O'Keeffe, Kayleigh R.; D'Aquila, Theresa; Yan, Qing Wu; Griffin, John D.; Killion, Elizabeth A.; Salter, Deanna M.; Mashek, Douglas G.; Buhman, Kimberly K.; Greenberg, Andrew S.

    2016-01-01

    Objective The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. Methods To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5−/−). Results Ablation of ACSL5 reduced ACSL activity by ∼80% in jejunal mucosa, ∼50% in liver, and ∼37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5−/−, as compared to control ACSL5loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5−/− had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5−/− mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (∼16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (∼13-fold) were increased in ACSL5−/− as compared to ACSL5loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5−/− mice as compared to control mice. Conclusions In summary, ACSL5−/− mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies

  7. Inoculation against forgetting: advantages of immediate versus delayed initial testing due to superior verbatim accessibility.

    PubMed

    Pansky, Ainat

    2012-11-01

    In this study, potential benefits of early memory testing were examined in terms of "inoculating" eyewitness memory against forgetting. As predicted by fuzzy trace theory (e.g., Reyna & Titcomb, 1997), a larger testing advantage in the delayed recall of event details was expected after immediate testing than after delayed testing because of the decline in accessibility of verbatim traces over time. However, memory for only the gist of these details was expected to be relatively stable over time, resulting in a smaller (if any) effect of the timing of interpolated testing. After viewing a target event, participants were questioned about event items immediately, after a 24-hr delay, or after a 48-hr delay and were free to respond at either the gist or the verbatim level. Verbatim memory for event details was tested 72 hr after the event. As expected, immediate interpolated testing improved verbatim memory performance on the final test more than delayed testing did, yielding a larger testing effect. Furthermore, the effect of the timing of interpolated testing on the magnitude of the testing effect was mediated by verbatim accessibility at interpolated testing. In contrast, memory for only the gist of event details was unaffected by the timing of interpolated testing, both on the interpolated test and on the final test. The findings highlight the role of declining verbatim memory over time in accounting for the advantage of immediate over delayed interpolated testing in inoculating eyewitness memory against forgetting of detailed information. PMID:22582965

  8. Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia.

    PubMed

    Üçok, Alp; Çikrikçili, Uğur; Karabulut, Sercan; Salaj, Ada; Öztürk, Meliha; Tabak, Öznur; Durak, Rümeysa

    2015-09-01

    The aim of this retrospective chart-review study was to investigate the relationship between delayed commencement of clozapine and the level of response in treatment-resistant schizophrenia (TRS). We included 162 patients with schizophrenia who used clozapine. The mean delay until starting clozapine after fulfillment of the TRS criteria was 29 months. The delay was shorter in those who gained benefit from clozapine (P=0.04), those who were treated in a specialized psychosis outpatient unit (P=0.01), and in men (P=0.009), and it correlated with age (P<0.001). The delay in starting clozapine and the maximum clozapine dose were independent contributors toward the response to clozapine in the logistic regression analysis. Moreover, of those who gained considerable benefit from clozapine, the patients were younger (P=0.01), the duration of illness before clozapine treatment was shorter (P=0.001), and the numbers of adequate antipsychotic trials before the use of clozapine were fewer (P=0.05). Our findings suggest that efforts aimed at reducing the delay for starting clozapine may increase the effectiveness of clozapine in TRS. PMID:26163875

  9. Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

    PubMed

    Maessen, Dionne E; Brouwers, Olaf; Gaens, Katrien H; Wouters, Kristiaan; Cleutjens, Jack P; Janssen, Ben J; Miyata, Toshio; Stehouwer, Coen D; Schalkwijk, Casper G

    2016-04-01

    Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity. PMID:26718500

  10. Cortical Suppression to Delayed Self-Initiated Auditory Stimuli in Schizotypy: Neurophysiological Evidence for a Continuum of Psychosis.

    PubMed

    Oestreich, Lena K L; Mifsud, Nathan G; Ford, Judith M; Roach, Brian J; Mathalon, Daniel H; Whitford, Thomas J

    2016-01-01

    Schizophrenia patients have been shown to exhibit subnormal levels of electrophysiological suppression to self-initiated, button press elicited sounds. These self-suppression deficits have been shown to improve following the imposition of a subsecond delay between the button press and the evoked sound. The current study aimed to investigate whether nonclinical individuals who scored highly on the personality dimension of schizotypy would exhibit similar patterns of self-suppression abnormalities to those exhibited in schizophrenia. Thirty-nine nonclinical individuals scoring above the median (High Schizotypy) and 41 individuals scoring below the median (Low Schizotypy) on the Schizotypal Personality Questionnaire (SPQ) underwent electroencephalographic recording. The amplitude of the N1-component was calculated while participants (1) listened to tones initiated by a willed button press and played back with varying delay periods between the button press and the tone (Active conditions) and (2) passively listened to a series of tones (Listen condition). N1-suppression was calculated by subtracting the amplitude of the N1-component of the auditory evoked potential in the Active condition from that of the Listen condition, while controlling for the activity evoked by the button press per se. The Low Schizotypy group exhibited significantly higher levels of N1-suppression to undelayed tones compared to the High Schizotypy group. Furthermore, while N1-suppression was found to decrease linearly with increasing delays between the button press and the tone in the Low Schizotypy group, this was not the case in the High Schizotypy group. The findings of this study suggest that nonclinical, highly schizotypal individuals exhibit subnormal levels of N1-suppression to undelayed self-initiated tones and an abnormal pattern of N1-suppression to delayed self-initiated tones. To the extent that these results are similar to those previously reported in patients with schizophrenia

  11. Initial screening of children treated with second-generation antipsychotics points to an association between physical activity and insulin resistance.

    PubMed

    Cote, Anita T; Devlin, Angela M; Panagiotopoulos, Constadina

    2014-11-01

    Second-generation antipsychotic (SGA) medications, used to treat youth for a wide-range of mental health conditions, are associated with excessive weight gain and other comorbidities, placing these individuals at high risk for cardiovascular disease. Little is known about the effect of physical activity (PA) on cardiovascular risk in these children. Anthropometrics, fasting blood sample and self-report PA were obtained in 386 children diagnosed with mental health conditions (6-18 y). PA was classified as below (<60 min/day) or meets (≥60 min/day) current recommended guidelines for daily PA in children. SGA-treated (n = 166) and SGA-naïve (n = 220) were compared in the analysis. The SGA-treated children had higher (p < .05) BMI z-score, waist-to-height ratio, fasting glucose, and LDL-cholesterol than SGA-naïve children. Waist circumference, waist-to-height ratio, HDL cholesterol, fasting insulin, and HOMA-IR were significantly different by PA status. After adjusting for SGA-treatment duration, sex, age, and ethnicity, higher PA was associated with lower insulin resistance (HOMA-IR) in SGA-treated (mean, 95% CI; below vs. meets: 2.10 [1.84, 2.37] vs. 1.59 [1.37, 1.81], p = .046) but not in SGA-naïve (1.70 [1.47, 1.94] vs. 1.55 [1.35, 1.75], p = .707) children. Upon initial screening, SGA-treated children that reported meeting the minimal recommendations for daily PA displayed lower measures of adiposity and improved insulin resistance. PMID:25372380

  12. Factors involved in the delay of treatment initiation for cervical cancer patients: A nationwide population-based study.

    PubMed

    Shen, Szu-Ching; Hung, Yao-Ching; Kung, Pei-Tseng; Yang, Wen-Hui; Wang, Yueh-Hsin; Tsai, Wen-Chen

    2016-08-01

    Cervical cancer ranks as the fourth leading cause of cancer death in women worldwide. In Taiwan, although the universal health insurance system has achieved 99.9% coverage and ensured easy access to medical care, some cervical cancer patients continue to delay initiation of definitive treatment after diagnosis. This study focused on cervical cancer patients who delayed treatment for at least 4 months, and examined the characteristics, related factors, and survival in these patients.Data on patients with a new confirmed diagnosis of cervical cancer by the International Federation of Gynecology and Obstetrics (FIGO) staging system between 2005 and 2010 were obtained from the National Health Insurance Research Database and the Taiwan Cancer Registry. Logistic regression analysis was performed to analyze the association of various factors with treatment delay. The Cox proportional hazards model was used to analyze the effects of various factors on mortality risk.The rate of treatment delay for cervical cancer decreased steadily from 6.46% in 2005 to 2.48% in 2010. Higher rates of treatment delay were observed among patients who were aged ≥75 years (9.91%), had severe comorbidity, had stage IV (9.50%), diagnosing hospital level at nonmedical center, or at public hospital ownership. Factors that correlated with treatment delay were age ≥75 years (odds ratio [OR] = 2.42), higher comorbidity Charlson comorbidity index (CCI) 4-6, or ≥7 (OR = 1.60, 2.00), cancer stage IV (OR = 2.60), the diagnosing hospital being a regional, district hospital, or other (OR = 3.00, 4.01, 4.60), and at public hospital ownership. Those who delayed treatment had 2.31 times the mortality risk of those who underwent timely treatment (P < 0.05).Delayed cervical cancer treatment in Taiwan was associated with age, comorbidity, cancer stage, diagnosing hospital level, and hospital ownership. Delaying treatment for ≥4 months substantially raised mortality risk in cervical cancer patients

  13. Initial Experiments on the Effects of System Delay on On-Line Problem-Solving.

    ERIC Educational Resources Information Center

    Morfield, M. A.; And Others

    The main purpose of the research reported in this document was to discover whether controlled experiments can be conducted on the relations between people and the complex computing systems which they use. Three increasingly complex experiments were designed to test the effect of varying delays of computer response on the number of commands issues…

  14. Delayed initiation of anti-retroviral therapy in TB/HIV co-infected patients, Sanyati District, Zimbabwe, 2011-2012

    PubMed Central

    Maponga, Brian Abel; Chirundu, Daniel; Gombe, Notion Tafara; Tshimanga, Mufuta; Bangure, Donewell; Takundwa, Lucia

    2015-01-01

    Introduction Tuberculosis (TB) remains a public health problem and is driven by HIV. Recent studies indicate that anti-retroviral therapy (ART) initiated during the first two months of anti-TB treatment (ATT) reduces risk of HIV morbidity and mortality. In Sanyati district, 14% of TB/HIV co-infected patients were initiated on ART during TB treatment, in 2010. The study was conducted to determine the magnitude and determinants of delay in ART initiation, in TB/HIV co-infected patients. Methods An analytic cross sectional study was conducted at three study sites in Sanyati district. The outcome was delayed ART initiation, being failure to be initiated on ART during the first two months of ATT. Respondents were interviewed using pre-tested questionnaires. Epi-Info™ was used to generate frequencies, means, odds ratios and 95% confidence intervals. Stratified and logistic regression analysis was done. Results Of the 186 respondents, 63% had delayed ART initiation. Median delay from initiation of ATT to ART was 48 days (Q1=20; Q3=82). Risk factors for delayed ART initiation were: being treated for TB first time, AOR=2.23 (p=0.03); initially registered for HIV care outside Sanyati, AOR=3.08 (p<0.01); staying more than 5km from a clinic, AOR=3.29 (p<0.01). Enabling factors for early ART initiation was having a family member on ART, AOR=0.23 (p<0.01). Conclusion Significant delay and barriers to ART initiation were identified. Decentralization of ART initiation should be expedited. ART initiation should be expedited in patients with identified risk factors for delaying ART initiation. Peer support should be strengthened in families and community. Periodic evaluation of magnitude of delay and impact of early ART initiation in TB/HIV patients is recommended. PMID:26401222

  15. Prepubertal Exposure to Arsenic(III) Suppresses Circulating Insulin-like Growth Factor-1 (IGF-1) Delaying Sexual Maturation in Female Rats

    PubMed Central

    Reilly, Michael P.; Saca, James C.; Hamilton, Alina; Solano, Rene F.; Rivera, Jesse R.; Whitehouse-Innis, Wendy; Parsons, Jason G.; Dearth, Robert K.

    2013-01-01

    Arsenic (As) is a prevalent environmental toxin; readily accessible for human consumption and has been identified as an endocrine disruptor. However, it is not known what impact As has on female sexual maturation. Therefore, in the present study, we investigated the effects of prepubertal exposure on mammary gland development and pubertal onset in female rats. Results showed that prepubertal exposure to 10mg/kg of arsenite (As(III)) delayed vaginal opening (VO) and prepubertal mammary gland maturation. We determined that As accumulates in the liver, disrupts hepatocyte function and suppresses serum levels of the puberty related hormone insulin-like growth factor 1 (IGF-1) in prepubertal animals. Overall, this is the first study to show that prepubertal exposure to As(III) acts peripherally to suppresses circulating levels of IGF-1 resulting in delayed sexual maturation. Furthermore, this study identifies a critical window of increased susceptibility to As(III) that may have a lasting impact on female reproductive function. PMID:24090629

  16. Lower risk of hypoglycaemia and greater odds for weight loss with initiation of insulin detemir compared with insulin glargine in Turkish patients with type 2 diabetes mellitus: local results of a multinational observational study

    PubMed Central

    2014-01-01

    Background The purpose of this analysis is to evaluate the safety and effectiveness of insulin initiation with once-daily insulin detemir (IDet) or insulin glargine (IGlar) in real-life clinical practice in Turkish patients with type 2 diabetes mellitus (T2DM). Methods This was a 24-week multinational observational study of insulin initiation in patients with T2DM. Results The Turkish cohort (n = 2886) included 2395 patients treated with IDet and 491 with IGlar. The change in glycosylated haemoglobin (HbA1c) from the pre-insulin levels was -2.21% [95% confidence interval (CI) -2.32, -2.09] in the IDet group and -1.88% [95% CI -2.17, -1.59] in the IGlar group at the final visit. The incidence rate of minor hypoglycaemia increased in both groups from the pre-insulin to the final visit (+0.66 and +2.23 events per patient year in the IDet and IGlar groups, respectively). Weight change in the IDet group was -0.23 kg [95% CI -0.49, 0.02 kg], and +1.55 kg [95% CI 1.11, 2.00 kg] in the IGlar group. Regression analysis with adjustment for previously identified confounders (age, gender, duration of diabetes, body mass index, previous history of hypoglycaemia, microvascular disease, number and change in oral anti-diabetic drug therapy, HbA1c at baseline and insulin dose) identified an independent effect of insulin type (IDet versus IGlar) with a risk of at least one episode of hypoglycaemia (odds ratio (OR): 0.33 [95% CI 0.21, 0.52], p <0.0001), and weight loss ≥1 kg (OR: 1.75 [95% CI 1.18, 2.59], p = 0.005), but not on HbA1c (+0.05% [95% CI -0.15, 0.25%], p = 0.6). Conclusions Initiation of basal insulin analogues, IDet and IGlar, were associated with clinically significant glycaemic improvements. A lower risk of minor hypoglycaemia and greater odds of weight loss ≥1 kg was observed with IDet compared with IGlar. Trial registration NCT00825643 and NCT00740519 PMID:25048824

  17. Delay and Probability Discounting as Candidate Markers for Dementia: An Initial Investigation

    PubMed Central

    Lindbergh, Cutter A.; Puente, Antonio N.; Gray, Joshua C.; Mackillop, James; Miller, L. Stephen

    2014-01-01

    The present study investigated delay discounting and probability discounting—behavioral economic indices of impulsivity and risk proneness, respectively—in 39 healthy older adults and 25 older adults with mild cognitive impairment (MCI). Relative to the healthy group, it was hypothesized that older adults with MCI would display greater levels of impulsivity, risk proneness, and response inconsistency. The MCI group was found to display a unique delay discounting profile characterized by increasing impulsivity with decreasing reward magnitude, such that cognitively impaired older adults were significantly more impulsive than healthy controls at the small reward magnitude. The two groups exhibited similar levels of probability discounting, though older adults with MCI were significantly less consistent in their risk preferences. The present findings shed light onto decision-making in pre-dementia disease stages and suggest that discounting performance holds potential to complement early diagnostic instruments, likely due to pathophysiological processes in relevant brain regions. PMID:25236720

  18. Marginal Structural Models to Assess Delays in Second-Line HIV Treatment Initiation in South Africa

    PubMed Central

    Ive, Prudence; Horsburgh, C. Robert; Berhanu, Rebecca; Shearer, Kate; Maskew, Mhairi; Long, Lawrence; Sanne, Ian; Bassett, Jean; Ebrahim, Osman; Fox, Matthew P.

    2016-01-01

    Background South African HIV treatment guidelines call for patients who fail first-line antiretroviral therapy (ART) to be switched to second-line ART, yet logistical issues, clinician decisions and patient preferences make delay in switching to second-line likely. We explore the impact of delaying second-line ART after first-line treatment failure on rates of death and virologic failure. Methods We include patients with documented virologic failure on first-line ART from an observational cohort of 9 South African clinics. We explored predictors of delayed second-line switch and used marginal structural models to analyze rates of death following first-line failure by categorical time to switch to second-line. Cox proportional hazards models were used to examine virologic failure on second-line ART among patients who switched to second-line. Results 5895 patients failed first-line ART, and 63% switched to second-line. Among patients who switched, median time to switch was 3.4 months (IQR: 1.1–8.7 months). Longer time to switch was associated with higher CD4 counts, lower viral loads and more missed visits prior to first-line failure. Worse outcomes were associated with delay in second-line switch among patients with a peak CD4 count on first-line treatment ≤100 cells/mm3. Among these patients, marginal structural models showed increased risk of death (adjusted HR for switch in 6–12 months vs. 0–1.5 months = 1.47 (95% CI: 0.94–2.29), and Cox models showed increased rates of second-line virologic failure despite the presence of survivor bias (adjusted HR for switch in 3–6 months vs. 0–1.5 months = 2.13 (95% CI: 1.01–4.47)). Conclusions Even small delays in switch to second-line ART were associated with increased death and second-line failure among patients with low CD4 counts on first-line. There is opportunity for healthcare providers to switch patients to second-line more quickly. PMID:27548695

  19. 15 CFR 4.10 - Appeals from initial determinations or untimely delays.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... be decided by the Assistant General Counsel for Administration (AGC-Admin), except that appeals for records which were initially denied by the AGC-Admin shall be decided by the General Counsel. Written appeals should be addressed to the AGC-Admin, or the General Counsel if the records were initially...

  20. 15 CFR 4.10 - Appeals from initial determinations or untimely delays.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... be decided by the Assistant General Counsel for Administration (AGC-Admin), except that appeals for records which were initially denied by the AGC-Admin shall be decided by the General Counsel. Written appeals should be addressed to the AGC-Admin, or the General Counsel if the records were initially...

  1. 15 CFR 4.10 - Appeals from initial determinations or untimely delays.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... be decided by the Assistant General Counsel for Administration (AGC-Admin), except that appeals for records which were initially denied by the AGC-Admin shall be decided by the General Counsel. Written appeals should be addressed to the AGC-Admin, or the General Counsel if the records were initially...

  2. 15 CFR 4.10 - Appeals from initial determinations or untimely delays.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... be decided by the Assistant General Counsel for Administration (AGC-Admin), except that appeals for records which were initially denied by the AGC-Admin shall be decided by the General Counsel. Written appeals should be addressed to the AGC-Admin, or the General Counsel if the records were initially...

  3. Delay of Antiretroviral Therapy Initiation is Common in East African HIV-Infected Individuals in Serodiscordant Partnerships

    PubMed Central

    MUJUGIRA, Andrew; CELUM, Connie; THOMAS, Katherine K.; FARQUHAR, Carey; MUGO, Nelly; KATABIRA, Elly; BUKUSI, Elizabeth A.; TUMWESIGYE, Elioda; BAETEN, Jared M.

    2014-01-01

    Objective WHO guidance recommends antiretroviral therapy (ART) initiation for all persons with a known HIV-uninfected partner, as a strategy to prevent HIV transmission. Uptake of ART among HIV-infected partners in serodiscordant partnerships is not known, which we evaluated in African HIV serodiscordant couples. Design Prospective cohort study. Methods Among HIV-infected persons from Kenya and Uganda who had a known heterosexual HIV-uninfected partner, we assessed ART initiation in those who became ART-eligible under national guidelines during follow-up. Participants received quarterly clinical and semi-annual CD4 monitoring, and active referral for ART upon becoming eligible. Results Of 1958 HIV-infected ART-eligible partners, 58% were women and the median age was 34 years. At the first visit when determined to be ART eligible, the median CD4 count was 273 cells/μL (IQR 221, 330), 77% had WHO stage 1 or 2 HIV disease, and 96% were receiving trimethoprim-sulfamethoxazole prophylaxis. The cumulative probabilities of initiating ART at 6, 12, and 24 months after eligibility were 49.9%, 70.0% and 87.6%, respectively. Younger age (<25 years) (adjusted hazard ratio [AHR] 1.39, p=0.001), higher CD4 count (AHR 1.95, p<0.001 for >350 compared with <200 cells/μL), higher education (AHR 1.25, p<0.001), and lack of income (AHR 1.15, p=0.02) were independent predictors for delay in ART initiation. Conclusions In the context of close CD4 monitoring, ART counseling, and active linkage to HIV care, a substantial proportion of HIV-infected persons with a known HIV-uninfected partner delayed ART initiation. Strategies to motivate ART initiation are needed, particularly for younger persons with higher CD4 counts. PMID:24798765

  4. Delays in antiretroviral therapy initiation among HIV-positive individuals: results of the positive living with HIV study

    PubMed Central

    Poudel, Krishna C.; Buchanan, David R.; Poudel-Tandukar, Kalpana

    2016-01-01

    Background Lack of early initiation of antiretroviral therapy (ART) remains a major health concern due to increased risk of premature mortality and further HIV transmission. This study explored CD4+ cell count monitoring in relation to delays in ART initiation among HIV-positive individuals in the Kathmandu Valley, Nepal, where ART coverage was only 23.7% in 2011. Design We recruited a total of 87 ART-naïve, HIV-positive individuals aged 18 to 60 years through the networks of five non-government organizations working with HIV-positive individuals. We collected data on the history of ART initiation, CD4+ cell count monitoring, socio-demographic variables, perceived family support (measured with 10-item Nepali Family Support and Difficulty Scale), depression, and HIV symptom burden. Correlates of ART eligibility were examined using multivariable logistic regression analysis. Results A total of 72 of the 87 ART-naïve participants (82.8%) had monitored their CD4+ cell count in the past 6 months. Of these, 36 (50%) participants were eligible for ART initiation with CD4+ cell count <350 cells/mm3. A total of 12 participants had CD4+ cell count <200 cells/mm3. Lower level of perceived family support was associated with 6.05-fold higher odds (95% confidence interval =1.95 to 18.73) of being ART eligible with a CD4+ cell count <350 cells/mm3. Conclusions High rate of delays in ART initiation and the strong association of low perceived family support with ART eligibility in our study participants suggest that HIV service providers should consider the role and impact of family support in influencing individual decisions to initiate ART among eligible HIV-positive individuals. PMID:27369221

  5. Considerations for diabetes: treatment with insulin pen devices.

    PubMed

    Cuddihy, Robert M; Borgman, Sarah K

    2013-01-01

    Insulin is essential for the treatment of type 1 diabetes, and most patients with type 2 diabetes will eventually require insulin for glycemic control. Several barriers contribute to delays in initiating insulin therapy in type 2 diabetes. Furthermore, insulin-treated patients often miss doses or otherwise fail to self-administer their insulin as prescribed, placing themselves at the risk of developing complications. Insulin pens can help overcome barriers to initiating insulin therapy and can facilitate the self-management of diabetes. Compared with the vial and syringe, insulin pens are more accurate, associated with greater adherence, and preferred by patients because of their convenience and ease of use. Large database analyses suggest that insulin pens may reduce the rate of occurrence of hypoglycemic events in patients with type 2 diabetes. Despite higher costs of insulin pens vs vials and syringes, studies suggest little or no increase in total health care costs and decreases in diabetes-related costs associated with reduced health care utilization with pens. Interestingly, the use of insulin pens within the United States lags far behind the use of pens in Europe and Japan. Insulin pens may be disposable or refillable, and some pens have special features [eg, audible clicks, large-dose selector and dial, memory function, half-unit dosing, high dosing (ie, 80 U)] that offer the opportunity to individualize treatment by meeting patients' needs. This review compares available insulin pens, describes strategies to facilitate their usage, and discusses how insulin pens can improve self-management of diabetes while reducing cost. PMID:21768872

  6. Delayed initiation of antiretroviral therapy among HIV-discordant couples in Kenya.

    PubMed

    Kahn, Talia R; Desmond, Michelle; Rao, Deepa; Marx, Grace E; Guthrie, Brandon L; Bosire, Rose; Choi, Robert Y; Kiarie, James N; Farquhar, Carey

    2013-01-01

    Timely initiation of antiretroviral therapy (ART) is particularly important for HIV-discordant couples because viral suppression greatly reduces the risk of transmission to the uninfected partner. To identify issues and concerns related to ART initiation among HIV-discordant couples, we recruited a subset of discordant couples participating in a longitudinal study in Nairobi to participate in in-depth interviews and focus group discussions about ART. Our results suggest that partners in HIV-discordant relationships discuss starting ART, yet most are not aware that ART can decrease the risk of HIV transmission. In addition, their concerns about ART initiation include side effects, sustaining an appropriate level of drug treatment, HIV/AIDS-related stigma, medical/biological issues, psychological barriers, misconceptions about the medications, the inconvenience of being on therapy, and lack of social support. Understanding and addressing these barriers to ART initiation among discordant couples is critical to advancing the HIV "treatment as prevention" agenda. PMID:22866934

  7. Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month ‘proof-of-concept’ study

    PubMed Central

    Owens, D R; Luzio, S D; Sert-Langeron, C; Riddle, M C

    2011-01-01

    Aim Stepwise intensification of insulin treatment to match the progressive decline of endogenous insulin secretion has been shown to be an effective management strategy in type 2 diabetes mellitus (T2DM). The efficacy of initiating and titrating a single bolus dose of insulin glulisine to baseline insulin glargine plus oral hypoglycaemic agents (OHAs) was investigated. Methods This was a 6-month, parallel-group, randomized, open-label, Phase IV study conducted in the US, UK and Russia. People with T2DM (HbA1c 7.5–9.5%) using any basal insulin underwent a 3-month run-in period on insulin glargine titrated to optimize fasting blood glucose (BG) control. Those with HbA1c >7.0% were randomized to either continue prior therapy (n = 57) or to add a single dose of insulin glulisine (n = 49) immediately prior to the main meal for a further 3 months. Two different titration algorithms were employed for the bolus dose, targeting 2-h postprandial BG ≤135 mg/dL (≤7.5 mmol/l; Russia and UK) or pre-meal/bedtime BG 100–120 mg/dl (5.5–6.7 mmol/l; US). Results HbA1c and fasting plasma glucose levels decreased during the run-in period. In the 3 months after randomization, more participants in the basal-plus-bolus group reached HbA1c <7.0% than the basal-only control group (22.4 vs. 8.8%; p < 0.05), with significantly greater reduction of HbA1c (−0.37 vs. −0.11%; p = 0.0290). Rates of hypoglycaemia and mean weight change were comparable between the treatment groups. Conclusions In people with T2DM inadequately controlled on basal insulin plus OHAs, adding a single injection of insulin glulisine prior to the main meal significantly improves glucose control without undesired side effects. PMID:21679291

  8. Human influenza A H5N1 in Indonesia: health care service-associated delays in treatment initiation

    PubMed Central

    2013-01-01

    Background Indonesia has had more recorded human cases of influenza A H5N1 than any other country, with one of the world’s highest case fatality rates. Understanding barriers to treatment may help ensure life-saving influenza-specific treatment is provided early enough to meaningfully improve clinical outcomes. Methods Data for this observational study of humans infected with influenza A H5N1 were obtained primarily from Ministry of Health, Provincial and District Health Office clinical records. Data included time from symptom onset to presentation for medical care, source of medical care provided, influenza virology, time to initiation of influenza-specific treatment with antiviral drugs, and survival. Results Data on 124 human cases of virologically confirmed avian influenza were collected between September 2005 and December 2010, representing 73% of all reported Indonesia cases. The median time from health service presentation to antiviral drug initiation was 7.0 days. Time to viral testing was highly correlated with starting antiviral treatment (p < 0.0001). We found substantial variability in the time to viral testing (p = 0.04) by type of medical care provider. Antivirals were started promptly after diagnosis (median 0 days). Conclusions Delays in the delivery of appropriate care to human cases of avian influenza H5N1 in Indonesia appear related to delays in diagnosis rather than presentation to health care settings. Either cases are not suspected of being H5N1 cases until nearly one week after presenting for medical care, or viral testing and/or antiviral treatment is not available where patients are presenting for care. Health system delays have increased since 2007. PMID:23786882

  9. Learning From Tests: Facilitation of Delayed Recall by Initial Recognition Alternatives.

    ERIC Educational Resources Information Center

    Whitten, William B., II; Leonard, Janet Mauriello

    1980-01-01

    Two experiments were designed to determine the effects of multiple-choice recognition test alternatives on subsequent memory for the correct answers. Results of both experiments are interpreted as demonstrations of the principle that long-term retention is facilitated such that memory evaluation occurs during initial recognition tests. (Author/RD)

  10. 15 CFR 4.10 - Appeals from initial determinations or untimely delays.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... the same level. The DAS shall advise the AGC-Admin, or the General Counsel, as appropriate, of his or..., giving rise to a right of judicial review under 5 U.S.C. 552(a)(6)(C). If the requester initiates a...

  11. Delayed Initiation of the Pharyngeal Swallow: Normal Variability in Adult Swallows

    ERIC Educational Resources Information Center

    Martin-Harris, Bonnie; Brodsky, Martin B.; Michel, Yvonne; Lee, Fu-Shing; Walters, Bobby

    2007-01-01

    Purpose: The purpose of this investigation was to determine bolus head timing and location relations with the onset of hyoid movement at the initiation of the pharyngeal swallow and at the onset of swallow-related apnea. Method: Bolus head timing and location and the timing of swallow-related apnea were recorded from frame-by-frame analyses of…

  12. Medication utilization patterns among type 2 diabetes patients initiating Exenatide BID or insulin glargine: a retrospective database study

    PubMed Central

    2013-01-01

    Background Type 2 diabetes is a common and costly illness, associated with significant morbidity and mortality. Despite this, there is relatively little information on the ‘real-world’ medication utilization patterns for patients with type 2 diabetes initiating exenatide BID or glargine. The objective of this study was to evaluate the ‘real-world’ medication utilization patterns in patients with type 2 diabetes treated with exenatide BID (exenatide) versus insulin glargine (glargine). Methods Adult patients( ≥18 years of age) with type 2 diabetes who were new initiators of exenatide or glargine from October 1, 2006 through March 31, 2008 with continuous enrollment for the 12 months pre- and 18 months post-index period were selected from the MarketScan® Commercial and Medicare Databases. To control for selection bias, propensity score matching was used to complete a 1:1 match of glargine to exenatide patients. Key study outcomes (including the likelihood of overall treatment modification, discontinuation, switching, or intensification) were analyzed using survival analysis. Results A total of 9,197 exenatide- and 4,499 glargine-treated patients were selected. Propensity score matching resulted in 3,774 matched pairs with a mean age of 57 years and a mean Deyo Charlson Comorbidity Index score of 1.6; 54% of patients were males. The 18-month treatment intensification rates were 15.9% and 26.0% (p < 0.0001) and the discontinuation rates were 38.3% and 40.0% (p = 0.14) for exenatide and glargine, respectively. Alternatively, 14.9% of exenatide-treated patients switched therapies, compared to 10.0% of glargine-treated patients (p < 0.0001). Overall, glargine-treated patients were more likely to modify their treatment [hazard ratio (HR) = 1.33, p < 0.0001] with shorter mean time on treatment until modification (123 vs. 159 days, p < 0.0001). Compared to exenatide-treated patients, glargine-treated patients were more likely to

  13. [Delayed diagnosis in a case of granulomatosis with polyangiitis (Wegener's) with initial predominance of joint involvement].

    PubMed

    Macri, Anca; Ulmeanu, Ruxandra; Mihălţan, Florin; Popa, Gabriela; Stoica, Radu

    2014-01-01

    The authors present the case of a 53-year-old female, initially admitted in a rheumatology department for fever and diffuse arthritis--being diagnosed with sero-positive rheumathoid arthritis. Although the chest X-ray and CT scan of thorax showed several abnormal features (medium lobe atelectasis, pseudo-cyst in the posterior segment of the right upper lobe with satellite milliary nodules, mediastinal lymph node enlargement), the investigations performed in our pneumology department couldn't establish the etiology of radiological abnormalities. With non-steroidal antiinflamatory treatment, the patient got worse, being readmitted in our hospital after 3 months for high fever, diffuse arthralgia with functional impairment, small hemoptysis, loss of hearing and left ear ache and on chest X-ray with bilateral macronodules, some of these with cavitation. The investigations showed a slight alveolar hemorrhagic syndrome, positive cANCA antibodies, negative antiCCP antibodies--the diagnosis of Wegener's granulomatosis with lung and ENT involvement being established. Puls-therapy with Solumedrol and i.v. Cyclophosphamide was thereafter initiated with a favorable evolution. This case is special because of the initial misdiagnosis due to the atypical pulmonary manifestations and the non-specific paraclinical findings, in the context of diffuse arthritis with positive rheumatoid factor. PMID:24800597

  14. Experimental warming delays autumn senescence in a boreal spruce bog: Initial results from the SPRUCE experiment

    NASA Astrophysics Data System (ADS)

    Richardson, Andrew; Furze, Morgan; Aubrecht, Donald; Milliman, Thomas; Nettles, Robert; Krassovski, Misha; Hanson, Paul

    2016-04-01

    Phenology is considered one of the most robust indicators of the biological impacts of global change. In temperate and boreal regions, long-term data show that rising temperatures are advancing spring onset (e.g. budburst and flowering) and delaying autumn senescence (e.g. leaf coloration and leaf fall) in a wide range of ecosystems. While warm and cold temperatures, day length and insolation, precipitation and water availability, and other factors, have all been shown to influence plant phenology, the future response of phenology to rising temperatures and elevated CO2 still remains highly uncertain because of the challenges associated with conducting realistic manipulative experiments to simulate future environmental conditions. At the SPRUCE (Spruce and Peatland Responses Under Climatic and Environmental Change) experiment in the north-central United States, experimental temperature (0 to +9° C above ambient) and CO2 (ambient and elevated) treatments are being applied to mature, and intact, Picea mariana-Sphagnum spp. bog communities in their native habitat through the use of ten large (approximately 12 m wide, 10 m high) open-topped enclosures. We are tracking vegetation green-up and senescence in these chambers, at both the individual and whole-community level, using repeat digital photography. Within each chamber, digital camera images are recorded every 30 minutes and uploaded to the PhenoCam (http://phenocam.sr.unh.edu) project web page, where they are displayed in near-real-time. Image processing is conducted nightly to extract quantitative measures of canopy color, which we characterize using Gcc, the green chromatic coordinate. Data from a camera mounted outside the chambers (since November 2014) indicate strong seasonal variation in Gcc for both evergreen shrubs and trees. Shrub Gcc rises steeply in May and June, and declines steeply in September and October. By comparison, tree Gcc rises gradually from March through June, and declines gradually from

  15. Clinical utility of insulin and insulin analogs

    PubMed Central

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  16. Reduction of Delay in Detecting Initial Dips from Functional Near-Infrared Spectroscopy Signals Using Vector-Based Phase Analysis.

    PubMed

    Hong, Keum-Shik; Naseer, Noman

    2016-05-01

    In this paper, we present a systematic method to reduce the time lag in detecting initial dips using a vector-based phase diagram and an autoregressive moving average with exogenous signals (ARMAX) model-based [Formula: see text]-step-ahead prediction algorithm. With functional near-infrared spectroscopy (fNIRS), signals related to mental arithmetic and right-hand clenching are acquired from the prefrontal and left primary motor cortices, respectively. The interrelationship between oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin and cerebral oxygen exchange are related to initial dips. Specifically, a threshold value from the resting state hemodynamics is incorporated, as a decision criterion, into the vector-based phase diagram to determine the occurrence of initial dips. To further reduce the time lag, a [Formula: see text]-step-ahead prediction method is applied to predict the occurrence of the dips. A combination of the threshold criterion and the prediction method resulted in the delay time of about 0.9[Formula: see text]s. The results demonstrate that rapid detection of initial dip is possible and therefore can be used for real-time brain-computer interfacing. PMID:26971785

  17. Factors influencing decision-making role preferences: A qualitative study of Malaysian patients with type 2 diabetes during insulin initiation.

    PubMed

    Lee, Yew Kong; Low, Wah Yun; Lee, Ping Yein; Ng, Chirk Jenn

    2015-05-01

    Patient decision-making role preference (DMRP) is a patient's preferred degree of control when making medical decisions. This descriptive qualitative study aimed to explore Malaysian patients' views on their DMRP. Between January 2011 and March 2012, 22 individual face-to-face in-depth interviews were conducted with patients with type 2 diabetes who were deciding about insulin initiation. The interviews were audio-recorded and analysed using a thematic approach. The age range of participants was 28-67 years old with 11 men. Ten patients preferred to make the decision themselves, six patients indicated that the clinician should make the decision and only one patient expressed a preference for a collaborative role. The following factors influenced DMRP: trust in clinicians, responsibility for diabetes care, level of knowledge and awareness, involvement of family and personal characteristics. In conclusion, the concept of shared decision-making is still alien, and a more participative communication style might help to facilitate patients' expression of DMRP. PMID:24804909

  18. Clinical Predictors for Delayed or Inappropriate Initial Diagnosis of Type A Acute Aortic Dissection in the Emergency Room

    PubMed Central

    Hirata, Kazuhito; Wake, Minoru; Takahashi, Takanori; Nakazato, Jun; Yagi, Nobuhito; Miyagi, Tadayoshi; Shimotakahara, Junichi; Mototake, Hidemitsu; Tengan, Toshiho; Takara, Tsuyoshi R.; Yamaguchi, Yutaka

    2015-01-01

    Background Initial diagnosis of acute aortic dissection (AAD) in the emergency room (ER) is sometimes difficult or delayed. The aim of this study is to define clinical predictors related to inappropriate or delayed diagnosis of Stanford type A AAD. Methods We conducted a retrospective analysis of 127 consecutive patients with type A AAD who presented to the ER within 12 h of symptom onset (age: 69.0 ± 15.4 years, male/female = 49/78). An inappropriate initial diagnosis (IID) was considered if AAD was not included in the differential diagnosis or if chest computed tomography or echocardiography was not performed as initial imaging tests. Clinical variables were compared between IID and appropriate diagnosis group. The time to final diagnosis (TFD) was also evaluated. Delayed diagnosis (DD) was defined as TFD > third quartile. Clinical factors predicting DD were evaluated in comparison with early diagnosis (defined as TFD within the third quartile). In addition, TFD was compared with respect to each clinical variable using a rank sum test. Results An IID was determined for 37% of patients. Walk-in (WI) visit to the ER [odds ratio (OR) 2.6, 95% confidence interval (CI) = 1.01–6.72, P = 0.048] and coronary malperfusion (CM, OR = 6.48, 95% CI = 1.14–36.82, P = 0.035) were predictors for IID. Overall, the median TFD was 1.5 h (first/third quartiles = 0.5/4.0 h). DD (>4.5 h) was observed in 27 cases (21.3%). TFD was significantly longer in WI patients (median and first/third quartiles = 1.0 and 0.5/2.85 h for the ambulance group vs. 3.0 and 1.0/8.0 h for the WI group, respectively; P = 0.003). Multivariate analysis revealed that WI visit was the only predictor for DD (OR = 3.72, 95% CI = 1.39–9.9, P = 0.009). TFD was significantly shorter for appropriate diagnoses than for IIDs (1.0 vs. 6.0 h, respectively; P < 0.0001). Conclusions WI visit to the ER and CM were predictors for IID, and WI was the only predictor for DD in acute type A AAD in the community hospital

  19. Basal insulin treatment in type 2 diabetes.

    PubMed

    Hedrington, Maka S; Pulliam, Lindsay; Davis, Stephen N

    2011-06-01

    Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia. Trials comparing insulin glargine with glucagon-like peptide-1 agonists showed comparable significant reductions in A1c with both regimens. Insulin glargine is well tolerated, has low immunogenicity, reduced risks for acute myocardial infarction, and a lower risk of hypoglycemia compared with NPH insulin in individuals with type 2 diabetes. PMID:21668335

  20. Basal Insulin Treatment in Type 2 Diabetes

    PubMed Central

    Hedrington, Maka S.; Pulliam, Lindsay

    2011-01-01

    Abstract Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia. Trials comparing insulin glargine with glucagon-like peptide-1 agonists showed comparable significant reductions in A1c with both regimens. Insulin glargine is well tolerated, has low immunogenicity, reduced risks for acute myocardial infarction, and a lower risk of hypoglycemia compared with NPH insulin in individuals with type 2 diabetes. PMID:21668335

  1. Development and Implementation of Mass Media Campaigns to Delay Sexual Initiation Among African American and White Youth

    PubMed Central

    NOAR, SETH M.; ZIMMERMAN, RICK S.; PALMGREEN, PHILIP; CUPP, PAMELA K.; FLOYD, BRENIKKI R.; MEHROTRA, PURNIMA

    2015-01-01

    Reducing new HIV/STD infections among at-risk adolescents requires developing and evaluating evidence-based health communication approaches. Research over-whelmingly supports the conclusion that early sexual initiation is associated with STDs and other negative outcomes in later years (e.g., unintended pregnancy). The authors’ research group secured funding from the National Institute of Mental Health to develop, implement, and rigorously evaluate televised mass media campaigns to delay initiation of sexual intercourse among African American and White adolescents in two cities in the Southeastern United States. The focus of the present study is on the development and implementation of the campaigns, including (a) rationale and theoretical underpinnings; (b) collection, screening, and assessment of existing public service announcements; (c) development of new public service announcements; (d) study design and campaign airing plan; and (e) message exposure achieved in the campaigns. Health communication campaigns hold much promise in reaching at-risk adolescent populations with targeted, timely, and relevant risk-reduction messages. PMID:24093220

  2. Insulin therapy in type 2 diabetes.

    PubMed

    Mudaliar, S; Edelman, S V

    2001-12-01

    Type 2 diabetes is a common disorder often accompanied by numerous metabolic abnormalities leading to a high risk of cardiovascular morbidity and mortality. Results from the UKPDS have confirmed that intensive glucose control delays the onset and retards the progression of microvascular disease and possibly of macrovascular disease in patients with type 2 diabetes. In the early stages of the disease, insulin resistance plays a major role in the development of hyperglycemia and other metabolic abnormalities, and patients with type 2 diabetes often benefit from measures to improve insulin sensitivity such as weight loss, dietary changes, and exercise. Later, the use of oral insulin secretagogues and insulin sensitizers as monotherapy and in combination helps maintain glycemia for varying periods of time. Ultimately, because of the progressive nature of the disease and the progressive decline in pancreatic beta-cell function, insulin therapy is almost always obligatory to achieve optimal glycemic goals. Not all patients are candidates for aggressive insulin management; therefore, the goals of therapy should be modified, especially in elderly individuals and those with co-morbid conditions. Candidates for intensive management should be motivated, compliant, and educable, without other major medical conditions and physical limitations that would preclude accurate and reliable HGM and insulin administration. In selected patients, combination therapy with insulin and oral antidiabetic medications can be an effective method for normalizing glycemia without the need for rigorous multiple-injection regimens. The patients for whom combination therapy is most commonly successful are those who do not achieve adequate glycemic control using daytime oral agents but who still show some evidence of responsiveness to the medications. Bedtime intermediate-acting or predinner premixed intermediate- and rapid-acting insulin is administered and progressively increased until the FPG

  3. Inflammation and Insulin Resistance

    PubMed Central

    de Luca, Carl; Olefsky, Jerrold M.

    2008-01-01

    Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. PMID:18053812

  4. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

    PubMed Central

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-01-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  5. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus.

    PubMed

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-11-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal-bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  6. The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians

    PubMed Central

    Chiu, Ken C; Chuang, Lee-Ming; Yoon, Carol

    2001-01-01

    Background Although vitamin D receptor (VDR) polymorphisms have been shown to be associated with abnormal glucose metabolism, the reported polymorphisms are unlikely to have any biological consequences. The VDR gene has two potential translation initiation sites. A T-to-C polymorphism has been noted in the first ATG (f allele), abolishing the first translation initiation site and resulting in a peptide lacking the first three amino acids (F allele). We examined the role of this polymorphism in insulin sensitivity and beta cell function. This study included 49 healthy Caucasian subjects (28 females, age 28 ± 1 years old, body mass index 24.57 ± 0.57 kg/m2, waist-hip ratio 0.81 ± 0.01 cm/cm). They were all normotensive (less than 140/90 mmHg) and glucose tolerant, which was determined by a standard 75-gm oral glucose tolerance test. Their beta cell function (%B) and insulin sensitivity (%S) were calculated based on the Homeostasis Model Assessment (HOMA). Their genotypes were determined by a polymerase chain reaction-restriction fragment length polymorphism analysis. Phenotypes were compared between genotypic groups. Results There were 18 FF, 21 Ff, and 10 ff subjects. Since only 10 ff subjects were identified, they were pooled with the Ff subjects during analyses. The FF and Ff/ff groups had similar glucose levels at each time point before and after a glucose challenge. The Ff/ff group had higher insulin levels than the FF group at fasting (P=0.006), 30 minutes (P=0.009), 60 minutes (P=0.049), and 90 minutes (P=0.042). Furthermore, the Ff/ff group also had a larger insulin area under the curve than the FF group (P=0.009). While no difference was noted in %B, the Ff/ff group had a lower %S than the FF group (0.53 vs. 0.78, P=0.006). A stepwise regression analysis confirmed that the Fok I polymorphism was an independent determinant for %S, accounting for 29.3% of variation in %S when combined with waist-hip ratio. Conclusions We report that the Fok I polymorphism

  7. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial

    PubMed Central

    Grinsztejn, Beatriz; Hosseinipour, Mina C; Ribaudo, Heather J; Swindells, Susan; Eron, Joseph; Chen, Ying Q; Wang, Lei; Ou, San-San; Anderson, Maija; McCauley, Marybeth; Gamble, Theresa; Kumarasamy, Nagalingeshwaran; Hakim, James G; Kumwenda, Johnstone; Pilotto, Jose H S; Godbole, Sheela V; Chariyalertsak, Suwat; de Melo, Marineide Gonçalves; Mayer, Kenneth H; Eshleman, Susan H; Piwowar-Manning, Estelle; Makhema, Joseph; Mills, Lisa A; Panchia, Ravindre; Sanne, Ian; Gallant, Joel; Hoffman, Irving; Taha, Taha E; Nielsen-Saines, Karin; Celentano, David; Essex, Max; Havlir, Diane; Cohen, Myron S

    2014-01-01

    Summary Background Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. Methods The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. Findings 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373–522) cells per μL in patients assigned to the early treatment group and 428 (357–522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group

  8. Initial Accuracy of HIV Rapid Test Kits Stored in Suboptimal Conditions and Validity of Delayed Reading of Oral Fluid Tests

    PubMed Central

    Choko, Augustine T.; Taegtmeyer, Miriam; MacPherson, Peter; Cocker, Derek; Khundi, McEwen; Thindwa, Deus; Sambakunsi, Rodrick S.; Kumwenda, Moses K.; Chiumya, Kondwani; Malema, Owen; Makombe, Simon D.; Webb, Emily L.; Corbett, Elizabeth L.

    2016-01-01

    Objectives To evaluate the effect of storing commonly used rapid diagnostic tests above manufacturer-recommended temperature (at 37°C), and the accuracy of delayed reading of oral fluid kits with relevance to HIV self-testing programmes. Design A quality assurance study of OraQuick (OraSure), Determine HIV 1/2™ (Alere) and Uni-Gold™ (Recombigen®). Methods Consecutive adults (≥18y) attending Ndirande Health Centre in urban Blantyre, Malawi in January to April 2012 underwent HIV testing with two of each of the three rapid diagnostic test kits stored for 28 days at either 18°C (optimally-stored) or at 37°C (pre-incubated). Used OraQuick test kits were stored in a laboratory for delayed day 1 and subsequent monthly re-reading was undertaken for one year. Results Of 378 individuals who underwent parallel testing, 5 (1.3%) were dropped from the final analysis due to discordant or missing reference standard results (optimally-stored Determine and Uni-Gold). Compared to the diagnostic reference standard, OraQuick had a sensitivity of 97.2% (95% CI: 93.6–99.6). There were 7 false negative results among all test kits stored at 37°C and three false negatives among optimally stored kits. Excellent agreement between pre-incubated tests and optimally-stored tests with Kappa values of 1.00 for Determine and Uni-Gold; and 0.97 (95% CI: 0.95; 1.00) for OraQuick were observed. There was high visual stability on re-reading of OraQuick, with only 1/375 pre-incubated and 1/371 optimally-stored OraQuick kits changing from the initial result over 12 months. Conclusion Erroneous results observed during HIV testing in low income settings are likely to be due to factors other than suboptimal storage conditions. Re-reading returned OraQuick kits may offer a convenient and accurate quality assurance approach, including in HIV self-testing programmes. PMID:27336161

  9. Delays in hiring Air Traffic Collegiate Training Initiative (AT-CTI) graduates and the impact on their training success rate

    NASA Astrophysics Data System (ADS)

    Jorgenson, Terra A.

    This research project identified three distinct groups of individuals the Federal Aviation Administration (FAA) utilizes when filling the employee ranks of Air Traffic Controllers (ATC). After a nationwide strike, President Reagan fired the entire ATC workforce in 1981 (Pavel, 2012). Since then the FAA has worked very diligently in filling the vacant positions. Now three decades later the impending retirements and attrition of those hired earlier is estimated at nearly 14,000 controllers over the next 10 years (FAA CWP, 2012). In response to this shortage it would be advantageous for the FAA to minimize the time lapsed in the selection, hiring and training processes. If the hiring process time was decreased, it would save the FAA money in terms of a reduction in the initial cost of training Air Traffic Controllers (GAO, 2012; IRP, 2011). Traditionally the FAA hires from three distinct groups of people. The first is those with prior ATC experience which was usually obtained through the military. Second the general public with no experience and third the Air Traffic Collegiate Training Initiative (AT-CTI) candidates. The AT-CTI program is a valued partner with the FAA that helps educate the next generation of Air Traffic Controllers; however in the past the program has had difficulty producing the total number of replacement controllers needed. Due to the delay some CTI graduates may choose other career paths rather than wait and be hired to go to the FAA Academy which will further reduce the number of candidates for the FAA to hire. To date, no public research has been done pertaining to the time delay in the hiring process of AT-CTI candidates and the impact on training success at the FAA Academy and at the CTI's first FAA facility. This study used a survey tool to gather information on how long AT-CTI graduates wait to be hired to attend the FAA Academy. Information was gathered on the factors that may affect the time lapse between graduation and the time they

  10. Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer.

    PubMed

    Gallagher, Christopher M; More, Kenneth; Kamath, Tripthi; Masaquel, Anthony; Guerin, Annie; Ionescu-Ittu, Raluca; Gauthier-Loiselle, Marjolaine; Nitulescu, Roy; Sicignano, Nicholas; Butts, Elizabeth; Wu, Eric Q; Barnett, Brian

    2016-05-01

    Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS. PMID:27107569

  11. The role of islet antigen presenting cells and the presentation of insulin in the initiation of autoimmune diabetes in the NOD mouse.

    PubMed

    Unanue, Emil R; Ferris, Stephen T; Carrero, Javier A

    2016-07-01

    We have been examining antigen presentation and the antigen presenting cells (APCs) in the islets of Langerhans of the non-obese diabetic (NOD) mouse. The purpose is to identify the earliest events that initiate autoimmunity in this confined tissue. Islets normally have a population of macrophages that is distinct from those that inhabit the exocrine pancreas. Also found in NOD islets is a minor population of dendritic cells (DCs) that bear the CD103 integrin. We find close interactions between beta cells and the two APCs that result in the initiation of the autoimmunity. Even under non-inflammatory conditions, beta cells transfer insulin-containing vesicles to the APCs of the islet. This reaction requires live cells and intimate contact. The autoimmune process starts in islets with the entrance of CD4(+) T cells and an increase in the CD103(+) DCs. Mice deficient in the Batf3 transcription factor never develop diabetes due to the absence of the CD103/CD8α lineage of DCs. We hypothesize that the 12-20 peptide of the beta chain of insulin is responsible for activation of the initial CD4(+) T-cell response during diabetogenesis. PMID:27319351

  12. Insulin-stimulated kinase from rat fat cells that phosphorylates initiation factor 4E-binding protein 1 on the rapamycin-insensitive site (serine-111).

    PubMed Central

    Heesom, K J; Avison, M B; Diggle, T A; Denton, R M

    1998-01-01

    The effects of insulin and rapamycin on the phosphorylation of the translation regulator, initiation factor 4E-binding protein 1 (4E-BP1) have been studied in rat fat cells by following changes in the incorporation of 32P from [32P]Pi under steady-state conditions. Both unbound 4E-BP1 and 4E-BP1 bound to eukaryotic initiation factor 4E (eIF4E) were isolated from the cells and then digested with trypsin and other proteases; the radiolabelled phosphopeptides were then separated by two-dimensional thin- layer analysis and HPLC. The results provide confirmation of the conclusion of Fadden, Haystead and Lawrence [J. Biol. Chem. (1997) 272, 10240-10247] that insulin increases the phosphorylation of four sites that fit a Ser/Thr-Pro motif (Thr-36, Thr-45, Ser-64 and Thr-69) and that taken together these phosphorylations result in the dissociation of 4E-BP1 from eIF4E. The effects of insulin on the phosphorylation of these sites, and hence dissociation from eIF4E, are blocked by rapamycin. However, the present study also provides evidence that insulin increases the phosphorylation of 4E-BP1 bound to eIF4E on a further site (Ser-111) and that this is by a rapamycin-insensitive mechanism. Extraction of rat epididymal fat cells followed by chromatography on Mono-S and Superose 12 columns resulted in the separation of both an insulin-stimulated eIF4E kinase and an apparently novel kinase that is highly specific for Ser-111 of 4E-BP1. The 4E-BP1 kinase was activated more than 10-fold by incubation of the cells with insulin and was markedly more active towards 4E-BP1 bound to eIF4E than towards unbound 4E-BP1. The effects of insulin were blocked by wortmannin, but not by rapamycin. A 14-mer peptide based on the sequence surrounding Ser-111 of 4E-BP1 was also a substrate for the kinase, but peptide substrates for other known protein kinases were not. The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these

  13. Haploinsufficiency in the prometastasis Kiss1 Receptor Gpr54 delays breast tumor initiation, progression and lung metastasis

    PubMed Central

    Cho, Sung-Gook; Wang, Ying; Rodriguez, Melissa; Tan, Kunrong; Zhang, Wenzheng; Luo, Jian; Li, Dali; Liu, Mingyao

    2016-01-01

    Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1-induced KISS1R signaling is known to inhibit tumor angiogenesis and metastasis. However, roles of KISS1 and KISS1R in earlier stages of tumor progression and metastasis in vivo are still unknown. In this study, we demonstrate a critical role for Kiss1r in early stages of tumor progression using mouse tumor models. PyMT/Kiss1r mice with different Kiss1r genotypes were obtained by crossing MMTV-PyMT transgenic mouse with Kiss1r heterozygous mouse (Kiss1r+/−). Kiss1r heterozygosity attenuated breast tumor initiation, growth, latency, multiplicity and metastasis in MMTV-PyMT/Kiss1r+/− mouse models. To confirm the effects of Kiss1r in tumor progression and limit any effect of endogenous hormones, we isolated primary tumor cells from PyMT/Kiss1r+/+ or PyMT/Kiss1r+/− mice and performed in vitro and in vivo tumorigenesis assays. Kiss1r heterozygosity inhibited PyMT-induced in vitro tumorigeneity and in vivo tumor growth in NOD.SCID/NCr mice. To understand the underlying mechanism, we showed that activation of KISS1R by kisspeptin-10 led to RhoA activation and RhoA-dependent gene expression through Gαq-p63RhoGEF signaling pathway. Furthermore, anchorage-independent growth was tightly linked to the dosage-dependent regulation of RhoA by KISS1R. When MCF10A cells overexpressing H-RasV12 were subjected to in vitro tumorigenesis assays, knockdown of KISS1R or inactivation of RhoA in MCF10A cells reduced Ras-induced anchorage-independent growth, similar to our data obtained from PyMT-Kiss1r+/− mouse models. Altogether, we conclude that Kiss1r haploinsufficiency delays breast tumor initiation, progression and metastasis through its downstream Gαq-p63RhoGEF-RhoA signaling pathway. PMID:21852382

  14. Delay and failure in treatment seeking after first onset of mental disorders in the World Health Organization's World Mental Health Survey Initiative

    PubMed Central

    WANG, PHILIP S; ANGERMEYER, MATTHIAS; BORGES, GUILHERME; BRUFFAERTS, RONNY; TAT CHIU, WAI; DE GIROLAMO, GIOVANNI; FAYYAD, JOHN; GUREJE, OYE; HARO, JOSEP MARIA; HUANG, YUEQIN; KESSLER, RONALD C; KOVESS, VIVIANE; LEVINSON, DAPHNA; NAKANE, YOSHIBUMI; OAKLEY BROWN, MARK A; ORMEL, JOHAN H; POSADA-VILLA, JOSÉ; AGUILAR-GAXIOLA, SERGIO; ALONSO, JORDI; LEE, SING; HEERINGA, STEVEN; PENNELL, BETH-ELLEN; CHATTERJI, SOMNATH; ÜSTÜN, T. BEDIRHAN

    2007-01-01

    Data are presented on patterns of failure and delay in making initial treatment contact after first onset of a mental disorder in 15 countries in the World Health Organization (WHO)'s World Mental Health (WMH) Surveys. Representative face-to-face household surveys were conducted among 76,012 respondents aged 18 and older in Belgium, Colombia, France, Germany, Israel, Italy, Japan, Lebanon, Mexico, the Netherlands, New Zealand, Nigeria, People's Republic of China (Beijing and Shanghai), Spain, and the United States. The WHO Composite International Diagnostic Interview (CIDI) was used to assess lifetime DSM-IV anxiety, mood, and substance use disorders. Ages of onset for individual disorders and ages of first treatment contact for each disorder were used to calculate the extent of failure and delay in initial help seeking. The proportion of lifetime cases making treatment contact in the year of disorder onset ranged from 0.8 to 36.4% for anxiety disorders, from 6.0 to 52.1% for mood disorders, and from 0.9 to 18.6% for substance use disorders. By 50 years, the proportion of lifetime cases making treatment contact ranged from 15.2 to 95.0% for anxiety disorders, from 7.9 to 98.6% for mood disorders, and from 19.8 to 86.1% for substance use disorders. Median delays among cases eventually making contact ranged from 3.0 to 30.0 years for anxiety disorders, from 1.0 to 14.0 years for mood disorders, and from 6.0 to 18.0 years for substance use disorders. Failure and delays in treatment seeking were generally greater in developing countries, older cohorts, men, and cases with earlier ages of onset. These results show that failure and delays in initial help seeking are pervasive problems worldwide. Interventions to ensure prompt initial treatment contacts are needed to reduce the global burdens and hazards of untreated mental disorders. PMID:18188443

  15. OVEREXPRESSION OF DES(1-3) INSULIN-LIKE GROWTH FACTOR 1 IN THE MAMMARY GLANDS OF TRANSGENIC MICE DELAYS THE LOSS OF MILK PRODUCTION WITH PROLONGED LACTATION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During prolonged lactation, the mammary gland gradually loses the capacity to produce milk. In agricultural species, this decline can be slowed by administration of exogenous growth hormone (GH), which is believed to act through insulin-like growth factor 1 (IGF1). Our previous work demonstrated del...

  16. What options are available when considering starting insulin: premix or basal?

    PubMed

    Lavernia, Frank

    2011-06-01

    Several large studies in diabetes have shown that early initiation of intensive therapy is better for the prevention of long-term complications and suggest that patients with more advanced disease may be at increased risk of adverse cardiovascular events. Despite these findings, insulin initiation is often delayed in patients with type 2 diabetes, typically until A1C exceeds 8.5%. Barriers to the use of insulin are many, arising from both a patient and a physician perspective, and the decision to initiate insulin treatment can be influenced by cost, risk of hypoglycemia, convenience, and the potential for weight gain. Choosing when to initiate insulin and which insulin/treatment regimen to adopt in patients with type 2 diabetes is key, and the importance of tailoring treatment to the patient is widely acknowledged. However, there is currently no universal consensus on the optimal course of action. Once-daily basal insulin and twice-daily premix insulin are commonly used for insulin initiation. Relatively few studies have directly compared these starter treatment regimens, although general findings suggest that, although glycemic control appears to be similar with once-daily basal insulin and twice-daily premix, the lower hypoglycemia rates, lower weight gain, simplicity, and convenience associated with basal insulin support its first-line use as a starter insulin regimen in patients failing on oral antidiabetes agents. Variables such as age, body mass index, and bedtime or post-breakfast plasma glucose levels may alter the efficacy of the chosen treatment regimen, further supporting the need to tailor treatment to meet individual patient's requirements. PMID:21668341

  17. The Impact of Initiating Biphasic Human Insulin 30 Therapy in Type 2 Diabetes Patients After Failure of Oral Antidiabetes Drugs

    PubMed Central

    Gu, Yunjuan; Hou, Xuhong; Zhang, Lei; Pan, Jiemin; Cai, Qingxia; Bao, Yuqian

    2012-01-01

    Abstract Background The present study evaluated the efficacy of biphasic human insulin 30 (BHI 30) in type 2 diabetes patients who had failed in therapy with two or more oral antidiabetes drugs (OADs). Methods This open-label, nonrandomized, 4-month, multicenter, clinical observational study was conducted in Shanghai, China. A total of 660 insulin-naive type 2 diabetes patients with poor glycemic control (glycosylated hemoglobin [HbA1c] ≥7.5%), despite treatment with two or more OADs for more than 6 months, were recruited and received BHI 30 monotherapy or BHI 30 plus OAD(s) (metformin only, α-glucosidase inhibitor only, or both). Results Among the 660 subjects, 644 completed the 4-month study. At the end of the study, the median level of HbA1c decreased by 2.0% (from 9.1% to 7.0%) in the BHI 30 monotherapy group and also 2.0% (from 9.5% to 7.3%) in the BHI 30 plus OAD group. More patients achieved the HbA1c <7.0% target in the BHI 30 monotherapy group than in the BHI 30 plus OAD(s) group (47.9% vs. 35.3%, P=0.002). Compared with the expenses of the prior treatment strategy, the median daily cost decreased by 39.8% (4.5 yuan, Chinese RMB) at the end point in the BHI 30 monotherapy group but increased by 20.0% (2.2 yuan) in the BHI 30 plus OAD(s) group (P<0.0001). Moreover, patients in the BHI 30 plus OAD(s) group had fewer minor hypoglycemic episodes than in the BHI 30 monotherapy group (mean of 1.06 vs. 2.77 per patient per year, P<0.0001). Conclusions Short-term BHI 30 therapy can improve glycemic control in insulin-naive type 2 diabetes patients after failure of two or more OADs. With higher baseline glucose level, the BHI 30 plus OAD(s) group had lower pharmacoeconomic efficacy than the BHI 30 monotherapy group despite having fewer hypoglycemia events. PMID:22047050

  18. Utilization of a Cloud-Based Diabetes Management Program for Insulin Initiation and Titration Enables Collaborative Decision Making Between Healthcare Providers and Patients

    PubMed Central

    Lau, Ka Hei Karen; Huang, Ruyi; Ghiloni, Suzanne; Le, Hung; Gilroy, Scott; Abrahamson, Martin; Moore, John

    2016-01-01

    Abstract Background: Overseeing proper insulin initiation and titration remains a challenging task in diabetes care. Recent advances in mobile technology have enabled new models of collaborative care between patients and healthcare providers (HCPs). We hypothesized that the adoption of such technology could help individuals starting basal insulin achieve better glycemic control compared with standard clinical practice. Materials and Methods: This was a 12 ± 2-week randomized controlled study with 40 individuals with type 2 diabetes who were starting basal insulin due to poor glycemic control. The control group (n = 20) received standard face-to-face care and phone follow-up as needed in a tertiary center, whereas the intervention group (n = 20) received care through the cloud-based diabetes management program where regular communications about glycemic control and insulin doses were conducted via patient self-tracking tools, shared decision-making interfaces, secure text messages, and virtual visits (audio, video, and shared screen control) instead of office visits. Results: By intention-to-treat analysis, the intervention group achieved a greater hemoglobin A1c decline compared with the control group (3.2 ± 1.5% vs. 2.0% ± 2.0%; P = 0.048). The Diabetes Treatment Satisfaction Questionnaire showed a significant improvement in the intervention group compared with the control group (an increase of 10.1 ± 11.7 vs. 2.1 ± 6.5 points; P = 0.01). HCPs spent less time with patients in the intervention group compared with those in the control group (65.9 min per subject vs. 81.6 min per subject). However, the intervention group required additional training time to use the mobile device. Conclusions: Mobile health technology could be an effective tool in sharing data, enhancing communication, and improving glycemic control while enabling collaborative decision making in diabetes care. PMID:26645932

  19. Elevation of the plasma level of insulin-like growth factor-I with reproductive maturation prior to initiation of spawning migration of chum salmon.

    PubMed

    Onuma, Takeshi A; Makino, Keita; Ban, Masatoshi; Ando, Hironori; Fukuwaka, Masa-aki; Azumaya, Tomonori; Swanson, Penny; Urano, Akihisa

    2009-04-01

    When, where, and how oceanic chum salmon initiate spawning migration is unknown although gonadal development and elevation of the activity of the pituitary-gonadal axis (PG-axis) are essential. Insulin-like growth factor-I (IGF-I) is a somatotropic signal that interacts with the PG-axis for gametogenesis. We thus examined the plasma level of IGF-I in immature and maturing chum salmon in the Bering Sea and the Gulf of Alaska. The maturing adults which had maturing gonads left the Bering Sea for the natal river by the end of summer, because almost all fish were immature in September. The plasma level of IGF-I and corresponding body size in the maturing adults were two- to threefold that of immature fish. The plasma IGF-I level correlated positively with the pituitary contents of follicle-stimulating hormone and the plasma levels of 11-ketotestosterone and estradiol-17beta. Therefore, the plasma level of IGF-I increased with elevation of the PG-axis activity prior to the initiation of spawning migration from the Bering Sea. Circulatory IGF-I from visceral organs may inform the status of body growth to the PG-axis for gonadal development that is inseparable from decision of chum salmon whether to initiate homing behavior from the Bering Sea or not to initiate spawning migration by the coming spawning season. PMID:19456398

  20. Insulin formulations--a review.

    PubMed

    Gualandi-Signorini, A M; Giorgi, G

    2001-01-01

    Although the improvement on insulin therapy since it was first conceived, it is still far from mimicking physiological secretion of pancreatic b-cells and research to find new insulin formulations and new routes of administration continues. Human biosynthetic insulin (rapid-acting, intermediate-acting and long-acting), produced by recombinant DNA technique, is currently available. The pharmacokinetic profile of rapid-acting insulin (regular) does not adequately reproduce the physiological post-prandial insulin response. This has led to the development of molecular analogues with slight modifications that prevent the spontaneous polymerisation underlying delayed absorption. Fast-acting analogues such as Lyspro and Aspart can be injected immediately before the meal, inducing a very fast and substantial peak of insulin, similar to that produced by b-cells, but have the disadvantage of short duration of action. For this reason, and because of the difficulty of obtaining sufficient basal insulin concentrations to control preprandial blood glucose levels with current long-acting insulins, analogues known as Glargine and Detemir have been synthesized. They have virtually no plasma peak and acts for about 24 h. These characteristics make it ideal to cover basal insulin requirement. With insulin analogues, it also seems possible to overcome the problem of intra- and inter-individual variability in absorption after subcutaneous injection. This variability is directly proportional to the duration of insulin action. Research into new routes of administration has led to production of inhaled insulin powder, soon to become commercially available. Insulin is absorbed through the lung alveoli. Trials to evaluate efficacy and toleration have shown that inhaled insulin has a similar kinetic profile to the fast-acting injected analogue and can therefore be used for mealtime requirement, combined with a single daily injection of long-acting insulin. Oral insulin is currently being

  1. Cigarette Demand and Delayed Reward Discounting in Nicotine Dependent Individuals with Schizophrenia and Controls: An Initial Study

    PubMed Central

    MacKillop, James; Tidey, Jennifer W.

    2012-01-01

    Rationale The high prevalence of smoking and low cessation rates among individuals with schizophrenia and similar conditions are not well understood. Behavioral economics has been extensively applied to studying addictive behavior and may contribute to understanding smoking in this subpopulation. Objectives This study compared smokers with schizophrenia or schizoaffective disorder (SS) and control smokers (CS) on indices of cigarette demand and delayed reward discounting, a behavioral economic index of impulsivity. Materials and methods The SS (n = 25) and CS (n = 24) groups participated in two sessions approximately one week apart. During the first session, delay discounting was assessed using the Monetary Choice Questionnaire. During the second session, participants smoked their usual brand ad libitum through a smoking topography assessment device, after which cigarette demand was assessed using a cigarette purchase task. Primary comparisons were of the hyperbolic discounting function, k, and indices of cigarette demand. Results Compared to the CS group, the SS group exhibited significantly higher intensity of demand, and significantly greater consumption and expenditure across the inelastic portion of the demand curve, but no differences were evident on the other demand indices. No differences were evident for delay discounting. The SS group also exhibited heavier smoking topography and two indices of smoking topography were significantly correlated with demand. Conclusions These results provide further evidence of higher incentive value of cigarettes among SS individuals, but not greater impulsivity, as measured by discounting. Considerations include potentially important methodological factors and the role of satiation/withdrawal. PMID:21327760

  2. Initiation of insulin aspart to Indian subjects on OADs show significant improvement in glycaemic outcomes: the A1chieve observational study.

    PubMed

    Rao, P V; Bhattacharyya, A; Sahay, R K

    2013-01-01

    The prevalence of diabetes is increasing worldwide and India stands second next only to china. The management of diabetes in real life settings needs to be evaluated for deriving better management practices. A1chieve observational study evaluated the use of modern insulin in real life settings. This was a 24-week, international, prospective, multicenter, non-interventional, observational study of people with type 2 diabetes. India recruited with 20,554 subjects and a total of 1815 patients were enrolled to receive insulin aspart as bolus insulin therapy of whom 1450 (79.9%) were insulin naïve and 365 (20.1%) were insulin users. At the end of 24 weeks, only one SAE was reported in this study and overall hypoglycemia events per patient year decreased from 2.49 (348 episodes) to 0.17 (20 episodes). There were no major hypoglycemic episodes reported in either insulin naive or insulin treated subjects. There was a significant improvement in the HbA(1c) values from the baseline in both insulin naive and insulin users. The mean HbA(1c) value was reduced from 9.5 to 7.4 (p < 0.001) for insulin naïve subjects and from 9.2 to 7.7 (p < 0.001) in insulin experienced subjects. Fasting plasma glucose values decreased by 70 mg/dL and 50 mg/dL in insulin naive and insulin experienced, respectively and the difference from baseline was statistically significant (P < 0.001). The post prandial glucose value was also significantly (p < 0.001) reduced by 105 mg/dL for insulin naïve subjects and 55 mg/dL for insulin experienced subjects. The composite end point was achieved by 46.6% of insulin naive and 38.1% of insulin-experienced subjects. The study concluded with good HbA(1c) reduction along with lower incidence of hypoglycemia and better health related quality of life outcomes in both in insulin naive and insulin experienced subjects who used insulin aspart as bolus insulin treatment. PMID:24482983

  3. Stepwise intensification of insulin therapy in Type 2 diabetes management—exploring the concept of the basal-plus approach in clinical practice

    PubMed Central

    Owens, D R

    2013-01-01

    Basal insulin provides an effective method for initiating insulin therapy in people with Type 2 diabetes, resulting in significant improvements in glycaemic control, lower rates of hypoglycaemia and less weight gain than either prandial or premixed insulin regimens. However, the progressive nature of Type 2 diabetes and the inability of basal insulin to correct excessive postprandial glucose excursions mean that insulin therapy will eventually need to be intensified, typically by adding prandial insulin as part of a basal–bolus or premixed insulin regimen. The aim of this review is to summarize recent clinical evidence for a staged ‘basal-plus’ strategy for insulin intensification where one, two or three prandial insulin injections are added to basal insulin according to individual need. In the early stages of insulin therapy, most individuals seem to achieve favourable glycaemic control with basal insulin alone, or in combination with a single prandial insulin injection. The addition of a single prandial insulin injection at the largest meal is well tolerated and associated with significant improvements in glycated haemoglobin (HbA1c), low rates of hypoglycaemia and limited weight gain. More people achieve recommended HbA1c targets with a basal-plus strategy, compared with twice-daily premixed insulin therapy, with lower rates of hypoglycaemia. The data indicate that a step-by-step approach with the basal-plus strategy is a promising alternative method of insulin intensification that allows for individualization of treatment and may delay progression to a full basal–bolus insulin replacement therapy for many individuals. PMID:22998363

  4. Optimizing Care and Outcomes for People with Type 2 Diabetes – Lessons from a Translational Research Program on Insulin Initiation in General Practice

    PubMed Central

    Furler, John; Blackberry, Irene; Manski-Nankervis, Jo-Anne; O’Neal, David; Best, James; Young, Doris

    2015-01-01

    Background: Clinical inertia, failure to intensify treatment according to evidence-based guidelines, leads to prolonged, avoidable hyperglycemia in people with type 2 diabetes (T2D). This is a challenge for General Practice and Primary Care, where most people with T2D receive most of their care. Sustained, integrated translational research programs are needed to embed effective treatments in routine practice, yet many challenges exist for developing such programs. Objectives: To explore challenges and facilitators to implementing a translational research program focused on insulin initiation and titration among people with T2D in general practice and to identify key factors important to support and sustain such translation research in primary care. Operationalizing a program of translational work in primary care: We describe a series of studies on insulin initiation and titration in general practice including theory and qualitative work (Phase 1), a small feasibility and acceptability pilot (Phase 2), a large scale pilot (Phase 3), and a pragmatic cluster randomized trial currently under way (Phase 4). We used mixed methods to explore practice level implementation issues, and reflective investigator discussions to explore broader research program sustainability. Challenges for translational research in primary care: Key facilitators and barriers at practice and research program levels, include: Appropriate funding structures to secure long-term capacity building and people support; Building and maintaining linkages between communities of practice, primary and secondary/tertiary care researchers, institutions, and industry partners; Strategies for engagement and support for practitioners and participants. Conclusion: Building effective and sustainable translational research programs are critical for developing evidence-based policy that drives improved outcomes at a population level. Diverse sources of funding that support extensive and sustained trans

  5. Initial design and physical characterization of a polymeric device for osmosis-driven delayed burst delivery of vaccines.

    PubMed

    Melchels, Ferry P W; Fehr, Ingo; Reitz, Annika S; Dunker, Urip; Beagley, Kenneth W; Dargaville, Tim R; Hutmacher, Dietmar W

    2015-09-01

    Achieving the combination of delayed and immediate release of a vaccine from a delivery device without applying external triggers remains elusive in implementing single administration vaccination strategies. Here a means of vaccine delivery is presented, which exploits osmosis to trigger delayed burst release of an active compound. Poly(ε-caprolactone) capsules of 2 mm diameter were prepared by dip-coating, and their burst pressure and release characteristics were evaluated. Burst pressures (in bar) increased with wall thickness (t in mm) following Pburst  = 131(.) t + 3(.) 4 (R(2)  = 0.93). Upon immersion in PBS, glucose solution-filled capsules burst after 8.7 ± 2.9 days. Copolymers of hydrophobic ε -caprolactone and hydrophilic polyethylene glycol were synthesized and their physico-chemical properties were assessed. With increasing hydrophilic content, the copolymer capsules showed increased water uptake rates and maximum weight increase, while the burst release was earlier: 5.6 ± 2.0 days and 1.9 ± 0.2 days for 5 and 10 wt% polyethylene glycol, respectively. The presented approach enables the reproducible preparation of capsules with high versatility in materials and properties, while these vaccine delivery vehicles can be prepared separately from, and independently of the active compound. PMID:25787134

  6. Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial

    PubMed Central

    Bakitas, Marie A.; Tosteson, Tor D.; Li, Zhigang; Lyons, Kathleen D.; Hull, Jay G.; Li, Zhongze; Dionne-Odom, J. Nicholas; Frost, Jennifer; Dragnev, Konstantin H.; Hegel, Mark T.; Azuero, Andres; Ahles, Tim A.

    2015-01-01

    Purpose Randomized controlled trials have supported integrated oncology and palliative care (PC); however, optimal timing has not been evaluated. We investigated the effect of early versus delayed PC on quality of life (QOL), symptom impact, mood, 1-year survival, and resource use. Patients and Methods Between October 2010 and March 2013, 207 patients with advanced cancer at a National Cancer Institute cancer center, a Veterans Affairs Medical Center, and community outreach clinics were randomly assigned to receive an in-person PC consultation, structured PC telehealth nurse coaching sessions (once per week for six sessions), and monthly follow-up either early after enrollment or 3 months later. Outcomes were QOL, symptom impact, mood, 1-year survival, and resource use (hospital/intensive care unit days, emergency room visits, chemotherapy in last 14 days, and death location). Results Overall patient-reported outcomes were not statistically significant after enrollment (QOL, P = .34; symptom impact, P = .09; mood, P = .33) or before death (QOL, P = .73; symptom impact, P = .30; mood, P = .82). Kaplan-Meier 1-year survival rates were 63% in the early group and 48% in the delayed group (difference, 15%; P = .038). Relative rates of early to delayed decedents' resource use were similar for hospital days (0.73; 95% CI, 0.41 to 1.27; P = .26), intensive care unit days (0.68; 95% CI, 0.23 to 2.02; P = .49), emergency room visits (0.73; 95% CI, 0.45 to 1.19; P = .21), chemotherapy in last 14 days (1.57; 95% CI, 0.37 to 6.7; P = .27), and home death (27 [54%] v 28 [47%]; P = .60). Conclusion Early-entry participants' patient-reported outcomes and resource use were not statistically different; however, their survival 1-year after enrollment was improved compared with those who began 3 months later. Understanding the complex mechanisms whereby PC may improve survival remains an important research priority. PMID:25800768

  7. Insulin, Aging, and the Brain: Mechanisms and Implications

    PubMed Central

    Akintola, Abimbola A.; van Heemst, Diana

    2015-01-01

    There is now an impressive body of literature implicating insulin and insulin signaling in successful aging and longevity. New information from in vivo and in vitro studies concerning insulin and insulin receptors has extended our understanding of the physiological role of insulin in the brain. However, the relevance of these to aging and longevity remains to be elucidated. Here, we review advances in our understanding of the physiological role of insulin in the brain, how insulin gets into the brain, and its relevance to aging and longevity. Furthermore, we examine possible future therapeutic applications and implications of insulin in the context of available models of delayed and accelerated aging. PMID:25705204

  8. The range of time delay and the global stability of the equilibrium for an IVGTT model☆

    PubMed Central

    Li, Jiaxu; Wang, Minghu; De Gaetano, Andrea; Palumbo, Pasquale; Panunzi, Simona

    2011-01-01

    Diabetes mellitus has become a prevalent disease in the world. Diagnostic protocol for the onset of diabetes mellitus is the initial step in the treatments. The intravenous glucose tolerance test (IVGTT) has been considered as the most accurate method to determine the insulin sensitivity and glucose effectiveness. It is well known that there exists a time delay in insulin secretion stimulated by the elevated glucose concentration level. However, the range of the length of the delay in the existing IVGTT models are not fully discussed and thus in many cases the time delay may be assigned to a value out of its reasonable range. In addition, several attempts had been made to determine when the unique equilibrium point is globally asymptotically stable. However, all these conditions are delay-independent. In this paper, we discuss the range of the time delay and provide easy-to-check delay-dependent conditions for the global asymptotic stability of the equilibrium point for a recent IVGTT model through Liapunov function approach. Estimates of the upper bound of the delay for global stability are given in corollaries. In addition, the numerical simulation in this paper is fully incorporated with functional initial conditions, which is natural and more appropriate in delay differential equation system. PMID:22123436

  9. Roles and relationships between health professionals involved in insulin initiation for people with type 2 diabetes in the general practice setting: a qualitative study drawing on relational coordination theory

    PubMed Central

    2014-01-01

    Background The majority of care for people with type 2 diabetes occurs in general practice, however when insulin initiation is required it often does not occur in this setting or in a timely manner and this may have implications for the development of complications. Increased insulin initiation in general practice is an important goal given the increasing prevalence of type 2 diabetes and a relative shortage of specialists. Coordination between primary and secondary care, and between medical and nursing personnel, may be important in achieving this. Relational coordination theory identifies key concepts that underpin effective interprofessional work: communication which is problem solving, timely, accurate and frequent and relationships between professional roles which are characterized by shared goals, shared knowledge and mutual respect. This study explores roles and relationships between health professionals involved in insulin initiation in order to gain an understanding of factors which may impact on this task being carried out in the general practice setting. Method 21 general practitioners, practice nurses, diabetes nurse educators and physicians were purposively sampled to participate in a semi-structured interview. Transcripts of the interviews were analysed using framework analysis. Results There were four closely interlinked themes identified which impacted on how health professionals worked together to initiate people with type 2 diabetes on insulin: 1. Ambiguous roles; 2. Uncertain competency and capacity; 3. Varying relationships and communication; and 4. Developing trust and respect. Conclusions This study has shown that insulin initiation is generally recognised as acceptable in general practice. The role of the DNE and practice nurse in this space and improved communication and relationships between health professionals across organisations and levels of care are factors which need to be addressed to support this clinical work. Relational

  10. Delayed initiation but not gradual advancement of enteral formula feeding reduces the incidence of necrotizing enterocolitis (NEC) in preterm pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Enteral formula feeding is a risk factor for necrotizing enterocolitis (NEC) in premature infants, yet studies are conflicting regarding the safest timing for introduction and advancement of feeds. Our aim was to test the effects of early vs. late initiation and abrupt vs. gradual advancement of ent...

  11. Evaluation of a Randomized Intervention to Delay Sexual Initiation among Fifth-Graders Followed through the Sixth Grade

    ERIC Educational Resources Information Center

    Koo, Helen P.; Rose, Allison; El-Khorazaty, M. Nabil; Yao, Qing; Jenkins, Renee R.; Anderson, Karen M.; Davis, Maurice; Walker, Leslie R.

    2011-01-01

    US adolescents initiate sex at increasingly younger ages, yet few pregnancy prevention interventions for children as young as 10-12 years old have been evaluated. Sixteen Washington, DC schools were randomly assigned to intervention versus control conditions. Beginning in 2001/02 with fifth-grade students and continuing during the sixth grade,…

  12. "Saving Sex for Later": Developing a Parent-Child Communication Intervention to Delay Sexual Initiation among Young Adolescents

    ERIC Educational Resources Information Center

    O'Donnell, Lydia; Wilson-Simmons, Renee; Dash, Kim; Jeanbaptiste, Varzi; Myint-U, Athi; Moss, Jesse; Stueve, Ann

    2007-01-01

    Young adolescents in communities with high rates of early sexual initiation are at risk of multiple negative health outcomes. Although sex education programs for this age group are often controversial, surveys document that many mothers and fathers would appreciate guidance about how to discuss sexuality with their children. This paper presents an…

  13. Initiation of delayed ovotoxicity by in vitro and in vivo exposures of rat ovaries to 4-vinylcyclohexene diepoxide.

    PubMed

    Devine, Patrick J; Sipes, I Glenn; Hoyer, Patricia B

    2004-11-01

    Repeated daily dosing of rats with the ovotoxic, occupational chemical 4-vinylcyclohexene diepoxide (VCD, 80 mg/kg, i.p.) selectively depletes primordial and primary ovarian follicles. This study was designed to investigate whether follicle loss can be achieved following a single, acute exposure to VCD. Ovaries removed from postnatal-day-4 female Fischer 344 rats were cultured in the absence or presence of VCD for 15 days. Continuous in vitro exposure to VCD (15 days) caused concentration-dependent loss of primordial and small primary follicles. A single exposure to VCD in vitro (30 microM, 24 h) also caused significant losses of primordial and primary follicles 14 days later. Additionally, 28-day-old female rats were given a single injection of VCD (40-320 mg/kg, i.p.). A single dose at 320 mg/kg resulted in substantial loss of all follicle stages beginning 6 days later. Overall, these results demonstrate that an acute exposure to high concentrations/doses of VCD is sufficient to cause subsequent delayed loss of follicles. PMID:15336714

  14. The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

    PubMed Central

    Pagel-Langenickel, Ines; Bao, Jianjun; Pang, Liyan; Sack, Michael N.

    2010-01-01

    Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM. PMID:19861693

  15. What to Expect from the Virtual Seismologist: Delay Times and Uncertainties of Initial Earthquake Alerts in California

    NASA Astrophysics Data System (ADS)

    Behr, Y.; Cua, G. B.; Clinton, J. F.; Racine, R.; Meier, M.; Cauzzi, C.

    2013-12-01

    The Virtual Seismologist (VS) method is a Bayesian approach to regional network-based earthquake early warning (EEW) originally formulated by Cua and Heaton (2007). Implementation of VS into real-time EEW codes has been an on-going effort of the Swiss Seismological Service at ETH Zürich since 2006, with support from ETH Zürich, various European projects, and the United States Geological Survey (USGS). VS is one of three EEW algorithms that form the basis of the California Integrated Seismic Network (CISN) ShakeAlert system, a USGS-funded prototype end-to-end EEW system that could potentially be implemented in California. In Europe, VS is currently operating as a real-time test system in Switzerland, western Greece and Istanbul. As part of the on-going EU project REAKT (Strategies and Tools for Real-Time Earthquake Risk Reduction), VS installations in southern Italy, Romania, and Iceland are planned or underway. The possible use cases for an EEW system will be determined by the speed and reliability of earthquake source parameter estimates. A thorough understanding of both is therefore essential to evaluate the usefulness of VS. For California, we present state-wide theoretical alert times for hypothetical earthquakes by analyzing time delays introduced by the different components in the VS EEW system. Taking advantage of the fully probabilistic formulation of the VS algorithm we further present an improved way to describe the uncertainties of every magnitude estimate by evaluating the width and shape of the probability density function that describes the relationship between waveform envelope amplitudes and magnitude. We evaluate these new uncertainty values for past seismicity in California through off-line playbacks and compare them to the previously defined static definitions of uncertainty based on real-time detections. Our results indicate where VS alerts are most useful in California and also suggest where most effective improvements to the VS EEW system

  16. Oral Insulin

    PubMed Central

    2010-01-01

    Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation. PMID:21059246

  17. Insulin therapy refusal among type II diabetes mellitus patients in Kubang Pasu district, Kedah, Malaysia

    PubMed Central

    Tan, Wei Leong; Asahar, Siti Fairus; Harun, Noor Liani

    2015-01-01

    INTRODUCTION Diabetes mellitus is a rising non-communicable disease in Malaysia. Insulin therapy refusal is a challenge for healthcare providers, as it results in delayed insulin initiation. This study was conducted to determine the prevalence of insulin therapy refusal and its associated factors. METHODS This cross-sectional study was conducted at seven public health clinics in Kubang Pasu district of Kedah, Malaysia, from March to October 2012. A newly developed and validated questionnaire was used and participants were selected via systematic random sampling. Only patients diagnosed with type II diabetes mellitus (T2DM) and under the public health clinic care in Kubang Pasu were included in the study. Multiple logistic regression was used to study the association between insulin therapy refusal and its associated factors. RESULTS There were 461 respondents and the response rate was 100%. Among these 461 patients with T2DM, 74.2% refused insulin therapy. The most common reason given for refusal was a lack of confidence in insulin injection (85.4%). Multiple logistic regression revealed that respondents who had secondary education were 55.0% less likely to refuse insulin therapy than those who had primary education or no formal education (adjusted odds ratio [OR] 0.45, 95% confidence interval [CI] 0.25–0.82, p = 0.009). There was also a significant inverse association between glycated haemoglobin (HbA1c) level and insulin therapy refusal (adjusted OR 0.87, 95% CI 0.76–1.00, p = 0.047). CONCLUSION Insulin therapy refusal is common in Kubang Pasu. Educational status and HbA1c level should be taken into consideration when counselling patients on insulin therapy initiation. PMID:25532511

  18. Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor.

    PubMed Central

    Herz, J; Qiu, S Q; Oesterle, A; DeSilva, H V; Shafi, S; Havel, R J

    1995-01-01

    Two endocytic receptors, the low density lipoprotein (LDL) receptor (LDLR) and the LDLR-related protein (LRP), are thought to act in concert in the hepatic uptake of partially metabolized dietary lipoproteins, the chylomicron remnants. We have evaluated the role of these two receptors in the hepatic metabolism of chylomicron remnants in normal mice and in LDLR-deficient [LDLR (-/-)] mice. The rate of chylomicron remnant removal by the liver was normal up to 30 min after intravenous injection of chylomicrons into LDLR (-/-) mice and was unaffected by receptor-associated protein (RAP), a potent inhibitor of ligand binding to LRP. In contrast, endocytosis of the remnants by the hepatocytes, measured by their accumulation in the endosomal fraction and by the rate of hydrolysis of component cholesteryl esters, was dramatically reduced in the absence of the LDLR. Coadministration of RAP prevented the continuing hepatic removal of chylomicron remnants in LDL (-/-) mice after 30 min, consistent with blockade of the slow endocytosis by a RAP-sensitive process. Taken together with previous studies, our results are consistent with a model in which the initial hepatic removal of chylomicron remnants is primarily mediated by mechanisms that do not include LDLR or LRP, possibly involving glycosaminoglycan-bound hepatic lipase and apolipoprotein E. After the remnants bind to these alternative sites on the hepatocyte surface, endocytosis is predominantly mediated by the LDLR and also by a slower and less efficient backup process that is RAP sensitive and therefore most likely involves LRP. PMID:7753850

  19. Reduced resuscitation fluid volume for second-degree experimental burns with delayed initiation of vitamin C therapy (beginning 6 h after injury).

    PubMed

    Sakurai, M; Tanaka, H; Matsuda, T; Goya, T; Shimazaki, S; Matsuda, H

    1997-11-01

    We studied the hemodynamic effects of delayed initiation (6 h postburn) of antioxidant therapy with high-dose vitamin C in second-degree thermal injuries. Seventy percent body surface area burns were produced by subxiphoid immersion of 12 guinea pigs into 100 degrees C water for 3 s. The animals were resuscitated with Ringer's lactate solution (R/L) according to the Parkland formula (4 ml/kg/% burn during the first 24 h) from 6 h postburn, after which the resuscitation fluid volume was reduced to 25% of the Parkland formula volume. Animals were divided into two groups. The vitamin C group (n = 6) received R/L to which vitamin C (340 mg/kg/24 h) was added after 6 h postburn. The control group (n = 6) received R/L only. Both groups received identical resuscitation volumes. Heart rates, mean arterial blood pressure, cardiac output, hematocrit level, and water content of burned and unburned tissue were measured before injury and at intervals thereafter. No animals died. There were no significant differences in heart rates or blood pressures between the two groups throughout the 24-h study period. The vitamin C group showed significantly (P < 0.05) lower hematocrits 8 and 24 h postburn, and higher cardiac outputs after 7 h postburn. At 24 h postburn, the burned skin in the vitamin C group had a significantly (P < 0.05) lower water content (73.1 +/- 1.1) than that of the control group (76.0 +/- 0.8). In conclusion, delayed initiation of high-dose vitamin C therapy beginning 6 h postburn with 25% of the Parkland formula volume significantly reduced edema formation in burned tissue, while maintaining stable hemodynamics. PMID:9441788

  20. Downhole delay assembly for blasting with series delay

    DOEpatents

    Ricketts, Thomas E.

    1982-01-01

    A downhole delay assembly is provided which can be placed into a blasthole for initiation of explosive in the blasthole. The downhole delay assembly includes at least two detonating time delay devices in series in order to effect a time delay of longer than about 200 milliseconds in a round of explosions. The downhole delay assembly provides a protective housing to prevent detonation of explosive in the blasthole in response to the detonation of the first detonating time delay device. There is further provided a connection between the first and second time delay devices. The connection is responsive to the detonation of the first detonating time delay device and initiates the second detonating time delay device. A plurality of such downhole delay assemblies are placed downhole in unfragmented formation and are initiated simultaneously for providing a round of explosive expansions. The explosive expansions can be used to form an in situ oil shale retort containing a fragmented permeable mass of formation particles.

  1. Insulin Delivery System

    NASA Technical Reports Server (NTRS)

    1988-01-01

    When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

  2. Biosimilar Insulins

    PubMed Central

    Hompesch, Marcus

    2014-01-01

    Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States. Differences in the manufacturing process (none of the insulin manufacturing procedures are 100% identical) can lead to insulins that to some extent may differ from the originator insulin. The key questions are if subtle differences in the structure of the insulins, purity, and so on are clinically relevant and may result in different biological effects. The aim of this article is to introduce and discuss basic aspects that may be of relevance with regard to BI. PMID:24876530

  3. Biosimilar insulins.

    PubMed

    Heinemann, Lutz

    2012-08-01

    Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets. PMID:22583127

  4. BeAM value: an indicator of the need to initiate and intensify prandial therapy in patients with type 2 diabetes mellitus receiving basal insulin

    PubMed Central

    Zisman, Ariel; Morales, Francienid; Stewart, John; Stuhr, Andreas; Vlajnic, Aleksandra; Zhou, Rong

    2016-01-01

    Introduction In patients with type 2 diabetes mellitus (T2DM) with uncontrolled glycemia despite ongoing upward titration of basal insulin, targeting postprandial hyperglycemia may be required. Nevertheless, the point at which basal insulin is fully optimized and postprandial glucose (PPG) should be targeted with additional treatment remains unclear. We report here on the BeAM value (difference between bedtime and morning blood glucose values) as an indicator of the need to target PPG. Methods This study had 3 stages: exploratory, main, and proof-of-concept analyses. For the exploratory and main analyses, data were pooled from phase 3 trials in adults with T2DM adding basal insulin to oral antidiabetic drugs (OADs). The main analysis included only patients who did not reach A1C ≤7.0% (53 mmol/mol) at week 24. The proof-of-concept analysis used pooled data from phase 3 trials in adults with T2DM adding insulin glargine and a single insulin glulisine injection to OADs. Results In patients undergoing basal insulin titration, BeAM value increased over 24 weeks (27.8–61.7 mg/dL, n=1188; 32.6–71.2 mg/dL, n=553; exploratory and main analyses, respectively). There were significant correlations between week 24 BeAM value and postprandial contribution to hyperglycemia (Pearson's correlation coefficient (r)=0.375, p<0.001; r=0.396, p<0.001; exploratory and main analyses, respectively). When PPG was targeted (proof-of-concept analysis), the BeAM value reduced from 77.0 to 40.4 mg/dL (n=299). Conclusions The BeAM value described in this study is a simple, easy-to-calculate value that may identify patients with T2DM using basal insulin that need targeting of postprandial control rather than advancing basal insulin dose. PMID:27110368

  5. Initial velocity distributions of ions generated by in-flight laser desorption/ionization of individual polystyrene latex microparticles as studied by the delayed ion extraction method.

    PubMed

    Vera, César Costa; Trimborn, Achim; Hinz, Klaus-Peter; Spengler, Bernhard

    2005-01-01

    The delayed ion extraction method has been used to study characteristics of the initial velocity distributions of positive and negative ions produced simultaneously by laser desorption/ionization (LDI) from non-impacted single aerosol polymeric particles, using a bipolar time-of-flight (TOF) instrument (LAMPAS 2). Due to the geometry of the setup and the characteristics of the ablation process, only the projections of the velocities on the axis of the mass spectrometer can be directly studied. Additionally, since the mean initial velocity under these conditions should be close to zero, it was necessary to extend the method by taking into account higher order contributions of the velocity distribution. Theoretical expressions for these higher order terms are presented and discussed. The bipolar characteristics of the instrument permit evaluation and treatment of a possible instrumental artifact caused by small inclinations of the ionizing laser with respect to the ideal incidence direction. Results of a number of experiments are presented and discussed in relation to the theoretical expressions presented, and to possible ablation scenarios. Evidence pointing out that, under our experimental conditions, only partial ablation of the latex particles occurs was obtained. The variance of the distribution of the projection of the initial velocities can be directly estimated from these results. By assuming that the total initial velocities of the ions are developed completely according to a single-temperature adiabatic expansion mechanism, temperatures of approximately 50 K/Da can be assigned to the ion clouds from the variance estimations. If a two-temperature model is used, a radial temperature of about 100 K/Da results. These values are in reasonable agreement with results for polymer ablation from the literature. PMID:15593241

  6. Intracellular insulin-receptor dissociation and segregation in a rat fibroblast cell line transfected with a human insulin receptor gene

    SciTech Connect

    Levy, J.R.; Olefsky, J.M.

    1988-05-05

    The cellular processing of insulin and insulin receptors was studied using a rat fibroblast cell line that had been transfected with a normal human insulin receptor gene, expressing approximately 500 times the normal number of native fibroblasts insulin receptors. These cells bind and internalize insulin normally. Biochemically assays based on the selective precipitation by polyethylene glycol of intact insulin-receptor complexes but not of free intracellular insulin were developed to study the time course of intracellular insulin-receptor dissociation. Fibroblasts were incubated with radiolabeled insulin at 4/sup 0/C, and internalization of insulin-receptor complexes was initiated by warming the cells to 37/sup 0/C. Within 2 min, 90% of the internalized radioactivity was composed of intact insulin-receptor complexes. The dissociation of insulin from internalized insulin-receptor complexes was markedly inhibited by monensin and chloroquine. Furthermore, chloroquine markedly increased the number of cross-linkable intracellular insulin-receptor complexes, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. These findings suggest that acidification of intracellular vesicles is responsible for insulin-receptor dissociation. Physical segregation of dissociated intracellular insulin from its receptor was monitored. The results are consistent with the view that segregation of insulin and receptor occurs 5-10 min after initiation of dissociation. These studies demonstrate the intracellular itinerary of insulin-receptor complexes, including internalization, dissociation of insulin from the internalized receptor within an acidified compartment, segregation of insulin from the receptor, and subsequent ligand degradation.

  7. Obviating much of the need for insulin therapy in type 2 diabetes mellitus: A re-assessment of insulin therapy's safety profile.

    PubMed

    Schwartz, Stanley S; Jellinger, Paul S; Herman, Mary E

    2016-08-01

    reduce reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and, potentially, reframes processes of care. PMID:27210018

  8. Delayed ejaculation

    MedlinePlus

    Ejaculatory incompetence; Sex - delayed ejaculation; Retarded ejaculation; Anejaculation; Infertility - delayed ejaculation ... include: Religious background that makes the person view sex as sinful Lack of attraction for a partner ...

  9. Insulin resistance and insulin sensitizers.

    PubMed

    Stumvoll, M; Häring, H

    2001-01-01

    Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance. PMID:11684868

  10. Initial and delayed right ventricular /sup 201/Tl rest-imaging following dipyridamole-induced coronary vasodilation: relationship to right coronary artery pathoanatomy

    SciTech Connect

    Brown, K.A.; Boucher, C.A.; Okada, R.D.; Strauss, H.W.; Pohost, G.

    1982-06-01

    The relationship of coronary anatomy to right ventricular (RV) appearance on serial /sup 201/Tl myocardial imaging (TI) following dipyridamole (DP)-induced coronary vasodilation was examined in 71 consecutive patients undergoing coronary angiography for the evaluation of chest pain. Transient defects of the RV were found in 18 patients. All 18 had significant (greater than or equal to 50%) stenosis of the proximal right coronary artery (RCA). Nonvisualization of RV activity occurred in 13 patients. Six of these 13 (46%) had proximal RCA disease (p less than 0.05 compared to transient defects). Normal RV appearance was seen in 40 patients, of whom only six (15%) had proximal RCA disease (p less than 0.001 compared to transient defects). RV appearance was not affected by left anterior descending or left circumflex artery disease or by the /sup 201/Tl uptake in the left ventricle. Thus with serial (initial and delayed) TI following DP (1) transient RV defect appears to indicate significant proximal RCA disease; (2) normal RV appearance suggests the absence of proximal RCA disease; and (3) however, nonvisualization of the RV appears to be nondiagnostic.

  11. Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to tr...

  12. The activation of insulin and nutrient signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin (INS) and amino acids (AA) act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the effect of INS and AA on the activation of signaling components leading to translation in...

  13. Insulin Test

    MedlinePlus

    ... people with type 2 diabetes , polycystic ovarian syndrome (PCOS) , prediabetes or heart disease , or metabolic syndrome . A ... resistance), especially in obese individuals and those with PCOS . This test involves an IV-infusion of insulin, ...

  14. Impact of Intranasal Insulin on Insulin Antibody Affinity and Isotypes in Young Children With HLA-Conferred Susceptibility to Type 1 Diabetes

    PubMed Central

    Ryhänen, Samppa J.; Härkönen, Taina; Siljander, Heli; Näntö-Salonen, Kirsti; Simell, Tuula; Hyöty, Heikki; Ilonen, Jorma; Veijola, Riitta; Simell, Olli; Knip, Mikael

    2011-01-01

    OBJECTIVE Despite promising results from studies on mouse models, intranasal insulin failed to prevent or delay the development of type 1 diabetes in autoantibody-positive children with HLA-conferred disease susceptibility. To analyze whether the insulin dose was inadequate to elicit an immunomodulatory response, we compared the changes observed in insulin antibody (IA) affinity and isotypes after treatment with nasal insulin or placebo. RESEARCH DESIGN AND METHODS Ninety-five children (47 in the placebo group and 48 in the insulin group of the total of 224 children randomized for the trial) with HLA-conferred susceptibility to type 1 diabetes derived from the intervention arm of the Finnish Type 1 Diabetes Prediction and Prevention study were included in these analyses. Blood samples drawn before or at the beginning of the treatment and after treatment for 3 and 6 months were analyzed for IA affinity and isotype-specific IAs (IgG1–4, IgA, IgM, and IgE). RESULTS IgG3- and IgA-IA levels (P = 0.031 and 0.015, respectively) and the number of IgG3-IA–positive subjects (P = 0.022) were significantly higher at 6 months after the initiation of the treatment in the insulin group. No significant differences were observed between the two groups in IA affinity or other IA isotypes. CONCLUSIONS The insulin dose administered induced a modest change in the IA isotype profile. The lack of impact of nasal insulin on IA affinity implies that the immune response of study subjects was already mature at the beginning of the intervention. PMID:21515841

  15. α-Casein Inhibits Insulin Amyloid Formation by Preventing the Onset of Secondary Nucleation Processes.

    PubMed

    Librizzi, Fabio; Carrotta, Rita; Spigolon, Dario; Bulone, Donatella; San Biagio, Pier Luigi

    2014-09-01

    α-Casein is known to inhibit the aggregation of several proteins, including the amyloid β-peptide, by mechanisms that are not yet completely clear. We studied its effects on insulin, a system extensively used to investigate the properties of amyloids, many of which are common to all proteins and peptides. In particular, as for other proteins, insulin aggregation is affected by secondary nucleation pathways. We found that α-casein strongly delays insulin amyloid formation, even at extremely low doses, when the aggregation process is characterized by secondary nucleation. At difference, it has a vanishing inhibitory effect on the initial oligomer formation, which is observed at high concentration and does not involve any secondary nucleation pathway. These results indicate that an efficient inhibition of amyloid formation can be achieved by chaperone-like systems, by sequestering the early aggregates, before they can trigger the exponential proliferation brought about by secondary nucleation mechanisms. PMID:26278257

  16. Diabetes and Insulin

    MedlinePlus

    ... years, but may eventually need insulin to maintain glucose control. What are the different types of insulin? Different ... glulisine • Short-acting: regular human insulin Basal insulin. Controls blood glucose levels between meals and throughout the night. This ...

  17. Acute poisoning following ingestion of medicines: initial management. How to treat life-threatening complications and to evaluate the risk of delayed effects and psychological distress.

    PubMed

    2010-12-01

    activated charcoal, provided the patient is fully conscious and capable of swallowing safely. Gastric lavage carries a risk of serious adverse effects. It is only justified in the rare cases in which the patient's life is at risk following ingestion of a drug that is not adsorbed by activated charcoal. Ipecac syrup should not be used under any circumstances. Purging and gastric lavage are not part of initial management. Few antidotes are suitable for use in the early stages of poisoning. Acetylcysteine can be used for some cases of paracetamol poisoning, and naloxone for some types of opioid poisoning. Paracetamol poisoning can cause life-threatening hepatocellular necrosis. Activated charcoal should be administered as soon as possible. Acetylcysteine protects the liver when administered within 24 hours after paracetamol ingestion. Paracetamol serum assay can be useful for guiding patient management. In practice, acetylcysteine should be given when access to emergency medical intervention is not feasible within 8 to 10 hours after paracetamol ingestion. Intravenous naloxone is useful for respiratory depression due to opioid poisoning, but its duration of action is often shorter than that of opioids, making continuous monitoring necessary. Hospital monitoring is warranted in case of potentially severe poisoning; this includes patients at increased risk, patients having taken a potentially lethal substance at a toxic or unknown dose. Some pharmacological substances and formulations can have delayed effects. In case of self-poisoning, the risk of short-term relapse should be evaluated, even when the patient's condition is not life-threatening. Hospital admission should be proposed, or sometimes imposed, until the acute risk of suicide has subsided. In practice, when faced with acute drug poisoning, the first step is to implement life-support measures, to gather and communicate prognostic information and details of any treatments to the ambulance crew or hospital team. PMID

  18. Delayed ejaculation

    MedlinePlus

    Ejaculatory incompetence; Sex - delayed ejaculation; Retarded ejaculation; Anejaculation ... include: Religious background that makes the person view sex as sinful Lack of attraction for a partner ...

  19. Technosphere insulin: an inhaled prandial insulin product.

    PubMed

    Neumiller, Joshua J; Campbell, R Keith

    2010-06-01

    Given the important role of insulin in the treatment of diabetes mellitus and in light of common barriers to insulin use, new strategies for insulin delivery by routes other than intravenous and subcutaneous injection have been investigated since the discovery of insulin in the 1920s. Most companies researching and developing pulmonary administration systems for the use of insulin announced the termination of product development following the failure of the first US FDA-approved inhaled insulin product, Exubera. One company in particular continued their pursuit of a useful inhaled insulin product. MannKind Corporation has developed a powder formulation of insulin that allows for a high percentage of the administered insulin to be absorbed via the lung. Their product, AFREZZA (Technosphere insulin), is currently under review by the FDA for use in patients with diabetes. Technosphere insulin appears to overcome some of the barriers that contributed to the market withdrawal of Exubera by the manufacturer. Studies with Technosphere insulin have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively short duration of action, and is efficacious in terms of improved glycemic control without contributing to increased weight gain or the incidence of hypoglycemia when compared with other prandial insulin products. Additionally, Technosphere insulin has demonstrated a favorable safety and tolerability profile in clinical studies to date. PMID:20462282

  20. Role of incretin-based therapies and sodium-glucose co-transporter-2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes, with special reference to IDegLira.

    PubMed

    Wilding, J P H; Bain, S C

    2016-07-01

    The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field. PMID:26525806

  1. PRECISION TIME-DELAY CIRCUIT

    DOEpatents

    Creveling, R.

    1959-03-17

    A tine-delay circuit which produces a delay time in d. The circuit a capacitor, an te back resistance, connected serially with the anode of the diode going to ground. At the start of the time delay a negative stepfunction is applied to the series circuit and initiates a half-cycle transient oscillatory voltage terminated by a transient oscillatory voltage of substantially higher frequency. The output of the delay circuit is taken at the junction of the inductor and diode where a sudden voltage rise appears after the initiation of the higher frequency transient oscillations.

  2. Prediction of Weather Related Center Delays

    NASA Technical Reports Server (NTRS)

    Deepak, Kulkarni; Banavar, Sridhar

    2008-01-01

    This paper presents results of an initial study of relations between national delay, center level delays and weather. The results presented in the paper indicate: (a) the methodology used for estimating the delay at the national level can be extended to estimate delays caused by a center and delays experienced by a center, (b)delays caused by a center can be predicted using that center's Weather Impacted Traffic Index (WITI) whereas delays experienced by a center are best predicted using WITI of that center and that of a few prominent centers (c) there is differential impact of weather of different centers on center delays.

  3. Insulin Human Inhalation

    MedlinePlus

    Insulin inhalation is used in combination with a long-acting insulin to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar ...

  4. Giving an insulin injection

    MedlinePlus

    ... One Type of Insulin Wash your hands with soap and water. Dry them well. Check the insulin ... syringe before injecting it. Wash your hands with soap and water. Dry them well. Check the insulin ...

  5. Insulin Lispro Injection

    MedlinePlus

    ... is a short-acting, man-made version of human insulin. Insulin lispro works by replacing the insulin ... niacin (Niacor, Niaspan, in Advicor); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) ...

  6. Misadventures in insulin therapy: are you at risk?

    PubMed Central

    Grissinger, Matthew; Lease, Michael

    2003-01-01

    About dollar 1 out of every dollar 7 spent on health care is related to diabetes mellitus, a leading cause of blindness and kidney failure and a strong risk factor for heart disease. Prevalence of the disease has increased by a third among adults in general in the last decade, but intensive therapy has been shown to delay the onset and slow the progression of diabetes-related complications. While insulin therapy remains key in the management of type 1 diabetes, many patients with type 2, or insulin-resistant, diabetes encounter insulin administration errors that compromise the quality of insulin delivery. Insulin errors are a major, but modifiable, barrier to dosing accuracy and optimal diabetes control for many patients. Future trends to combat the problem include increased use of insulin inhalers and smaller doses of rapid- or short-acting insulin to supplement longer-acting injections. PMID:12653373

  7. Misadventures in insulin therapy: are you at risk?

    PubMed

    Grissinger, Matthew; Lease, Michael

    2003-02-01

    About dollar 1 out of every dollar 7 spent on health care is related to diabetes mellitus, a leading cause of blindness and kidney failure and a strong risk factor for heart disease. Prevalence of the disease has increased by a third among adults in general in the last decade, but intensive therapy has been shown to delay the onset and slow the progression of diabetes-related complications. While insulin therapy remains key in the management of type 1 diabetes, many patients with type 2, or insulin-resistant, diabetes encounter insulin administration errors that compromise the quality of insulin delivery. Insulin errors are a major, but modifiable, barrier to dosing accuracy and optimal diabetes control for many patients. Future trends to combat the problem include increased use of insulin inhalers and smaller doses of rapid- or short-acting insulin to supplement longer-acting injections. PMID:12653373

  8. Delayed discharge.

    PubMed

    Allen, Daniel

    2016-07-01

    Essential facts Delays in discharging older peo ple from hospital cost the NHS £820 million a year, according to a report from the National Audit Office (NAO). Last year in acute hospitals, 1.15 million bed days were lost to delayed transfers of care, an increase of 31% since 2013. The NAO says rising demand for NHS services is compounded by reduced local authority spending on adult social care - down by 10% since 2009-10. PMID:27380673

  9. Insulin accelerates global and mitochondrial protein synthesis rates in neonatal muscle during sepsis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In neonatal pigs, sepsis decreases protein synthesis in skeletal muscle by decreasing translation initiation. However, insulin stimulates muscle protein synthesis despite persistent repression of translation initiation signaling. To determine whether the insulin-induced increase in global rates of m...

  10. Concentrated insulins: the new basal insulins

    PubMed Central

    Lamos, Elizabeth M; Younk, Lisa M; Davis, Stephen N

    2016-01-01

    Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration. PMID:27022271

  11. Is Dynamic Autocrine Insulin Signaling Possible? A Mathematical Model Predicts Picomolar Concentrations of Extracellular Monomeric Insulin within Human Pancreatic Islets

    PubMed Central

    Wang, Minghu; Li, Jiaxu; Lim, Gareth E.; Johnson, James D.

    2013-01-01

    Insulin signaling is essential for -cell survival and proliferation in vivo. Insulin also has potent mitogenic and anti-apoptotic actions on cultured -cells, with maximum effect in the high picomolar range and diminishing effect at high nanomolar doses. In order to understand whether these effects of insulin are constitutive or can be subjected to physiological modulation, it is essential to estimate the extracellular concentration of monomeric insulin within an intact islet. Unfortunately, the in vivo concentration of insulin monomers within the islet cannot be measured directly with current technology. Here, we present the first mathematical model designed to estimate the levels of monomeric insulin within the islet extracellular space. Insulin is released as insoluble crystals that exhibit a delayed dissociation into hexamers, dimers, and eventually monomers, which only then can act as signaling ligands. The rates at which different forms of insulin dissolve in vivo have been estimated from studies of peripheral insulin injection sites. We used this and other information to formulate a mathematical model to estimate the local insulin concentration within a single islet as a function of glucose. Model parameters were estimated from existing literature. Components of the model were validated using experimental data, if available. Model analysis predicted that the majority of monomeric insulin in the islet is that which has been returned from the periphery, and the concentration of intra-islet monomeric insulin varies from 50–300 pM when glucose is in the physiological range. Thus, our results suggest that the local concentration of monomeric insulin within the islet is in the picomolar ‘sweet spot’ range of insulin doses that activate the insulin receptor and have the most potent effects on -cells in vitro. Together with experimental data, these estimations support the concept that autocrine/paracrine insulin signalling within the islet is dynamic, rather

  12. The Use of Video Modeling with the Picture Exchange Communication System to Increase Independent Communicative Initiations in Preschoolers with Autism and Developmental Delays

    ERIC Educational Resources Information Center

    Cihak, David F.; Smith, Catherine C.; Cornett, Ashlee; Coleman, Mari Beth

    2012-01-01

    The use of video modeling (VM) procedures in conjunction with the picture exchange communication system (PECS) to increase independent communicative initiations in preschool-age students was evaluated in this study. The four participants were 3-year-old children with limited communication skills prior to the intervention. Two of the students had…

  13. Developmental delay

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nutrition support is essential for the care of the child with developmental delay. After a thorough evaluation, an individualized intervention plan that accounts for the child’s nutrition status, feeding ability, and medical condition may be determined. Nutrition assessments may be performed at leas...

  14. Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity.

    PubMed

    Kim, Tae-Hueng; Moodycliffe, Angus M; Yarosh, Daniel B; Norval, Mary; Kripke, Margaret L; Ullrich, Stephen E

    2003-09-01

    UV radiation suppresses the immune response, and UV-induced immune suppression contributes to UV-induced photocarcinogenesis. For UV-induced immune suppression to occur, electromagnetic energy (i.e. UV radiation) must be converted to a biological signal. Two photoreceptors have been identified in the skin that serves this purpose, epidermal DNA and trans-urocanic acid (UCA). Although compelling evidence exists to support a role for each pathway (UV-induced DNA damage or photoisomerization of UCA) in UV-induced immune suppression, it is not clear what determines which photoreceptor pathway is activated. To address this question, we injected UV-irradiated mice with a monoclonal antibody with specificity for cis-UCA or applied liposomes containing DNA repair enzymes to the skin of UV-irradiated mice. The effect that each had on UV-induced suppression of delayed-type hypersensitivity was measured. We asked whether the light source used (FS-40 sunlamps vs solar-simulated UV radiation) altered whichever pathway of immune suppression was activated. Different doses of UV radiation and the viability of the antigen were also considered. Neither the dose of UV nor the light source had any influence on determining which pathway was activated. Rather, we found that the viability of the antigen was the critical determinant. When live antigens were used, UV-induced immune suppression was blocked with monoclonal anti-cis-UCA but not with T4 endonuclease V-containing liposomes. The reverse was observed when formalin-fixed or killed antigens were used. Our findings indicate that antigen viability dictates which photoreceptor pathway predominates after UV exposure. PMID:14556308

  15. Pursuit of a perfect insulin.

    PubMed

    Zaykov, Alexander N; Mayer, John P; DiMarchi, Richard D

    2016-06-01

    Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration. PMID:26988411

  16. Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors▿

    PubMed Central

    Denley, Adam; Carroll, Julie M.; Brierley, Gemma V.; Cosgrove, Leah; Wallace, John; Forbes, Briony; Roberts, Charles T.

    2007-01-01

    The insulin-like growth factors (insulin-like growth factor I [IGF-I] and IGF-II) exert important effects on growth, development, and differentiation through the IGF-I receptor (IGF-IR) transmembrane tyrosine kinase. The insulin receptor (IR) is structurally related to the IGF-IR, and at high concentrations, the IGFs can also activate the IR, in spite of their generally low affinity for the latter. Two mechanisms that facilitate cross talk between the IGF ligands and the IR at physiological concentrations have been described. The first of these is the existence of an alternatively spliced IR variant that exhibits high affinity for IGF-II as well as for insulin. A second phenomenon is the ability of hybrid receptors comprised of IGF-IR and IR hemireceptors to bind IGFs, but not insulin. To date, however, direct activation of an IR holoreceptor by IGF-I at physiological levels has not been demonstrated. We have now found that IGF-I can function through both splice variants of the IR, in spite of low affinity, to specifically activate IRS-2 to levels similar to those seen with equivalent concentrations of insulin or IGF-II. The specific activation of IRS-2 by IGF-I through the IR does not result in activation of the extracellular signal-regulated kinase pathway but does induce delayed low-level activation of the phosphatidylinositol 3-kinase pathway and biological effects such as enhanced cell viability and protection from apoptosis. These findings suggest that IGF-I can function directly through the IR and that the observed effects of IGF-I on insulin sensitivity may be the result of direct facilitation of insulin action by IGF-I costimulation of the IR in insulin target tissues. PMID:17325037

  17. Whittling Down the Wait Time: Exploring Models to Minimize the Delay from Initial Concern to Diagnosis and Treatment of Autism Spectrum Disorder.

    PubMed

    Gordon-Lipkin, Eliza; Foster, Jessica; Peacock, Georgina

    2016-10-01

    The process from initial concerns to diagnosis of autism spectrum disorder (ASD) can be a long and complicated process. The traditional model for evaluation and diagnosis of ASD often consists of long wait-lists and evaluations that result in a 2-year difference between the earliest signs of ASD and mean age of diagnosis. Multiple factors contribute to this diagnostic bottleneck, including time-consuming evaluations, cost of care, lack of providers, and lack of comfort of primary care providers to diagnose autism. This article explores innovative clinical models that have been implemented to address this as well as future directions and opportunities. PMID:27565363

  18. Insulin pumps.

    PubMed

    Pickup, J

    2011-02-01

    The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (< 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing

  19. Early versus delayed initiation of nasal continuous positive airway pressure for treatment of respiratory distress syndrome in premature newborns: A randomized clinical trial

    PubMed Central

    Badiee, Zohreh; Naseri, Fatemeh; Sadeghnia, Alireza

    2013-01-01

    Background: This prospective study was performed to identify whether the early use of nasal continuous positive airway pressure (n CPAP) would reduce the rate of endotracheal intubation, mechanical ventilation and surfactant administration. Materials and Methods: This study was conducted from June 2009 to September 2010 in the Shahid Beheshti University Hospital, Isfahan-Iran. A total of 72 preterm infants with 25-30 weeks gestation who needed respiratory support at 5 min after birth entered the study. Infants were randomly assigned to the very early CPAP (initiated 5 min after birth) or to the late CPAP (initiated 30 min after birth) treatment groups. The primary outcomes were need for intubation and mechanical ventilation during the first 48 h after birth and secondary outcomes were death, pneumothorax, intraventricular hemorrhage, duration of mechanical ventilation and bronchopulmonary dysplasia. Results: There were no significant differences between the two groups with regard to mortality rate, bronchopulmonary dysplasia and patent ductus arteriosus. The need for surfactant administration was significantly reduced in the early CPAP group (P = 0.04). Infants in the early CPAP group less frequently required intubation and mechanical ventilation. Conclusions: Early n CPAP is more effective than late n CPAP for the treatment of respiratory distress syndrome. In addition, the early use of n CPAP would reduce the need for some invasive procedures such as intubation and mechanical ventilation. PMID:23930249

  20. Delayed traumatic diaphragmatic hernia

    PubMed Central

    Lu, Jing; Wang, Bo; Che, Xiangming; Li, Xuqi; Qiu, Guanglin; He, Shicai; Fan, Lin

    2016-01-01

    Abstract Background: Traumatic diaphragmatic hernias (TDHs) are sometimes difficult to identify at an early stage and can consequently result in diagnostic delays with life-threatening outcomes. It is the aim of this case study to highlight the difficulties encountered with the earlier detection of traumatic diaphragmatic hernias. Methods: Clinical data of patients who received treatment for delayed traumatic diaphragmatic hernias in registers of the First Affiliated Hospital of Xi’an Jiaotong University from 1998 to 2014 were analyzed retrospectively. Results: Six patients were included in this study. Left hemidiaphragm was affected in all of them. Most of the patients had a history of traffic accident and 1 a stab-penetrating injury. The interval from injury to developing symptoms ranged from 2 to 11 years (median 5 years). The hernial contents included the stomach, omentum, small intestine, and colon. Diaphragmatic injury was missed in all of them during the initial managements. All patients received operations once the diagnosis of delayed TDH was confirmed, and no postoperative mortality was detected. Conclusions: Delayed TDHs are not common, but can lead to serious consequences once occurred. Early detection of diaphragmatic injuries is crucial. Surgeons should maintain a high suspicion for injuries of the diaphragm in cases with abdominal or lower chest traumas, especially in the initial surgical explorations. We emphasize the need for radiographical follow-up to detect diaphragmatic injuries at an earlier stage. PMID:27512848

  1. Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression

    PubMed Central

    Ndumbi, Patricia; Falutz, Julian; Pant Pai, Nitika; Tsoukas, Christos M.

    2014-01-01

    Background Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype. Methods We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm3); Group II (CD4: 200–350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2–3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%–85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP). Results Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio. Conclusions Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated. PMID:24710051

  2. Human insulin genome sequence map, biochemical structure of insulin for recombinant DNA insulin.

    PubMed

    Chakraborty, Chiranjib; Mungantiwar, Ashish A

    2003-08-01

    Insulin is a essential molecule for type I diabetes that is marketed by very few companies. It is the first molecule, which was made by recombinant technology; but the commercialization process is very difficult. Knowledge about biochemical structure of insulin and human insulin genome sequence map is pivotal to large scale manufacturing of recombinant DNA Insulin. This paper reviews human insulin genome sequence map, the amino acid sequence of porcine insulin, crystal structure of porcine insulin, insulin monomer, aggregation surfaces of insulin, conformational variation in the insulin monomer, insulin X-ray structures for recombinant DNA technology in the synthesis of human insulin in Escherichia coli. PMID:12769691

  3. Can primary care team-based transition to insulin improve outcomes in adults with type 2 diabetes: the stepping up to insulin cluster randomized controlled trial protocol

    PubMed Central

    2014-01-01

    Background Type 2 diabetes (T2D) brings significant human and healthcare costs. Its progressive nature means achieving normoglycaemia is increasingly difficult, yet critical to avoiding long term vascular complications. Nearly one-half of people with T2D have glycaemic levels out of target. Insulin is effective in achieving glycaemic targets, yet initiation of insulin is often delayed, particularly in primary care. Given limited access to specialist resources and the size of the diabetes epidemic, primary care is where insulin initiation must become part of routine practice. This would also support integrated holistic care for people with diabetes. Our Stepping Up Program is based on a general practitioner (GP) and practice nurse (PN) model of care supported appropriately by endocrinologists and credentialed diabetes educator-registered nurses. Pilot work suggests the model facilitates integration of the technical work of insulin initiation within ongoing generalist care. Methods This protocol is for a cluster randomized controlled trial to examine the effectiveness of the Stepping Up Program to enhance the role of the GP-PN team in initiating insulin and improving glycaemic outcomes for people with T2D. 224 patients between the ages of 18 and 80 years with T2D, on two or more oral hypoglycaemic agents and with an HbA1c ≥7.5% in the last six months will be recruited from 74 general practices. The unit of randomization is the practice. Primary outcome is change in glycated haemoglobin HbA1c (measured as a continuous variable). We hypothesize that the intervention arm will achieve an absolute HbA1c mean difference of 0.5% lower than control group at 12 months follow up. Secondary outcomes include the number of participants who successfully transfer to insulin and the proportion who achieve HbA1c measurement of <7.0%. We will also collect data on patient psychosocial outcomes and healthcare utilization and costs. Discussion The study is a pragmatic translational

  4. Insulin transport across capillaries is rate limiting for insulin action in dogs.

    PubMed Central

    Yang, Y J; Hope, I D; Ader, M; Bergman, R N

    1989-01-01

    This study examined the relationship between transcapillary insulin transport and insulin action in vivo. During euglycemic clamps (n = 7) in normal conscious dogs we simultaneously measured plasma and thoracic duct lymph insulin and glucose utilization (Rd). Clamps consisted of an activation phase with constant insulin infusion (0.6 mU/kg per min) and a deactivation phase. [14C]Inulin was infused as a passively transported control substance. While [14C]inulin reached an equilibrium between plasma and lymph, steady-state (ss) plasma insulin was higher than lymph (P less than 0.05) and the ratio of 3:2 was maintained during basal, activation, and deactivation phases: 18 +/- 2 vs. 12 +/- 1, 51 +/- 2 vs. 32 +/- 1, and 18 +/- 3 vs. 13 +/- 1 microU/ml. In addition, it took longer for lymph insulin to reach ss than plasma insulin during activation and deactivation: 11 +/- 2 vs. 31 +/- 5 and 8 +/- 2 vs. 32 +/- 6 min (P less than 0.02). Rd increased from 2.6 +/- 0.1 to a ss of 6.6 +/- 0.4 mg/kg per min within 50 +/- 8 min. There was a remarkable similarity in the dynamics of insulin in lymph and Rd: the time to reach ss for Rd was not different from lymph insulin (P greater than 0.1), and the relative increases of the two measurements were similar, 164 +/- 45% and 189 +/- 29% (P greater than 0.05). While there was only a modest correlation (r = 0.78, P less than 0.01) between Rd and plasma insulin, the dynamic changes of lymph insulin and Rd showed a strong correlation (r = 0.95, P less than 0.01). The intimate relationship between lymph insulin and Rd suggests that the transcapillary insulin transport is primarily responsible for the delay in Rd. Thus, transcapillary transport may be rate limiting for insulin action, and if altered, it could be an important component of insulin resistance in obesity and diabetes mellitus. PMID:2681272

  5. Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

    PubMed

    Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

    2016-03-01

    Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND

  6. Contingency Tracking during Unsignaled Delayed Reinforcement

    ERIC Educational Resources Information Center

    Keely, Josue; Feola, Tyler; Lattal, Kennon A.

    2007-01-01

    Three experiments were conducted with rats in which responses on one lever (labeled the functional lever) produced reinforcers after an unsignaled delay period that reset with each response during the delay. Responses on a second, nonfunctional, lever did not initiate delays, but, in the first and third experiments, such responses during the last…

  7. Intensifying Insulin Therapy in Type 2 Diabetes: Choices & Challenges.

    PubMed

    Kumar, Ajay; Kesavadev, Jothydev; Sethi, Bipin; Jain, Sunil M; Guruprasad, C S; Shah, Siddharth N

    2015-05-01

    Insulin therapy remains the cornerstone of effective diabetes management. Timely intensification of insulin therapy reduces the progression of diabetes and the development of diabetes-related complications. Given that overall hyperglycaemia is a relative contribution of both fasting and postprandial hyperglycaemia, use of basal insulin alone may not achieve optimal glucose control due to its inability to cover postprandial glucose excursions. Intensifying therapy with addition of bolus insulin or switching to premixed insulin is a viable option in patients failing on basal alone therapy. Although the benefits of early insulin treatment are well established, a considerable delay in intensifying insulin therapy in patients with sub-optimal glycaemic control is still observed. Most of the patients and physicians are reluctant to intensify therapy due to the fear of hypoglycaemia, regimen complexity, and increased burden of multiple daily injections. In this context, there is a need for a flexible, alternative intensification option taking into account individual patient considerations to achieve or maintain individual glycaemic targets. An ideal insulin regimen should mimic physiological insulin release while providing optimal glycaemic control with low risk of hypoglycaemia, weight gain and fewer daily injections. The current paper reviews the challenges of insulin intensification in patients with type 2 diabetes mellitus poorly controlled on current treatment regimens. PMID:26548029

  8. Giving an insulin injection

    MedlinePlus

    ... room temperature for a month. Gather your supplies: insulin, needles, syringes, alcohol wipes, and a container for used needles ... the plunger to get the right dose of insulin into the syringe. Check the syringe for air bubbles. If there ...

  9. High-mix insulins

    PubMed Central

    Kalra, Sanjay; Farooqi, Mohammad Hamed; El-Houni, Ali E.

    2015-01-01

    Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID:26425485

  10. Insulin pump (image)

    MedlinePlus

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  11. Adherence to Insulin Therapy.

    PubMed

    Sarbacker, G Blair; Urteaga, Elizabeth M

    2016-08-01

    IN BRIEF Six million people with diabetes use insulin either alone or in combination with an oral medication. Many barriers exist that lead to poor adherence with insulin. However, there is an underwhelming amount of data on interventions to address these barriers and improve insulin adherence. Until pharmacological advancements create easier, more acceptable insulin regimens, it is imperative to involve patients in shared decision-making. PMID:27574371

  12. Insulin therapy in pregnancy.

    PubMed

    Kalra, Sanjay; Jawad, Fatema

    2016-09-01

    Insulin is the mainstay of pharmacotherapy in pregnancy complicated by diabetes. This review covers the various insulin regimes and preparations, explaining how to use them, and decide appropriate doses in pregnancy. It approaches insulin treatment from a patient - centred, as well as physician and obstetrician friendly viewpoint, providing pragmatic guidance for management of diabetes in pregnancy. PMID:27582152

  13. Insulin Granule Biogenesis, Trafficking and Exocytosis

    PubMed Central

    Hou, June Chunqiu; Min, Le; Pessin, Jeffrey E.

    2015-01-01

    It is becoming increasingly apparent that beta cell dysfunction resulting in abnormal insulin secretion is the essential element in the progression of patients from a state of impaired glucose tolerance to frank type 2 diabetes (Del Prato, 2003; Del Prato and Tiengo, 2001). Although extensive studies have examined the molecular, cellular and physiologic mechanisms of insulin granule biogenesis, sorting, and exocytosis the precise mechanisms controlling these processes and their dysregulation in the developed of diabetes remains an area of important investigation. We now know that insulin biogenesis initiates with the synthesis of preproinsulin in rough endoplastic reticulum and conversion of preproinsulin to proinsulin. Proinsulin begins to be packaged in the Trans-Golgi Network and is sorting into immature secretory granules. These immature granules become acidic via ATP-dependent proton pump and proinsulin undergoes proteolytic cleavage resulting the formation of insulin and C-peptide. During the granule maturation process, insulin is crystallized with zinc and calcium in the form of dense-core granules and unwanted cargo and membrane proteins undergo selective retrograde trafficking to either the constitutive trafficking pathway for secretion or to degradative pathways. The newly formed mature dense-core insulin granules populate two different intracellular pools, the readily releasable pools (RRP) and the reserved pool. These two distinct populations are thought to be responsible for the biphasic nature of insulin release in which the RRP granules are associated with the plasma membrane and undergo an acute calcium-dependent release accounting for first phase insulin secretion. In contrast, second phase insulin secretion requires the trafficking of the reserved granule pool to the plasma membrane. The initial trigger for insulin granule fusion with the plasma membrane is a rise in intracellular calcium and in the case of glucose stimulation results from

  14. Active suppression of diabetes after oral administration of insulin is determined by antigen dosage.

    PubMed

    Bergerot, I; Fabien, N; Mayer, A; Thivolet, C

    1996-02-13

    We have previously demonstrated that feeding six-week-old female mice with 20 units of human insulin every 2 - 3 days for 15 or 30 days induced an active mechanism of suppression through the generation of regulatory T cells that reduced the number of successful diabetic transfers in irradiated NOD recipients. In the present study, we analyzed the effects of antigen dosage and the critical period of cell injection to obtain protection. The effects of the dose of insulin feeding were therefore compared during cotransfer experiments of 5 x 10(6) T cells from diabetic mice and 5 x 10(6) T cells from the spleen of mice receiving 10 units, 20 units, or 40 units of insulin or saline every 2 - 3 days for 15 days. Only T lymphocytes from mice fed with 20 units conferred active cellular protection during adoptive transfer with a significant delay in diabetes onset (p = 0.002). No significant difference was noticed during histological analysis of pancreatic glands, indicating tha insulitis was not prevented. However, mice receiving T lymphocytes from the 20 units of insulin-fed animals had a milder form of inflammation, with a significantly lower percentage of severely infiltrated islets. Injecting regulatory T cells 7 days and 14 days after iv injection of diabetogenic T cells did not modify the incidence curves of diabetes in the recipients, suggesting that cellular interactions and delay in cell trafficking were determinants. These results may have important clinical implications in humans. In conclusion, this study indicates the importance but also the limits of antigen therapy in type I diabetes. Antigen dosage is a critical element for active suppression. Such analysis is important to perform in humans before the initiation of a large-scale prevention trial in prediabetic individuals. PMID:8610991

  15. The Rationale for Insulin Therapy in Alzheimer's Disease.

    PubMed

    Ribarič, Samo

    2016-01-01

    Alzheimer's disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD. PMID:27240327

  16. Delaying obsolescence.

    PubMed

    Lawlor, Rob

    2015-04-01

    This paper argues that those who emphasise that designers and engineers need to plan for obsolescence are too conservative. Rather, in addition to planning for obsolescence, designers and engineers should also think carefully about what they could do in order delay obsolescence. They should so this by thinking about the design itself, thinking of ways in which products could be useful and appealing for longer before becoming obsolete, as well thinking about the wider context in terms of the marketing of products, and also the social and legal. The paper also considers objections that these suggestions are unrealistically idealistic, failing to recognise the economic realities. I respond to these objections appealing to research in advertising, psychology, cognitive linguistics, philosophy, history, and economics, as well as drawing on the Statement of Ethical Principles developed by the Royal Academy of Engineering and the Engineering Council. PMID:24792878

  17. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin degludec works by replacing the insulin that is normally produced ... insulin label to make sure you received the right type of insulin from the pharmacy.Insulin degludec ...

  18. Basin stability in delayed dynamics

    PubMed Central

    Leng, Siyang; Lin, Wei; Kurths, Jürgen

    2016-01-01

    Basin stability (BS) is a universal concept for complex systems studies, which focuses on the volume of the basin of attraction instead of the traditional linearization-based approach. It has a lot of applications in real-world systems especially in dynamical systems with a phenomenon of multi-stability, which is even more ubiquitous in delayed dynamics such as the firing neurons, the climatological processes, and the power grids. Due to the infinite dimensional property of the space for the initial values, how to properly define the basin’s volume for delayed dynamics remains a fundamental problem. We propose here a technique which projects the infinite dimensional initial state space to a finite-dimensional Euclidean space by expanding the initial function along with different orthogonal or nonorthogonal basis. A generalized concept of basin’s volume in delayed dynamics and a highly practicable calculating algorithm with a cross-validation procedure are provided to numerically estimate the basin of attraction in delayed dynamics. We show potential applicabilities of this approach by applying it to study several representative systems of biological or/and physical significance, including the delayed Hopfield neuronal model with multistability and delayed complex networks with synchronization dynamics. PMID:26907568

  19. Basin stability in delayed dynamics

    NASA Astrophysics Data System (ADS)

    Leng, Siyang; Lin, Wei; Kurths, Jürgen

    2016-02-01

    Basin stability (BS) is a universal concept for complex systems studies, which focuses on the volume of the basin of attraction instead of the traditional linearization-based approach. It has a lot of applications in real-world systems especially in dynamical systems with a phenomenon of multi-stability, which is even more ubiquitous in delayed dynamics such as the firing neurons, the climatological processes, and the power grids. Due to the infinite dimensional property of the space for the initial values, how to properly define the basin’s volume for delayed dynamics remains a fundamental problem. We propose here a technique which projects the infinite dimensional initial state space to a finite-dimensional Euclidean space by expanding the initial function along with different orthogonal or nonorthogonal basis. A generalized concept of basin’s volume in delayed dynamics and a highly practicable calculating algorithm with a cross-validation procedure are provided to numerically estimate the basin of attraction in delayed dynamics. We show potential applicabilities of this approach by applying it to study several representative systems of biological or/and physical significance, including the delayed Hopfield neuronal model with multistability and delayed complex networks with synchronization dynamics.

  20. Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096)

    PubMed Central

    Ratner, R; Wynne, A; Nakhle, S; Brusco, O; Vlajnic, A; Rendell, M

    2011-01-01

    Aim: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. Methods: This was a multicenter, randomized, open-label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A1c (HbA1c) ≥7.5% and ≤10.0% were screened; 345 were randomized and 322 comprised the intent-to-treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, ±metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA1c, fasting plasma glucose and weight from study baseline to endpoint (week 52). Results: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA1c: 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of −0.87 kg (p = 0.243). Conclusion: Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated. PMID:21812890

  1. Oral Insulin Reloaded

    PubMed Central

    Heinemann, Lutz; Plum-Mörschel, Leona

    2014-01-01

    Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structured approach, we aim to provide a systematic update on the most recent developments toward an orally available insulin formulation with a clear focus on data from clinical-experimental and clinical studies. Thirteen companies that claim to be working on oral insulin formulations were identified. However, only 6 of these companies published new clinical trial results within the past 5 years. Interestingly, these clinical data reports make up a mere 4% of the considerably high total number of publications on the development of oral insulin formulations within this time period. While this picture clearly reflects the rising research interest in orally bioavailable insulin formulations, it also highlights the fact that the lion’s share of research efforts is still allocated to the preclinical stages. PMID:24876606

  2. Closed-loop insulin delivery: towards improved diabetes care.

    PubMed

    Kumareswaran, Kavita; Evans, Mark L; Hovorka, Roman

    2012-02-01

    The prevalence of type 1 diabetes is escalating worldwide. Novel therapies and management strategies are needed to reduce associated morbidity. Aggressive blood glucose lowering using conventional insulin replacement regimens is limited by the risk of hypoglycemia. Even the most motivated patients may struggle to manage day-to-day variability in insulin requirements. The artificial pancreas or closed-loop insulin delivery may improve outcomes, building on recent technological progress and combining continuous glucose monitoring with insulin pump therapy. So far, closed-loop prototypes have been evaluated under controlled conditions suggesting improved glucose control and a reduced risk of hypoglycemia. Limitations include suboptimal accuracy and reliability of continuous glucose monitors and delays associated with subcutaneous insulin delivery. Outpatient evaluation is required as the next step, leading to deployment into clinical practice. PMID:22369975

  3. A primer on concentrated insulins: what an internist should know.

    PubMed

    Barnosky, Adrienne; Shah, Lisa; Meah, Farah; Emanuele, Nicholas; Emanuele, Mary Ann; Mazhari, Alaleh

    2016-05-01

    The common insulin concentration in most preparations of insulin is 100 units per mL or U-100. Human regular U-500 insulin was the first concentrated insulin introduced and it has been available in the United States since the 1950s. Humulin R is the only human regular U-500 available on the market. Human regular U-500 is five times more concentrated than U-100 and because of its pharmacodynamic properties, works as both a basal and a bolus insulin. Human regular U500 allows for delivery of a larger insulin dose with a smaller volume leading to better absorption compared to U-100 and has traditionally been used in patients with moderate to severe insulin resistance. More recently other forms of concentrated insulin have become available and the newer concentrated insulin preparations can be used in diabetic patients with or without insulin resistance. Our intent is to provide primary care physicians with a review of the pharmacology and current literature on concentrated insulins as well as recommendations for patient selection, dose initiation, and dose adjustment. PMID:26924668

  4. The Variable Rate Intravenous Insulin Infusion Protocol.

    PubMed

    Collard, Benjamin; Sturgeon, Jonathan; Patel, Natasha; Asharia, Shabbar

    2014-01-01

    Insulin use among inpatients is high and associated with severe and regular medication errors. An initial baseline audit showed a wide variation in the prescription of intravenous insulin within the trust. These included variation in the choice of fluid prescribed, electrolyte levels not consistently checked, handwritten illegible prescriptions, and varying parameters set for adjustment of the prescription. A Variable Rate Intravenous Insulin Infusion protocol (VRIII)) was introduced to standardize intravenous insulin prescription throughout the trust by all members of the clinical team. We looked at and measured uptake and effects of the VRIII protocol in improving standardization of insulin prescription for inpatients on insulin at St George's NHS trust. The protocol was uploaded to the intranet to allow access 24 hours a day and the staff educated about it. The VRIII protocol was routinely used successfully throughout the trust. Any initial problems were addressed through education of clinical staff. The protocol has shown decreased prescribing and administrative errors, whilst demonstrating good glucose and electrolyte control. Use of a standardized protocol helps reduce medication errors and demonstrates good glycaemic control. Regular and continued education of clinical staff is necessary to maintain its efficacy. PMID:26734228

  5. Inhaled insulin: too soon to be forgotten?

    PubMed

    Zarogoulidis, Paul; Papanas, Nikolaos; Kouliatsis, Georgios; Spyratos, Dionysis; Zarogoulidis, Kostas; Maltezos, Efstratios

    2011-10-01

    Inhalation is a potentially viable route of administration for numerous agents. In diabetes mellitus, the need for frequent injections to achieve ideal glycemic control remains a significant limitation for initiating and complying with insulin therapy in a large number of patients. To overcome this barrier, inhaled insulin was developed. The inhalation form of regular human insulin has been tested and administered in a large number of trials. Respiratory capacity was evaluated in patients with normal lung parenchyma in whom inhaled insulin was administered without complications. However, issues like cost, bulky device, fear for lung safety, and the small number of studies in subjects with underlying respiratory disease prevented widespread use of this new mode of delivery. In the present review, we will suggest a number of methods that could be applied in this form of administration to maximize drug absorption and fully exploit the advantages of this route of administration. PMID:21689020

  6. [HLA typing and insulin antibody production in insulin-dependent diabetics].

    PubMed

    Bruni, B; Barolo, P; Gadaleta, G; Gamba Ansaldi, S; Grassi, G; Zerbinati, A; Molinatti, M; Salvetti, E

    1984-01-01

    The literature of the past ten years shows that the introduction of highly purified heterologous and, lastly, homologous insulins has notably lowered the production of IgG and IgE specific insulin antibodies, but has not succeeded in completely eliminating clinical manifestations of the immune or hyper-immune response to insulin therapy. In particular, insulin allergy with or without lipodystrophy is still seen. Among the factors of insulin immunogenicity, there is a possible genetic control of the immune response in type I diabetes: determining HLA halloantigens (A, B, C, D) might identify specific immune response genes (Ir genes). Initial researches, performed until now almost exclusively upon diabetics treated with conventional heterologous insulin, seem to indicate a positive relationship between haplotype HLA - B15 - DR4 and an elevated immune response, whereas haplotypes HLA - B8 - DR3 and HLA - B18 - DR3 might protect against the formation of anti-insulin antibodies. Antigens D/DR3 and D/DR4 are known to be primitively associated to susceptibility for type I diabetes, whereas antigens B8, B15, B18 are secondarily associated to the rise in frequency of DR3 and DR4 for the "linkage disequilibrium" existing between alleles of B and D loci. The results of HLA typing are presented in 2 groups of insulin-dependent diabetics (ID) followed from an immunological viewpoint during therapy with monocomponent heterologous insulin for over 5 years. The first group is composed of 50 patients with low IgG anti-insulin antibody titers (less than 1 mU/ml, Christiansen: low responders); the second group is made up of 23 patients with high IgG anti-insulin antibody titers (greater than 2.5 mU/ml, Christiansen: high responders) and includes 5 subjects with insulin allergy (associated or not with insulin lipoatrophy) and high levels of insulin specific IgE antibodies. A study of the frequencies of various HLA-B antigens in both groups of patients, in regard to a control group of

  7. Evidence-based clinical use of insulin premixtures.

    PubMed

    Tambascia, Marcos Antônio; Nery, Márcia; Gross, Jorge Luiz; Ermetice, Mariana Narbot; de Oliveira, Carolina Piras

    2013-01-01

    Brazil is expected to have 19.6 million patients with diabetes by the year 2030. A key concept in the treatment of type 2 diabetes mellitus (T2DM) is establishing individualized glycemic goals based on each patient's clinical characteristics, which impact the choice of antihyperglycemic therapy. Targets for glycemic control, including fasting blood glucose, postprandial blood glucose, and glycated hemoglobin (A1C), are often not reached solely with antihyperglycemic therapy, and insulin therapy is often required. Basal insulin is considered an initial strategy; however, premixed insulins are convenient and are equally or more effective, especially for patients who require both basal and prandial control but desire a more simplified strategy involving fewer daily injections than a basal-bolus regimen. Most physicians are reluctant to transition patients to insulin treatment due to inappropriate assumptions and insufficient information. We conducted a nonsystematic review in PubMed and identified the most relevant and recently published articles that compared the use of premixed insulin versus basal insulin analogues used alone or in combination with rapid-acting insulin analogues before meals in patients with T2DM. These studies suggest that premixed insulin analogues are equally or more effective in reducing A1C compared to basal insulin analogues alone in spite of the small increase in the risk of nonsevere hypoglycemic events and nonclinically significant weight gain. Premixed insulin analogues can be used in insulin-naïve patients, in patients already on basal insulin therapy, and those using basal-bolus therapy who are noncompliant with blood glucose self-monitoring and titration of multiple insulin doses. We additionally provide practical aspects related to titration for the specific premixed insulin analogue formulations commercially available in Brazil. PMID:24011173

  8. Study Design for the IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care) Trial: A Double-blind Randomized Controlled Trial of Intravenous Glucose, Insulin, and Potassium (GIK) for Acute Coronary Syndromes in Emergency Medical Services

    PubMed Central

    Selker, Harry P.; Beshansky, Joni R.; Griffith, John L.; D’Agostino, Ralph B.; Massaro, Joseph M.; Udelson, James E.; Rashba, Eric J.; Ruthazer, Robin; Sheehan, Patricia R.; Desvigne-Nickens, Patrice; Rosenberg, Yves D.; Atkins, James M.; Sayah, Assaad J.; Aufderheide, Tom P.; Rackley, Charles E.; Opie, Lionel H.; Lambrew, Costas T.; Cobb, Leonard A.; MacLeod, Bruce A.; Ingwall, Joanne S.; Zalenski, Robert J.; Apstein, Carl S.

    2014-01-01

    Background Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris (UAP) to acute myocardial infarction (AMI), and MI size. However, trials of hospital administration of IV GIK to patients with ST elevation MI (STEMI) have generally not shown favorable effects, possibly due to the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. Objective The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK 1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and 2) administered in prehospital emergency medical service (EMS) settings, rather than later, in hospitals, following emergency department evaluation. Design IMMEDIATE was an EMS-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the US which enrolled 911 participants. Eligible were patients age 30 or older for whom a paramedic performed a 12-lead electrocardiogram (ECG)to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based ACI-TIPI (acute cardiac ischemia time-insensitive predictive instrument) indicated a > 75% probability of ACS, and/or the TPI (thrombolytic predictive instrument) indicated presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Pre-specified were the primary endpoint of progression of ACS to infarction, and as major secondary endpoints

  9. One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care] Trial).

    PubMed

    Selker, Harry P; Udelson, James E; Massaro, Joseph M; Ruthazer, Robin; D'Agostino, Ralph B; Griffith, John L; Sheehan, Patricia R; Desvigne-Nickens, Patrice; Rosenberg, Yves; Tian, Xin; Vickery, Ellen M; Atkins, James M; Aufderheide, Tom P; Sayah, Assaad J; Pirrallo, Ronald G; Levy, Michael K; Richards, Michael E; Braude, Darren A; Doyle, Delanor D; Frascone, Ralph J; Kosiak, Donald J; Leaming, James M; Van Gelder, Carin M; Walter, Gert-Paul; Wayne, Marvin A; Woolard, Robert H; Beshansky, Joni R

    2014-05-15

    The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefits. Here we report 1-year outcomes. Prespecified 1-year end points of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Of 871 participants randomized to GIK versus placebo, death occurred within 1 year in 11.6% versus 13.5%, respectively (unadjusted hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.57 to 1.23, p = 0.36). The composite of cardiac arrest or 1-year mortality was 12.8% versus 17.0% (HR 0.71, 95% CI 0.50 to 1.02, p = 0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% versus 17.2% (HR 0.98, 95% CI 0.70 to 1.37, p = 0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% versus 20.4% (HR 0.85, 95% CI 0.62 to 1.16, p = 0.30). In patients presenting with suspected ST elevation myocardial infarction, HRs for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33 to 1.27, p = 0.21), 0.52 (95% CI 0.30 to 0.92, p = 0.03), 0.63 (95% CI 0.35 to 1.16, p = 0.14), and 0.51 (95% CI 0.30 to 0.87, p = 0.01). In patients with suspected acute coronary syndromes, serious end points generally were lower with GIK than placebo, but the differences were not statistically significant. However, in those with ST elevation myocardial infarction, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced. PMID:24792735

  10. Flexibility in insulin prescription

    PubMed Central

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  11. Flexibility in insulin prescription.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  12. Molecular Basis of Catalytic Chamber-assisted Unfolding and Cleavage of Human Insulin by Human Insulin-degrading Enzyme

    SciTech Connect

    Manolopoulou, Marika; Guo, Qing; Malito, Enrico; Schilling, Alexander B.; Tang, Wei-Jen

    2009-06-02

    Insulin is a hormone vital for glucose homeostasis, and insulin-degrading enzyme (IDE) plays a key role in its clearance. IDE exhibits a remarkable specificity to degrade insulin without breaking the disulfide bonds that hold the insulin A and B chains together. Using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to obtain high mass accuracy, and electron capture dissociation (ECD) to selectively break the disulfide bonds in gas phase fragmentation, we determined the cleavage sites and composition of human insulin fragments generated by human IDE. Our time-dependent analysis of IDE-digested insulin fragments reveals that IDE is highly processive in its initial cleavage at the middle of both the insulin A and B chains. This ensures that IDE effectively splits insulin into inactive N- and C-terminal halves without breaking the disulfide bonds. To understand the molecular basis of the recognition and unfolding of insulin by IDE, we determined a 2.6-A resolution insulin-bound IDE structure. Our structure reveals that IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. This structure also highlights how the unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity ( approximately 100 nm) for insulin. In addition, this structure shows how IDE utilizes the interaction of its exosite with the N terminus of the insulin A chain as well as other properties of the catalytic chamber to guide the unfolding of insulin and allowing for the processive cleavages.

  13. Insight into Insulin Secretion from Transcriptome and Genetic Analysis of Insulin-Producing Cells of Drosophila

    PubMed Central

    Cao, Jian; Ni, Julie; Ma, Wenxiu; Shiu, Vanessa; Milla, Luis A.; Park, Sangbin; Spletter, Maria L.; Tang, Sheng; Zhang, Jun; Wei, Xing; Kim, Seung K.; Scott, Matthew P.

    2014-01-01

    Insulin-producing cells (IPCs) in the Drosophila brain produce and release insulin-like peptides (ILPs) to the hemolymph. ILPs are crucial for growth and regulation of metabolic activity in flies, functions analogous to those of mammalian insulin and insulin-like growth factors (IGFs). To identify components functioning in IPCs to control ILP production, we employed genomic and candidate gene approaches. We used laser microdissection and messenger RNA sequencing to characterize the transcriptome of larval IPCs. IPCs highly express many genes homologous to genes active in insulin-producing β-cells of the mammalian pancreas. The genes in common encode ILPs and proteins that control insulin metabolism, storage, secretion, β-cell proliferation, and some not previously linked to insulin production or β-cell function. Among these novelties is unc-104, a kinesin 3 family gene, which is more highly expressed in IPCs compared to most other neurons. Knockdown of unc-104 in IPCs impaired ILP secretion and reduced peripheral insulin signaling. Unc-104 appears to transport ILPs along axons. As a complementary approach, we tested dominant-negative Rab genes to find Rab proteins required in IPCs for ILP production or secretion. Rab1 was identified as crucial for ILP trafficking in IPCs. Inhibition of Rab1 in IPCs increased circulating sugar levels, delayed development, and lowered weight and body size. Immunofluorescence labeling of Rab1 showed its tight association with ILP2 in the Golgi of IPCs. Unc-104 and Rab1 join other proteins required for ILP transport in IPCs. PMID:24558258

  14. Insulin structure and function.

    PubMed

    Mayer, John P; Zhang, Faming; DiMarchi, Richard D

    2007-01-01

    Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported. PMID:17410596

  15. Alternative Devices for Taking Insulin

    MedlinePlus

    ... pumps contain enough insulin for several days. An infusion set carries insulin from the pump to the ... tube or needle inserted under the skin. Disposable infusion sets are used with insulin pumps to deliver ...

  16. Anti-insulin antibody test

    MedlinePlus

    Insulin antibodies - serum; Insulin Ab test ... Normally, there are no antibodies against insulin in your blood. Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or ...

  17. Spotlight on insulin glargine in type 1 and 2 diabetes mellitus.

    PubMed

    McKeage, Kate; Goa, Karen L

    2002-01-01

    Insulin glargine is a recombinant human insulin analog produced by DNA technology using a nonpathogenic strain of Escherichia coli. Two modifications of human insulin result in a stable molecule which is soluble in slightly acidic conditions (pH 4.0) and precipitates in the neutral pH of subcutaneous tissue. Because of these properties, absorption of insulin glargine is delayed and the analog provides a fairly constant, basal insulin supply without peaks in plasma insulin levels for approximately 24 hours, similar to that achieved by a continuous subcutaneous insulin infusion. Insulin glargine is indicated as a once daily subcutaneous injection to provide basal glycemic control in adults and children aged >6 years with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Fasting plasma glucose and fasting blood glucose levels generally improved to a greater extent in patients with type 1 diabetes mellitus receiving insulin glargine than patients who administered Neutral Protamine Hagedorn (NPH) insulin. In patients with type 1 or 2 disease, glycosylated hemoglobin levels were slightly reduced and to a similar extent with insulin glargine and NPH insulin. Most clinical trials in patients with type 1 or 2 diabetes mellitus demonstrated a lower incidence of hypoglycemia, especially nocturnal hypoglycemia, with insulin glargine compared with NPH insulin. One of the most common adverse events with insulin glargine treatment was injection site pain which, in some studies, occurred more frequently than in patients receiving NPH insulin. In all cases the symptoms were mild and treatment discontinuation was not required. Otherwise, the drug is well tolerated and does not appear to be immunogenic. In conclusion, insulin glargine once a day provides basal control of glycemia for approximately 24 hours without inducing peaks in plasma insulin levels in patients with type 1 or 2 diabetes mellitus. In long-term, well designed trials insulin glargine once daily

  18. Conversion of linear time-invariant time-delay feedback systems into delay-differential equations with commensurate delays

    NASA Astrophysics Data System (ADS)

    Yamazaki, Tatsuya; Hagiwara, Tomomichi

    2014-08-01

    A new stability analysis method of time-delay systems (TDSs) called the monodromy operator approach has been studied under the assumption that a TDS is represented as a time-delay feedback system consisting of a finite-dimensional linear time-invariant (LTI) system and a pure delay. For applying this approach to TDSs described by delay-differential equations (DDEs), the problem of converting DDEs into representation as time-delay feedback systems has been studied. With regard to such a problem, it was shown that, under discontinuous initial functions, it is natural to define the solutions of DDEs in two different ways, and the above conversion problem was solved for each of these two definitions. More precisely, the solution of a DDE was represented as either the state of the finite-dimensional part of a time-delay feedback system or a part of the output of another time-delay feedback system, depending on which definition of the DDE solution one is talking about. Motivated by the importance in establishing a thorough relationship between time-delay feedback systems and DDEs, this paper discusses the opposite problem of converting time-delay feedback systems into representation as DDEs, including the discussions about the conversion of the initial conditions. We show that the state of (the finite-dimensional part of) a time-delay feedback system can be represented as the solution of a DDE in the sense of one of the two definitions, while its 'essential' output can be represented as that of another DDE in the sense of the other type of definition. Rigorously speaking, however, it is also shown that the latter representation is possible regardless of the initial conditions, while some initial condition could prevent the conversion into the former representation. This study hence establishes that the representation of TDSs as time-delay feedback systems possesses higher ability than that with DDEs, as description methods for LTI TDSs with commensurate delays.

  19. [Factors limiting glycaemic control in insulin-treated type 2 diabetes].

    PubMed

    Ferencz, Viktória; Domján, Beatrix; Gerő, László; Tänczer, Tímea; Tabák, Gy Ádám

    2015-09-01

    Insulin therapy is the most effective treatment of diabetes. It is proven to prevent microvascular disease and likely to decrease the risk of cardiovascular complications. However, these benefits are associated with a 2-3 times increased risk of hypoglycaemia and a faster weight gain compared to other antidiabetic medications. In addition, one study found elevated all-cause mortality among patients on intensive therapy (requiring more frequent insulinisation). Insulin has growth factor properties that may translate to increased mitogenicity. These factors could prevent the medical team or the patient from initiation or intensification of insulin therapy. The authors describe evidence on long-term remission related to transient intensified insulin therapy at diabetes diagnosis. The currently recommended method of insulin initiation is once daily basal insulin treatment that offers different schedules for intensification. The authors review the pharmacokinetics of analogue insulins that translate to similar efficacy to human insulins with a 20-30% lower risk of hypoglycaemia. PMID:26320598

  20. Flexibility in the insulin receptor ectodomain enables docking of insulin in crystallographic conformation observed in a hormone-bound microreceptor.

    PubMed

    Vashisth, Harish

    2014-01-01

    Insulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of the epitopes (Site 1) is beginning to emerge from recent structural evidence. However, insulin-bound structures of truncated IR suggest that crystallographic conformation of insulin cannot be accommodated in the full IR ectodomain due to steric overlap of insulin with the first two type III fibronectin domains (F1 and F2), which are contributed to the insulin binding-pocket by the second subunit in the IR homodimer. A conformational change in the F1-F2 pair has thus been suggested. In this work, we present an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed. This structural model was arrived at by flexibly fitting parts of our earlier insulin/IR all-atom model into the simulated density maps of crystallized constructs combined with conformational sampling from apo-IR solution conformations. Importantly, our experimentally-consistent model helps rationalize yet unresolved Site. PMID:25309993

  1. Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes?

    PubMed

    Home, P D

    2015-11-01

    Many people with diabetes rely on insulin therapy to achieve optimal blood glucose control. A fundamental aim of such therapy is to mimic the pattern of 'normal' physiological insulin secretion, thereby controlling basal and meal-time plasma glucose and fatty acid turnover. In people without diabetes, insulin release is modulated on a time base of 3-10 min, something that is impossible to replicate without intravascular glucose sensing and insulin delivery. Overnight physiological insulin delivery by islet β cells is unchanging, in contrast to requirements once any degree of hyperglycaemia occurs, when diurnal influences are evident. Subcutaneous pumped insulin or injected insulin analogues can approach the physiological profile, but there remains the challenge of responding to day-to-day changes in insulin sensitivity. Physiologically, meal-time insulin release begins rapidly in response to reflex activity and incretins, continuing with the rise in glucose and amino acid concentrations. This rapid response reflects the need to fill the insulin space with maximum concentration as early as 30 min after starting the meal. Current meal-time insulins, by contrast, are associated with a delay after injection before absorption begins, and a delay to peak because of tissue diffusion. While decay from peak for monomeric analogues is not dissimilar to average physiological needs, changes in meal type and, again, in day-to-day insulin sensitivity, are difficult to match. Recent and current developments in insulin depot technology are moving towards establishing flatter basal and closer-to-average physiological meal-time plasma insulin profiles. The present article discusses the ideal physiological insulin profile, how this can be met by available and future insulin therapies and devices, and the challenges faced by healthcare professionals and people with diabetes in trying to achieve an optimum plasma insulin profile. PMID:26041603

  2. Protein Crystal Bovine Insulin

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The comparison of protein crystal, Bovine Insulin space-grown (left) and earth-grown (right). Facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  3. Devices for insulin administration.

    PubMed

    Selam, J L; Charles, M A

    1990-09-01

    There is a significant need for revised, safe, and more effective insulin-delivery methods than subcutaneous injections in the treatment of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. The aim of this review is to describe the rationale and methods for better use of injection and infusion devices for intensive insulin therapy and to describe results of animal and human research that will lead to an implantable artificial pancreas. Injection devices, e.g., jet injectors, insulin pens, and access ports, cannot be considered as a major breakthrough in the quest for improved control, although they may improve the patient's comfort. External pumps have benefits over multiple injections and conventional insulin therapy only in specific subgroups of patients, e.g., those with recurrent severe hypoglycemia, but only when used by experienced personnel. The external artificial pancreas (Biostator) is also to be used by experienced personnel for limited clinical and research applications, e.g., surgery of the diabetic patient. The development of an implantable version of the artificial pancreas is linked to progress in the field of reliable long-duration glucose sensors. Finally, programmable implantable insulin pumps, used as an open-loop delivery system, are the most promising alternative to intensive subcutaneous insulin strategies in the short term, although clear evidence of improved safety and efficacy remains to be documented. PMID:2226111

  4. Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin Pumps

    PubMed Central

    Valla, Vasiliki

    2010-01-01

    Aim. Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Results. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial “closed-loop” systems mimicking the pancreatic activity have been also developed. Conclusions. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients. PMID:20589066

  5. Insulin use: preventable errors.

    PubMed

    2014-01-01

    Insulin is vital for patients with type 1 diabetes and useful for certain patients with type 2 diabetes. The serious consequences of insulin-related medication errors are overdose, resulting in severe hypoglycaemia, causing seizures, coma and even death; or underdose, resulting in hyperglycaemia and sometimes ketoacidosis. Errors associated with the preparation and administration of insulin are often reported, both outside and inside the hospital setting. These errors are preventable. By analysing reports from organisations devoted to medication error prevention and from poison control centres, as well as a few studies and detailed case reports of medication errors, various types of error associated with insulin use have been identified, especially in the hospital setting. Generally, patients know more about the practicalities of their insulin treatment than healthcare professionals with intermittent involvement. Medication errors involving insulin can occur at each step of the medication-use process: prescribing, data entry, preparation, dispensing and administration. When prescribing insulin, wrong-dose errors have been caused by the use of abbreviations, especially "U" instead of the word "units" (often resulting in a 10-fold overdose because the "U" is read as a zero), or by failing to write the drug's name correctly or in full. In electronic prescribing, the sheer number of insulin products is a source of confusion and, ultimately, wrong-dose errors, and often overdose. Prescribing, dispensing or administration software is rarely compatible with insulin prescriptions in which the dose is adjusted on the basis of the patient's subsequent capillary blood glucose readings, and can therefore generate errors. When preparing and dispensing insulin, a tuberculin syringe is sometimes used instead of an insulin syringe, leading to overdose. Other errors arise from confusion created by similar packaging, between different insulin products or between insulin and other

  6. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  7. Is it dietary insulin?

    PubMed

    Vaarala, Outi

    2006-10-01

    In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect beta cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets. PMID:17130578

  8. Government delays release of medical marijuana supply.

    PubMed

    Scanlon, Liz

    2002-07-01

    The federal government's initiative to make marijuana available for medical use continues to run into problems and delays. In a recent development, the first crop produced by the government's designated grower turned out to be too impure to use. The delays have led to the launch of a lawsuit against the federal government. PMID:14765485

  9. Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites

    SciTech Connect

    Duckworth, W.C.; Garcia, J.V.; Liepnieks, J.J.; Hamel, F.G.; Hermodson, M.A.; Frank, B.H.; Rosner, M.R. )

    1989-03-21

    Insulin degradation is an integral part of the cellular action of insulin. Recent evidence suggests that the enzyme insulin protease is involved in the degradation of insulin in mammalian tissues. Drosophila, which has insulin-like hormones and insulin receptor homologues, also expresses an insulin degrading enzyme with properties that are very similar to those of mammalian insulin protease. In the present study, the insulin cleavage products generated by the Drosophila insulin degrading enzyme were identified and compared with the products generated by the mammalian insulin protease. Both purified enzymes were incubated with porcine insulin specifically labeled with {sup 125}I on either the A19 or B26 position, and the degradation products were analyzed by HPLC before and after sulfitolysis. Isolation and sequencing of the cleavage products indicated that both enzymes cleave the A chain of intact insulin at identical sites between residues A13 and A14 and A14 and A15. These results demonstrate that all the insulin cleavage sites generated by the Drosopohila insulin degrading enzyme are shared in common with the mammalian insulin protease. These data support the hypothesis that there is evolutionary conservation of the insulin degrading enzyme and further suggest that this enzyme plays an important role in cellular function.

  10. Tagging insulin in microgravity

    NASA Technical Reports Server (NTRS)

    Dobeck, Michael; Nelson, Ronald S.

    1992-01-01

    Knowing the exact subcellular sites of action of insulin in the body has the potential to give basic science investigators a basis from which a cause and cure for this disease can be approached. The goal of this project is to create a test reagent that can be used to visualize these subcellular sites. The unique microgravity environment of the Shuttle will allow the creation of a reagent that has the possibility of elucidating the subcellular sites of action of insulin. Several techniques have been used in an attempt to isolate the sites of action of items such as insulin. One of these is autoradiography in which the test item is obtained from animals fed radioactive materials. What is clearly needed is to visualize individual insulin molecules at their sites of action. The insulin tagging process to be used on G-399 involves the conjugation of insulin molecules with ferritin molecules to create a reagent that will be used back on Earth in an attempt to elucidate the sites of action of insulin.

  11. Technosphere inhaled insulin (Afrezza).

    PubMed

    Rendell, M

    2014-12-01

    Technosphere® insulin uses a unique carrier -fumaryl diketopiperazine (FDKP)- which adsorbs insulin to form microparticles to permit delivery to the alveoli by inhalation. Toxicity studies have been entirely negative. The pulmonary absorption of insulin is very rapid, and the disappearance time is shorter than for subcutaneously delivered rapid-acting insulins. As a result, after inhalation, there is a rapid drop in glucose levels which subsequently return to normal in a shorter time than after subcutaneous insulin administration. Consequently, there is a lower incidence of hypoglycemic reactions. Pulmonary function studies have shown a small, reversible decrease in FEV1, and pulmonary imaging studies have shown no adverse effect. The inhalation of Technosphere insulin can produce a cough in up to 27% of patients. The cough has resulted in discontinuance in as many as 9% of users. Technosphere insulin has been approved for use in type 1 and type 2 diabetes. Long-term studies of pulmonary safety and surveillance for malignancy will be performed in the future. Studies to assess the optimal time dosing regimen are needed. PMID:25588086

  12. [Alleged suicide by insulin].

    PubMed

    Birngruber, Christoph G; Krüll, Ralf; Dettmeyer, Reinhard; Verhoff, Marcel A

    2015-01-01

    A 26-year-old man, who was on probation, was found dead in his home by his mother. Insulin vials and 2 insulin pens, which the man's stepfather (an insulin-dependent diabetic) had been missing for over a week, were found next to the deceased. The circumstances suggested suicide by an injected insulin overdose. At the time of the autopsy, the corpse showed already marked signs of autolysis. Clinical chemical tests confirmed the injection of insulin, but indicated hyperglycemia at the time of death. Toxicological analyses revealed that the man had consumed amphetamine, cannabinoids, and tramadol in the recent past. Histological examination finally revealed extensive bronchopneumonia as the cause of death. The most plausible explanation for the results of the autopsy and the additional examinations was an injection of insulin as a failed attempt of self-treatment. It is conceivable that the man had discovered by a rapid test that he was a diabetic, but had decided not to go to a doctor to avoid disclosure of parole violation due to continued drug abuse. He may have misinterpreted the symptoms caused by his worsening bronchitis and the developing bronchopneumonia as symptoms of a diabetic metabolic status and may have felt compelled to treat himself with insulin. PMID:26419091

  13. Computation of signal delays in RC networks

    NASA Technical Reports Server (NTRS)

    Hidalgo, Juan Carlos; Narendran, Paliath; Chaiken, Seth

    1993-01-01

    A model for signal delay computation in RC networks is presented. The strength of the paradigm is its generality and simplicity. The definition of delay is applicable to RC meshes with potential resistive attenuating paths to ground. The algorithms can also be applied to undriven circuits (static charge sharing) and circuits with initial charge. To compute the delays, each node in the network is explored locally to derive a system of sparse linear equations. The solutions of the system are delay values based on the Elmore time constant at each point in the circuit.

  14. Computation of signal delays in RC networks

    NASA Astrophysics Data System (ADS)

    Hidalgo, Juan Carlos; Narendran, Paliath; Chaiken, Seth

    A model for signal delay computation in RC networks is presented. The strength of the paradigm is its generality and simplicity. The definition of delay is applicable to RC meshes with potential resistive attenuating paths to ground. The algorithms can also be applied to undriven circuits (static charge sharing) and circuits with initial charge. To compute the delays, each node in the network is explored locally to derive a system of sparse linear equations. The solutions of the system are delay values based on the Elmore time constant at each point in the circuit.

  15. Insulin and the law.

    PubMed

    Marks, Vincent

    2015-11-01

    Hypoglycaemia, if it can be proved, may be used as a defence against almost any criminal charge provided it can be established that the perpetrator was in a state of neuroglycopenic (hypoglycaemic) automatism at the time of the offence. Hypoglycaemia produced by exogenous insulin can also be used as a suicidal or homicidal weapon. This paper discusses some of the pitfalls confronting the investigator of suspected insulin misuse including problems arising from the increasing prevalence of insulin analogues and the unreliability of immunoassays for their detection and measurement in the forensic context. PMID:26092979

  16. Insulin glulisine: insulin receptor signaling characteristics in vivo.

    PubMed

    Hennige, Anita M; Lehmann, Rainer; Weigert, Cora; Moeschel, Klaus; Schäuble, Myriam; Metzinger, Elisabeth; Lammers, Reiner; Häring, Hans-Ulrich

    2005-02-01

    In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment. PMID:15677493

  17. Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise.

    PubMed

    Cartee, Gregory D

    2015-12-15

    Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24-48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

  18. Delay banking for air traffic management

    NASA Technical Reports Server (NTRS)

    Green, Steven M. (Inventor)

    2007-01-01

    A method and associated system for time delay banking for aircraft arrival time, aircraft departure time and/or en route flight position. The delay credit value for a given flight may decrease with passage of time and may be transferred to or traded with other flights having the same or a different user (airline owner or operator). The delay credit value for a given aircraft flight depends upon an initial delay credit value, which is determined by a central system and depends upon one or more other flight characteristics. Optionally, the delay credit value decreases with passage of time. Optionally, a transaction cost is assessed against a delay credit value that is used on behalf of another flight with the same user or is traded with a different user.

  19. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  20. Insulin Resistance and Prediabetes

    MedlinePlus

    ... sleep apnea; and cigarette smoking. [ Top ] Does sleep matter? Yes. Studies show that untreated sleep problems, especially ... a severe form of insulin resistance may have dark patches of skin, usually on the back of ...

  1. Insulin Lispro Injection

    MedlinePlus

    ... a solution (liquid) and a suspension (liquid with particles that will settle on standing) to inject subcutaneously ( ... if it is colored, cloudy, or contains solid particles. If you are using insulin lispro suspension, the ...

  2. Insulin Human Inhalation

    MedlinePlus

    ... inhalation comes as a powder to inhale by mouth using a special inhaler. It is usually used ... to your doctor.Before you use your insulin oral inhaler the first time, read the written instructions ...

  3. Moving toward the ideal insulin for insulin pumps.

    PubMed

    Cengiz, Eda; Bode, Bruce; Van Name, Michelle; Tamborlane, William V

    2016-01-01

    Advances in insulin formulations have been important for diabetes management and achieving optimal glycemic control. Rapid-acting insulin analogs provide a faster time-action profile than regular insulin and are approved for use in pumps. However, the need remains for therapy to deliver a more physiologic insulin profile. New insulin formulations and delivery methods are in development, with the aim of accelerating insulin absorption to accomplish ultra-fast-acting insulin time-action profiles. Furthermore, the integration of continuous glucose monitoring with insulin pump therapy enables on-going adjustment of insulin delivery to optimize glycemic control throughout the day and night. These technological and pharmacological advances are likely to facilitate the development of closed-loop pump systems (i.e., artificial pancreas), and improve glycemic control and quality of life for patients with diabetes. PMID:26560137

  4. Insulin allergy treated with human insulin (recombinant DNA).

    PubMed

    De Leeuw, I; Delvigne, C; Bekaert, J

    1982-01-01

    Two insulin-dependent diabetic subjects treated with pork and beef insulin during a period of 6 mo developed severe local reactions. Both patients had an important allergic history (asthma, urticaria, drug reactions, rhinitis). Skin-testing revealed type I allergy to beef and pork insulin. Specific IgE-insulin binding was demonstrated with both insulins. After negative skin testing with NPH Lilly human insulin (recombinant DNA), treatment was started with this compound and remained successful during a period of 6-9 mo. In one patient a local reaction occurred when regular human insulin (recombinant DNA) was added to NPH in order to obtain better control. Skin testing with regular human insulin was positive, but not with NPH human insulin alone. The mechanism of this phenomenon remains unsolved. PMID:6765530

  5. Early identification of motor delay

    PubMed Central

    Harris, Susan R.

    2016-01-01

    Objective To describe the Harris Infant Neuromotor Test (HINT), an infant neuromotor test using Canadian norms published in 2010 that could be used to screen for motor delay during the first year of life. Quality of evidence Extensive research has been published on the intrarater, interrater, and test-retest reliability and the content, concurrent, predictive, and known-groups validity of the HINT, as well as on the sensitivity, specificity, and positive and negative predictive values of parental concerns, as assessed by the HINT. Most evidence is level II. Main message Diagnosing motor delays during the first year of life is important because these often indicate more generalized developmental delays or specific disabilities, such as cerebral palsy. Parental concerns about their children’s motor development are strongly predictive of subsequent diagnoses involving motor delay. Conclusion Only through early identification of developmental motor delays, initially with screening tools such as the HINT, is it possible to provide referrals for early intervention that could benefit both the infant and the family. PMID:27521388

  6. Practical aspects and considerations when switching between continuous subcutaneous insulin infusion and multiple daily injections.

    PubMed

    Meneghini, Luigi; Sparrow-Bodenmiller, Jane

    2010-06-01

    Insulin pump therapy is considered the gold standard for insulin management in patients requiring full physiologic insulin replacement. Compared to traditional delivery of short- and long-acting insulin preparations by multiple daily insulin injections, delivery of insulin via continuous subcutaneous infusion brings with it several advantages, which in the past have translated into better glycemic control and treatment satisfaction. Delivery of insulin via pump reduces the number needle insertions (from four or five per day to once every 2-3 days), allows for greater flexibility of insulin delivery with regard to both the basal and prandial component, facilitates portability of the insulin preparation, and allows for more accurate dosing. Continuous subcutaneous insulin infusion does have some drawbacks, including a greater risk of inadvertent insulin non-delivery, greater costs of therapy, and the need to be "tethered" with some systems that might be considered "burdensome" or even undesirable to some patients. For the most part patients who initiate insulin pump therapy are satisfied and continue using the technology, but there might be instances that arise that require the re-introduction of insulin delivery by pen or syringe. This article will review some of the reasons and strategies for switching from one mode of delivery to the other. PMID:20515298

  7. Insulin regulation of Na/K pump activity in rat hepatoma cells

    SciTech Connect

    Gelehrter, T.D.; Shreve, P.D.; Dilworth, V.M.

    1984-05-01

    Insulin rapidly increases Na/K pump activity in HTC rat hepatoma cells in tissue culture, as measured by the ouabain-sensitive influx of the potassium analogue 86Rb+. Increased influx is observed within minutes and is maximal (70% above control) within 1-2 h. The effect appears to be mediated by the insulin receptors, as: the concentration dependence on insulin is identical to that for insulin induction of tyrosine aminotransferase and stimulation of 2-aminoisobutyric acid transport, proinsulin is 6% as potent as insulin, and the effect is blocked by anti-receptor antibodies. The early stimulation of potassium influx is not blocked by cycloheximide and is not associated with an increased number of pump sites as measured by /sup 3/H-ouabain binding. The insulin effect is blocked by amiloride, which blocks sodium influx, and is mimicked by the sodium ionophore monensin, which increases sodium influx and intracellular accumulation. Insulin also rapidly increases the initial rate of /sup 22/Na+ influx, suggesting that insulin may enhance Na/K pump activity, in part, by increasing intracellular sodium concentration. Incubation of HTC cells with insulin for 24 h causes complete unresponsiveness to the insulin induction of transaminase and stimulation of amino acid transport, a phenomenon mediated by postbinding mechanisms. In contrast, similar incubation with insulin does not cause unresponsiveness to the insulin stimulation of Na/K pump activity. Therefore, the site of regulation of responsiveness to insulin must be distal to, or separate from, those events causing stimulation of ion fluxes.

  8. Do the Adjusting- and Increasing-Delay Tasks Measure the Same Construct – Delay Discounting?

    PubMed Central

    Craig, Andrew R.; Maxfield, Adam D.; Stein, Jeffrey S.; Renda, C. Renee; Madden, Gregory J.

    2014-01-01

    Delay discounting describes the subjective devaluation of a reward when it is delayed. In animals, the adjusting- and increasing-delay tasks often are used to assess individual differences in, and drug effects on, delay discounting. No study to date, however, has compared systematically the measures of discounting produced in these tasks. The current study examined the correlation between measures of delay discounting derived from adjusting- and increasing-delay procedures. Twenty rats completed 30 sessions under each task (order counterbalanced across rats). Quantitative measures of delay discounting produced by the two tasks were positively correlated, suggesting that the adjusting-and increasing-delay tasks measure the same underlying facet of impulsive choice (i.e., individual or conjoint sensitivities to reward delay and magnitude). The measures derived from either task, however, depended on the sequences in which the tasks were experienced. That is, pre-exposure to one task decreased discounting of delayed rewards in the second task. Consistent with other published findings, exposure to delayed consequences during the initial discounting assessment might explain this effect. Despite the observed correlation between ID and AD indifference delays, we suggest that the ID procedure might be a more appropriate procedure for pharmacological studies. PMID:24978484

  9. Insulin pump therapy in pregnancy.

    PubMed

    Kesavadev, Jothydev

    2016-09-01

    Control of blood glucose during pregnancy is difficult because of wide variations, ongoing hormonal changes and mood swings. The need for multiple injections, pain at the injection site, regular monitoring and skillful handling of the syringes/pen further makes insulin therapy inconvenient. Insulin pump is gaining popularity in pregnancy because it mimics the insulin delivery of a healthy human pancreas. Multiple guidelines have also recommended the use of insulin pump in pregnancy to maintain the glycaemic control. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal and the newer devices can shut down insulin delivery before the occurrence of hypoglycaemia. Pump insulin of choice is rapid acting analogue insulin. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinic experience. PMID:27582150

  10. Delayed orgasm and anorgasmia.

    PubMed

    Jenkins, Lawrence C; Mulhall, John P

    2015-11-01

    Delayed orgasm/anorgasmia defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm and anorgasmia are associated with significant sexual dissatisfaction. A focused medical history can shed light on the potential etiologies, which include medications, penile sensation loss, endocrinopathies, penile hyperstimulation, and psychological etiologies. Unfortunately, there are no excellent pharmacotherapies for delayed orgasm/anorgasmia, and treatment revolves largely around addressing potential causative factors and psychotherapy. PMID:26439762

  11. Influence of anti-insulin antibodies on insulin immunoassays in the autoimmune insulin syndrome.

    PubMed

    Casesnoves, A; Mauri, M; Dominguez, J R; Alfayate, R; Picó, A M

    1998-11-01

    The autoimmune insulin syndrome (AIS) is a rare, benign syndrome characterized by hyperinsulinaemia and hypoglycaemia associated with the presence of autoantibodies to insulin in patients who have not been treated with insulin. We report here the case of a 52-year-old patient with recurrent attacks of severe postprandial hypoglycaemia and we also present the effect of anti-insulin antibodies on insulin immunoassays. The patient was submitted to the following diagnostic tests: 5-h oral glucose tolerance test (OGTT), a prolonged 72-h fast and an insulin tolerance test (ITT). Serum glucose, total and free insulin, C-peptide, proinsulin, insulin antibodies and other autoantibodies were measured. Insulin concentrations were measured by two methods: a double antibody radioimmunoassay (RIA) and an immunoradiometric assay (IRMA). Insulin concentration measured by RIA was extremely high in the OGTT and 72-h fast. In contrast, insulin concentrations measured by IRMA were between 120 and 888 pmol/L in the OGTT and between 37 and 133 pmol/L during the 72-h fast. Fasting free-insulin concentrations measured by RIA were between 2224 and 2669 pmol/L, whereas free-insulin concentrations measured by IRMA ranged between 93 and 237 pmol/L. Total insulin concentrations measured by RIA and IRMA were 57,615 and 94,021 pmol/L, respectively. The C-peptide concentrations were moderately high in the three tests. Serum insulin antibody concentrations were extremely high (62-71%), compared with less than 3% in normal serum samples. In conclusion, the high insulin concentrations measured by RIA were caused by insulin autoantibodies. However, insulin concentrations measured by IRMA were not influenced by them. We conclude that IRMA is the more accurate method for measuring insulin concentrations in such cases. PMID:9838991

  12. Autonomic blockade improves insulin sensitivity in obese subjects.

    PubMed

    Gamboa, Alfredo; Okamoto, Luis E; Arnold, Amy C; Figueroa, Rocio A; Diedrich, André; Raj, Satish R; Paranjape, Sachin Y; Farley, Ginnie; Abumrad, Naji; Biaggioni, Italo

    2014-10-01

    Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake (MBW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m(2) body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P=0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects (MBW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P=0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation. PMID:25001269

  13. Insulin algorithms in the self-management of insulin-dependent diabetes: the interactive 'Apple Juice' program.

    PubMed

    Williams, A G

    1996-01-01

    The 'Apple Juice' program is an interactive diabetes self-management program which runs on a lap-top Macintosh Powerbook 100 computer. The dose-by-dose insulin advisory program was initially designed for children with insulin-dependent (type 1) diabetes mellitus. It utilizes several different insulin algorithms, measurement formulae, and compensation factors for meals, activity, medication and the dawn phenomenon. It was developed to assist the individual with diabetes and/or care providers, in determining specific insulin dosage recommendations throughout a 24 h period. Information technology functions include, but are not limited to automated record keeping, data recall, event reminders, data trend/pattern analyses and education. This paper highlights issues, observations and recommendations surrounding the use of the current version of the software, along with a detailed description of the insulin algorithms and measurement formulae applied successfully with the author's daughter over a six year period. PMID:9179836

  14. Speech and Language Delay

    MedlinePlus

    MENU Return to Web version Speech and Language Delay Overview How do I know if my child has speech delay? Every child develops at his or her ... of the same age, the problem may be speech delay. Your doctor may think your child has ...

  15. Delay Discounting and Gambling

    PubMed Central

    Madden, Gregory J.; Francisco, Monica T.; Brewer, Adam T.; Stein, Jeffrey S.

    2011-01-01

    Delay discounting describes the decline in the value of a reinforcer as the delay to that reinforcer increases. A review of the available studies revealed that steep delay discounting is positively correlated with problem or pathological gambling. One hypothesis regarding this correlation derives from the discounting equation proposed by Mazur (1989). According to the equation, steeper discounting renders the difference between fixed-delayed rewards and gambling-like variable-delayed rewards larger; with the latter being more valuable. The present study was designed to test this prediction by first assessing rats’ impulsive choices across four delays to a larger-later reinforcer. A second condition quantified strength of preference for mixed- over fixed-delays, with the duration of the latter adjusted between sessions to achieve indifference. Strength of preference for the mixed-delay alternative is given by the fixed delay at indifference (lower fixed-delay values reflect stronger preferences). Percent impulsive choice was not correlated with the value of the fixed delay at indifference and, therefore, the prediction of the hyperbolic model of gambling was not supported. A follow-up assessment revealed a significant decrease in impulsive choice after the second condition. This shift in impulsive choice could underlie the failure to observe the predicted correlation between impulsive choice and degree of preference for mixed- over fixed delays. PMID:21352902

  16. Depression and Insulin Resistance

    PubMed Central

    Pearson, Sue; Schmidt, Mike; Patton, George; Dwyer, Terry; Blizzard, Leigh; Otahal, Petr; Venn, Alison

    2010-01-01

    OBJECTIVE To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview to ascertain depression status. RESEARCH DESIGN AND METHODS Cross-sectional data were collected from 1,732 participants aged between 26 and 36 years. Insulin resistance was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method. Those identified with mild, moderate, or severe depression were classified as having depressive disorder. RESULTS The 12-month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean insulin resistance was 17.2% (95% CI 0.7–36.0%, P = 0.04) higher in men and 11.4% (1.5–22.0%, P = 0.02) higher in women with depressive disorder. After adjustment for behavioral and dietary factors, the increased level of insulin resistance associated with depressive disorder was 13.2% (−3.1 to 32.3%, P = 0.12) in men and 6.1% (−4.1 to 17.4%, P = 0.25) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance, reducing the β coefficient in the fully adjusted models in men by 38% and in women by 42%. CONCLUSIONS A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference. PMID:20185745

  17. [Insulinization in type 2 diabetes mellitus. Intensification options].

    PubMed

    Fuente, Graciela V; Sinay, Isaac; Costa Gil, José E; Puchulu, Félix; Dieuzeide, Guillermo; Rodríguez, Martín; Faingold, María C; Litwak, León E

    2016-01-01

    Diabetes mellitus is associated with vascular complications and high rates of morbidity and mortality. Timely insulin therapy, intensified when necessary, represent appropriate measures to prevent or delay the onset of complications. However, the incidence of hypoglycemia and difficulties in treatment adherence represent barriers to achieve therapeutic success. Premixes analogs and, specially, combinations of insulin analogues are associated with pharmacokinetic and pharmacodynamic advantages, that translate into clinical benefits such as improved metabolic control, decreased hypoglycemic events and, for their simplicity, potentially greater adherence. PMID:27295707

  18. The Brain Response to Peripheral Insulin Declines with Age: A Contribution of the Blood-Brain Barrier?

    PubMed Central

    Heni, Martin; Maetzler, Walter; Fritsche, Andreas; Häring, Hans-Ulrich; Hennige, Anita M.

    2015-01-01

    Objectives It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity. Methods Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements. Results In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved. Conclusions This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system. PMID:25965336

  19. Effects of aldosterone on insulin sensitivity and secretion

    PubMed Central

    Luther, James M.

    2014-01-01

    Dr. Conn originally reported an increased risk of diabetes in patients with hyperaldosteronism in the 1950’s, although the mechanism remains unclear. Aldosterone-induced hypokalemia was initially described to impair glucose tolerance by impairing insulin secretion. Correction of hypokalemia by potassium supplementation only partially restored insulin secretion and glucose tolerance, however. Aldosterone also impairs glucose-stimulated insulin secretion in isolated pancreatic islets via reactive oxygen species in a mineralocorticoid receptor-independent manner. Aldosterone-induced mineralocorticoid receptor activation also impairs insulin sensitivity in adipocytes and skeletal muscle. Aldosterone may produce insulin resistance secondarily by altering potassium, increasing inflammatory cytokines, and reducing beneficial adipokines such as adiponectin. Renin-angiotensin system antagonists reduce circulating aldosterone concentrations and also the risk of type 2 diabetes in clinical trials. These data suggest that primary and secondary hyperaldosteronism may contribute to worsening glucose tolerance by impairing insulin sensitivity or insulin secretion in humans. Future studies should define the effects of MR antagonists and aldosterone on insulin secretion and sensitivity in humans. PMID:25194457

  20. Insulin Cannot Induce Adipogenic Differentiation in Primary Cardiac Cultures.

    PubMed

    Parameswaran, Sreejit; Sharma, Rajendra K

    2016-09-01

    Cardiac tissue contains a heterogeneous population of cardiomyocytes and nonmyocyte population especially fibroblasts. Fibroblast differentiation into adipogenic lineage is important for fat accumulation around the heart which is important in cardiac pathology. The differentiation in fibroblast has been observed both spontaneously and due to increased insulin stimulation. The present study aims to observe the effect of insulin in adipogenic differentiation of cardiac cells present in primary murine cardiomyocyte cultures. Oil Red O (ORO) staining has been used for observing the lipid accumulations formed due to adipogenic differentiation in murine cardiomyocyte cultures. The accumulated lipids were quantified by ORO assay and normalized using protein estimation. The lipid accumulation in cardiac cultures did not increase in presence of insulin. However, addition of other growth factors like insulin-like growth factor 1 and epidermal growth factor promoted adipogenic differentiation even in the presence of insulin and other inhibitory molecules such as vitamins. Lipid accumulation also increased in cells grown in media without insulin after an initial exposure to insulin-containing growth media. The current study adds to the existing knowledge that the insulin by itself cannot induce adipogenic induction in the cardiac cultures. The data have significance in the understanding of cardiovascular health especially in diabetic patients. PMID:27574386

  1. Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

    PubMed Central

    Iovino, Salvatore; Burkart, Alison M.; Warren, Laura; Patti, Mary Elizabeth; Kahn, C. Ronald

    2016-01-01

    Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance. PMID:26831110

  2. The Effects of Delay of Feedback on a Delayed Concept Formation Transfer Task.

    ERIC Educational Resources Information Center

    Schroth, Marvin L.

    1992-01-01

    Delay and completeness of verbal information feedback were investigated within a transfer of learning paradigm involving concept formation. An experiment with 192 undergraduates indicates that, although delay of feedback (up to 30 seconds) slows speed of learning on the initial task, it has positive effects on the transfer task. (SLD)

  3. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  4. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. PMID:26233724

  5. Insulin Aspart (rDNA Origin) Injection

    MedlinePlus

    ... unless it is used in an external insulin pump. In patients with type 2 diabetes, insulin aspart ... also can be used with an external insulin pump. Before using insulin aspart in a pump system, ...

  6. Insulin Detemir (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin detemir works by replacing the insulin that is normally produced ... using an insulin pen, always remove the needle right after you inject your dose. Dispose of needles ...

  7. Development of insulin delivery systems.

    PubMed

    Siddiqui, N I; Siddiqui, Ni; Rahman, S; Nessa, A

    2008-01-01

    Delivery system of insulin is vital for its acceptance and adherence to therapy for achieving the glycemic targets. Enormous developments have occurred in the delivery system of insulin during the last twenty years and each improvement was aimed at two common goals: patients convenience and better glycemic control. Till to date, the various insulin delivery systems are: syringes/vials, injection aids, jet injectors, transmucosal delivery, transdermal delivery, external insulin infusion pump, implantable insulin pumps, insulin pens and insulin inhalers. Syringe/vial is the oldest and conventional method, still widely used and relatively cheaper. Modern plastic syringes are disposable, light weight with microfine needle for patients convenience and comfort. Oral route could be the most acceptable and viable, if the barriers can be overcome and under extensive trial. Insulin pen device is an important milestone in the delivery system of insulin as it is convenient, discrete, painless, attractive, portable with flexible life style and improved quality of life. More than 80% of European diabetic patients are using insulin pen. Future digital pen will have better memory option, blood glucose monitoring system, insulin dose calculator etc. Insulin infusion pump is a good option for the children, busy patients with flexible lifestyle and those who want to avoid multiple daily injections. Pulmonary route of insulin delivery is a promising, effective, non-invasive and acceptable alternative method. Exubera, the world first insulin inhaler was approved by FDA in 28 January 2006. But due to certain limitations, it has been withdrawn from the market in October 2007. The main concern of inhaled insulin are: long term pulmonary safety issues, cost effectiveness and user friendly device. In future, more acceptable and cost effective insulin inhaler will be introduced. Newer avenues are under extensive trial for better future insulin delivery systems. PMID:18285745

  8. Diabetes Care – Insulin Delivery in a Changing World

    PubMed Central

    Marcus, Alan

    2008-01-01

    Controlling blood glucose levels within acceptable limits is crucial to the long-term health of patients with type 2 diabetes, and patient involvement is a vital element in achieving this goal. The benefits of patient education and chronic disease management tools cannot be underestimated as many patients will require initiation of insulin therapy to achieve glycemic targets. The wide choice of insulin formulations and the ever-expanding range of delivery methods now available make insulin administration easier, less painful, more discreet, and more accurate than ever before, thus providing important tools to overcome barriers to insulin initiation and improve achievement of glycemic goals. In addition, exciting developments in technology for self-monitoring of blood glucose have increased the potential for optimal glycemic control. This review discusses how these approaches can help patients manage their diabetes. PMID:18596953

  9. [Physiopathology of non-insulin-dependent diabetes: current data and therapeutic consequences].

    PubMed

    Broussolle, C; Orgiazzi, J; Noël, G

    1990-01-01

    Non insulin-dependent diabetes mellitus results from the combination in varying proportions of low plasma insulin levels (insulinopenia), peripheral resistance to insulin and increased hepatic glucose production. Abnormalities of insulin secretion can be demonstrated without and after stimulation. Insulin resistance mainly occurs in skeletal muscle and is primarily due to a "postreceptor" defect. A pancreatic peptide, amylin, may participate in insulin resistance. Hepatic glucose production correlates with high fasting plasma glucose concentrations. Whatever its initial mechanism, hyperglycaemia maintains low insulin secretion and insulin resistance by its toxicity. In the light of these data, the effects of weight loss in obese non insulin-dependent diabetics have become clearer. The action of biguanides on insulin sensitivity is confirmed. Sulphonylureas have a pancreatic and an extrapancreatic action. The normoglycaemia obtained by intermittent insulin therapy can break the vicious circle of glucose toxicity. The use of prolonged insulin therapy is discussed. Finally, new compounds with an original mode of action offer hopes for the future. PMID:2204978

  10. Time-dependent insulin oligomer reaction pathway prior to fibril formation: Cooling and seeding

    PubMed Central

    Sorci, Mirco; Grassucci, Robert A.; Hahn, Ingrid; Frank, Joachim; Belfort, Georges

    2009-01-01

    The difficulty in identifying the toxic agents in all amyloid-related diseases is likely due to the complicated kinetics and thermodynamics of the nucleation process and subsequent fibril formation. The slow progression of these diseases suggests that the formation, incorporation and/or action of toxic agents is possibly rate limiting. Candidate toxic agents include precursors (some at very low concentrations), also called oligomers and protofibrils, and the fibrils. Here, we investigate the kinetic and thermodynamic behavior of human insulin oligomers (imaged by cryo-EM) under fibril forming conditions (pH 1.6 and 65°C) by probing the reaction pathway to insulin fibril formation using two different types of experiments – cooling and seeding – and confirm the validity of the nucleation model and its effect on fibril growth. The results from both the cooling and seeding studies confirm the existence of a time-changing oligomer reaction process prior to fibril formation that likely involves a rate-limiting nucleation process followed by structural rearrangements of intermediates (into β-sheet rich entities) to form oligomers that then form fibrils. The latter structural rearrangement step occurs even in the absence of nuclei (i.e. with added heterologous seeds). Nuclei are formed at the fibrillation conditions (pH 1.6 and 65°C) but are also continuously formed during cooling at pH 1.6 and 25°C. Within the time-scale of the experiments, only after increasing the temperature to 65°C are the trapped insulin nuclei and resultant structures able to induce the structural rearrangement step and overcome the energy barrier to form fibrils. This delay in fibrillation and accumulation of nuclei at low temperature (25°C), result in a decrease in the mean length of the fibers when placed at 65°C. Fits of an empirical model to the data provide quantitative measures of the delay in the lag-time during the nucleation process and subsequent reduction in fibril growth rate

  11. Euglycemic Infusion of Insulin Detemir Compared With Human Insulin Appears to Increase Direct Current Brain Potential Response and Reduces Food Intake While Inducing Similar Systemic Effects

    PubMed Central

    Hallschmid, Manfred; Jauch-Chara, Kamila; Korn, Oliver; Mölle, Matthias; Rasch, Björn; Born, Jan; Schultes, Bernd; Kern, Werner

    2010-01-01

    OBJECTIVE In the treatment of diabetic patients, the long-acting insulin analog insulin detemir is less prone to induce weight gain than other insulin formulations. Assuming that because of its pharmacologic properties, detemir displays stronger central nervous anorexigenic efficacy than human insulin, we compared acute effects of human insulin and detemir on electroencephalography (EEG) measures and food intake. RESEARCH DESIGN AND METHODS Frontocortical EEG direct current (DC) potentials were recorded in 15 healthy men during two hyperinsulinemic-euglycemic clamps that included an insulin bolus injection (human insulin, 17.75 mU/kg body wt; detemir, 90 mU/kg body wt) followed by a steady 90-min infusion (1.0 vs. 2.0 mU · kg−1 · min−1). A higher dosage was chosen for detemir to compensate for its delay in impact relative to human insulin and to elicit similar systemic effects. At 20 min after infusion, subjects were allowed to eat ad libitum from a test buffet. RESULTS Mean glucose infusions to maintain euglycemia (P > 0.93) and blood glucose concentrations (P > 0.34) did not differ between conditions. Detemir infusion induced a negative DC-potential shift, averaging −372.2 μV from 21 to 90 min that was not observed during human insulin infusion (146.5 μV, P = 0.02). Detemir, in comparison with human insulin, reduced subsequent food intake by 303 kcal (1,257 vs. 1,560, P < 0.04). CONCLUSIONS While inducing comparable peripheral effects, detemir exerts stronger acute effects on brain functions than human insulin and triggers a relative decrease in food consumption, suggesting an enhanced anorexigenic impact of detemir compared with human insulin on central nervous networks that control nutrient uptake. PMID:20068139

  12. Ovarian tumors secreting insulin.

    PubMed

    Battocchio, Marialberta; Zatelli, Maria Chiara; Chiarelli, Silvia; Trento, Mariangela; Ambrosio, Maria Rosaria; Pasquali, Claudio; De Carlo, Eugenio; Dassie, Francesca; Mioni, Roberto; Rebellato, Andrea; Fallo, Francesco; Degli Uberti, Ettore; Martini, Chiara; Vettor, Roberto; Maffei, Pietro

    2015-08-01

    Combined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation. PMID:25896552

  13. Acetoacetylation of insulin

    PubMed Central

    Lindsay, D. G.; Shall, S.

    1969-01-01

    Insulin was treated with diketen at pH6·9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged insulin. The second and third components were shown by end-group analysis to be substituted on phenylalanine B-1 and glycine A-1 respectively. The fourth component was disubstituted on both phenylalanine B-1 and glycine A-1. The ∈-amino group of lysine B-29 was not involved in the reaction at low reagent concentrations. The purity of these derivatives was checked by their electrophoretic behaviour and by measurement of the rate of their reaction with trinitrobenzenesulphonic acid. The hormonal activity of the derivatives was determined. The effect of the modifications on the hormonal activity and the tertiary structure of insulin is discussed. ImagesFig. 10. PMID:5353531

  14. Insulin and carbohydrate dysregulation.

    PubMed

    Gelato, Marie C

    2003-04-01

    Patients with human immunodeficiency virus receiving highly active antiretroviral therapy (HAART) may experience abnormal body composition changes as well as metabolic abnormalities, including dyslipidemia, increases in triglycerides, low high-density lipoprotein cholesterol levels, and abnormal carbohydrate metabolism, ranging from insulin resistance with and without glucose intolerance to frank diabetes. Whether the body composition changes (i.e., increased visceral adiposity and fat wasting in the peripheral tissues) are linked to abnormalities in carbohydrate metabolism is unclear. The use of HAART with and without therapy with protease inhibitors (PIs) is related to carbohydrate abnormalities and changes in body composition. Regimens that include PIs appear to have a higher incidence of insulin resistance (up to 90%) and diabetes mellitus (up to 40%). The etiology of these abnormalities is not well understood; what is known about insulin and carbohydrate dysregulation with HAART is discussed. PMID:12652377

  15. Insulin C-peptide test

    MedlinePlus

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  16. Alternative Devices for Taking Insulin

    MedlinePlus

    ... continuous glucose monitoring (CGM) system an insulin delivery system a computer program that adjusts insulin delivery based on changes in glucose levels CGM systems approved by the U.S. Food and Drug Administration ( ...

  17. Oral Insulin and Buccal Insulin: A Critical Reappraisal

    PubMed Central

    Heinemann, Lutz; Jacques, Yves

    2009-01-01

    Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a “tablet” in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical–experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration. PMID:20144297

  18. Cinnamon, glucose and insulin sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compounds found in cinnamon not only improve the function of insulin but also function as antioxidants and may be anti-inflammatory. This is very important since insulin function, antioxidant status, and inflammatory response are closely linked; with decreased insulin sensitivity there is also decr...

  19. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  20. Titrating-delay matching-to-sample in the pigeon.

    PubMed

    Kangas, Brian D; Vaidya, Manish; Branch, Marc N

    2010-07-01

    The titrating-delay matching-to-sample (TDMTS) procedure offers researchers an additional behavioral task thought to capture some important features of remembering. In this procedure, the delay between sample offset and comparison onset adjusts as a function of the subject's performance. Specifically, correct matches increase the delay and incorrect matches decrease the delay, and steady-state titrated delays serve as the primary dependent measure. The present series of experiments investigated the effects of several procedural variables on performance in TDMTS procedures in an effort to elucidate better its features to allow for more precision in future use. Experiment 1 reports results from a parametric analysis of fixed-ratio response requirements on the sample key that indicated improved remembering in the form of higher daily titrated delay values as the requirement was increased. Experiment 2 investigated the extent to which the initial delay value in each session affected session-wide delay values. Results indicated that regardless of value of the initial delay, the subjects' performances adjusted the delay values in the direction of the known baseline delay-value levels. Experiment 3 manipulated the step size by which delay values were adjusted and the results indicated that larger step sizes increased both session-to-session variability and within-session range of titrated delay values, although the average values remained approximately the same. These results suggest that the TDMTS task serves as a promising procedure to study what many refer to as memory. PMID:21279163

  1. Clinical Considerations for Insulin Pharmacotherapy in Ambulatory Care, Part Two: Review of Primary Literature and an Evidence-Based Approach for Treatment

    PubMed Central

    Thurston, Maria Miller; Bourg, Catherine A.

    2015-01-01

    IN BRIEF This article reinforces the dosing guidance from the package inserts of available insulin products and supplemental information provided by the manufacturers of insulin products. It reviews and evaluates pertinent primary literature detailing algorithms for the initiation and titration of insulin therapy that have helped to shape current clinical practice guidelines. The article discusses the clinical applicability of the evidence on insulin pharmacotherapy and offers recommendations for initiation and titration of various insulin products for insulin-requiring people with type 2 diabetes in the ambulatory care setting. PMID:25653469

  2. Subcutaneous insulin infusion: change in basal infusion rate has no immediate effect on insulin absorption rate

    SciTech Connect

    Hildebrandt, P.; Birch, K.; Jensen, B.M.; Kuehl, C.

    1986-11-01

    Eight insulin-dependent diabetic patients were simultaneously given subcutaneous infusions (1.12 IU/h each) of /sup 125/I-labeled Actrapid insulin in each side of the abdominal wall. After 24 h of infusion, the size of the infused insulin depots was measured by external counting for 5 h. The basal infusion rate was then doubled in one side and halved in the other for the next 4 h. Finally, 1.12 IU/h of insulin was given in both sides of the abdominal wall for an additional 3 h. The changes in the size of the depots were measured, and the absorption rates for each hour were calculated. During the first 5 h of infusion, the depot size was almost constant (approximately 5 IU) with an absorption rate that equaled the infusion rate. Doubling the infusion rate led to a significant increase in depot size, but the absorption rate remained unchanged for the first 3 h, and only thereafter was a significant increase seen. When the infusion rate was reduced to the initial 1.12 IU/h, the absorption rate remained elevated during the next 3 h. Correspondingly, when the infusion rate was decreased, the depot size also decreased, but the absorption rate remained unchanged for the first 3 h. The results show that a change in the basal insulin infusion rate does not lead to any immediate change in the insulin absorption rate. This should be considered when planning an insulin-infusion program that includes alteration(s) in the basal-rate setting.

  3. Molecular Basis of Catalytic Chamber-assisted Unfolding and Cleavage of Human Insulin by Human Insulin-degrading Enzyme*S⃞

    PubMed Central

    Manolopoulou, Marika; Guo, Qing; Malito, Enrico; Schilling, Alexander B.; Tang, Wei-Jen

    2009-01-01

    Insulin is a hormone vital for glucose homeostasis, and insulin-degrading enzyme (IDE) plays a key role in its clearance. IDE exhibits a remarkable specificity to degrade insulin without breaking the disulfide bonds that hold the insulin A and B chains together. Using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to obtain high mass accuracy, and electron capture dissociation (ECD) to selectively break the disulfide bonds in gas phase fragmentation, we determined the cleavage sites and composition of human insulin fragments generated by human IDE. Our time-dependent analysis of IDE-digested insulin fragments reveals that IDE is highly processive in its initial cleavage at the middle of both the insulin A and B chains. This ensures that IDE effectively splits insulin into inactive N- and C-terminal halves without breaking the disulfide bonds. To understand the molecular basis of the recognition and unfolding of insulin by IDE, we determined a 2.6-Å resolution insulin-bound IDE structure. Our structure reveals that IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. This structure also highlights how the unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity (∼100 nm) for insulin. In addition, this structure shows how IDE utilizes the interaction of its exosite with the N terminus of the insulin A chain as well as other properties of the catalytic chamber to guide the unfolding of insulin and allowing for the processive cleavages. PMID:19321446

  4. Insulin resistance in the liver: Deficiency or excess of insulin?

    PubMed Central

    Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

    2014-01-01

    In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

  5. CGI delay compensation

    NASA Technical Reports Server (NTRS)

    Mcfarland, Richard E.

    1986-01-01

    Computer-generated graphics in real-time helicopter simulation produces objectionable scene-presentation time delays. In the flight simulation laboratory at Ames Research Center, it has been determined that these delays have an adverse influence on pilot performance during aggressive tasks such as nap-of-the-earth (NOE) maneuvers. Using contemporary equipment, computer-generated image (CGI) time delays are an unavoidable consequence of the operations required for scene generation. However, providing that magnitide distortions at higher frequencies are tolerable, delay compensation is possible over a restricted frequency range. This range, assumed to have an upper limit of perhaps 10 or 15 rad/sec, conforms approximately to the bandwidth associated with helicopter handling qualities research. A compensation algorithm is introduced here and evaluated in terms of tradeoffs in frequency responses. The algorithm has a discrete basis and accommodates both a large, constant transport delay interval and a periodic delay interval, as associated with asynchronous operations.

  6. Insulin therapy in critically ill patients

    PubMed Central

    Ellahham, Samer

    2010-01-01

    Hyperglycemia frequently occurs with acute medical illness, especially among patients with cardiovascular disease, and has been linked to increased morbidity and mortality in critically ill patients. Even patients who are normoglycemic can develop hyperglycemia in response to acute metabolic stress. An expanding body of literature describes the benefits of normalizing hyperglycemia with insulin therapy in hospitalized patients. As a result, both the American Diabetes Association and the American College of Endocrinology have developed guidelines for optimal control of hyperglycemia, specifically targeting critically ill, hospitalized patients. Conventional blood glucose values of 140–180 mg/dL are considered desirable and safely achievable in most patients. More aggressive control to <110 mg/dL remains controversial, but has shown benefits in certain patients, such as those in surgical intensive care. Intravenous infusion is often used for initial insulin administration, which can then be transitioned to subcutaneous insulin therapy in those patients who require continued insulin maintenance. This article reviews the data establishing the link between hyperglycemia and its risks of morbidity and mortality, and describes strategies that have proven effective in maintaining glycemic control in high-risk hospitalized patients. PMID:21191429

  7. [Insulin therapy of diabetes].

    PubMed

    Lechleitner, Monika; Roden, Michael; Weitgasser, Raimund; Ludvik, Bernhard; Fasching, Peter; Hoppichler, Friedrich; Kautzky-Willer, Alexandra; Schernthaner, Guntram; Prager, Rudolf; Wascher, Thomas C

    2016-04-01

    Hyperglycemia contributes to morbidity and mortality in patients with diabetes. Thus, reaching treatment targets with regard to control of glycemia is a central goal in the therapy of diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the practical use of insulin according to current scientific evidence and clinical studies. PMID:27052221

  8. Insulin Resistance and Prediabetes

    MedlinePlus

    ... to be used in most health care providers' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism. Research has shown that if blood tests indicate prediabetes, insulin ... care provider's office or commercial facility and sending the sample to ...

  9. New Insulin Delivery Recommendations.

    PubMed

    Frid, Anders H; Kreugel, Gillian; Grassi, Giorgio; Halimi, Serge; Hicks, Debbie; Hirsch, Laurence J; Smith, Mike J; Wellhoener, Regine; Bode, Bruce W; Hirsch, Irl B; Kalra, Sanjay; Ji, Linong; Strauss, Kenneth W

    2016-09-01

    Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes. PMID:27594187

  10. VARIABLE TIME DELAY MEANS

    DOEpatents

    Clemensen, R.E.

    1959-11-01

    An electrically variable time delay line is described which may be readily controlled simuitaneously with variable impedance matching means coupied thereto such that reflections are prevented. Broadly, the delay line includes a signal winding about a magnetic core whose permeability is electrically variable. Inasmuch as the inductance of the line varies directly with the permeability, the time delay and characteristic impedance of the line both vary as the square root of the permeability. Consequently, impedance matching means may be varied similariy and simultaneously w:th the electrically variable permeability to match the line impedance over the entire range of time delay whereby reflections are prevented.

  11. Basal insulin delivery reduction for exercise in type 1 diabetes: finding the sweet spot.

    PubMed

    Thabit, Hood; Leelarathna, Lalantha

    2016-08-01

    Exercise poses significant challenges to glucose management in type 1 diabetes. In spite of careful planning and manipulation of subcutaneous insulin administration, increased risk of hypoglycaemia and glycaemic variability during and after exercise may occur as a result of inherent delays in insulin action and impaired counter-regulatory hormone responses. Various strategies to mitigate this issue have been advocated in clinical practice, including ingestion of supplementary carbohydrate prior to exercise, reducing background and pre-meal insulin bolus and performing bouts of resistance/high intensity exercise before aerobic exercise. Insulin pump therapy, considered the most physiological form of insulin replacement for type 1 diabetes allows modulation of basal insulin delivery before, during and after exercise. However uncertainty remains regarding the optimal strategy to reduce basal insulin delivery and its efficacy. In this issue of Diabetologia, McAuley and colleagues (DOI: 10.1007/s00125-016-3981-9 ) report on the impact of a 50% reduction of basal insulin delivery before, during and after moderate-intensity aerobic exercise. Results from this study may contribute to a better understanding of the effects of basal insulin delivery manipulation and may aid in devising therapeutic approaches for glucose management during exercise. PMID:27287376

  12. Selective Insulin Resistance in Adipocytes*

    PubMed Central

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  13. Adipocyte lipolysis and insulin resistance.

    PubMed

    Morigny, Pauline; Houssier, Marianne; Mouisel, Etienne; Langin, Dominique

    2016-06-01

    Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved. PMID:26542285

  14. Transdermal Insulin Delivery Using Microdermabrasion

    PubMed Central

    Andrews, Samantha; Lee, Jeong Woo; Choi, Seong-O

    2011-01-01

    Purpose Transdermal insulin delivery is an attractive needle-free alternative to subcutaneous injection conventionally used to treat diabetes. However, skin’s barrier properties prevent insulin permeation at useful levels. Methods We investigated whether microdermabrasion can selectively remove skin’s surface layers to increase skin permeability as a method to administer insulin to diabetic rats. We further assessed the relative roles of stratum corneum and viable epidermis as barriers to insulin delivery. Results Pretreatment of skin with microdermabrasion to selectively remove stratum corneum did not have a significant effect on insulin delivery or reduction in blood glucose level (BGL). Removal of full epidermis by microdermabrasion significantly reduced BGL, similar to the positive control involving subcutaneous injection of 0.1U insulin. Significant pharmacokinetic differences between microdermabrasion and subcutaneous injection were faster time to peak insulin concentration after injection and larger peak insulin concentration and area-under-the-curve after microdermabrasion. Conclusions Microdermabrasion can increase skin permeability to insulin at levels sufficient to reduce BGL. Viable epidermis is a barrier to insulin delivery such that removal of full epidermis enables significantly more insulin delivery than removal of stratum corneum alone. PMID:21499837

  15. Inhibition of clathrin-mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways.

    PubMed

    Ceresa, B P; Kao, A W; Santeler, S R; Pessin, J E

    1998-07-01

    To examine the role of clathrin-dependent insulin receptor internalization in insulin-stimulated signal transduction events, we expressed a dominant-interfering mutant of dynamin (K44A/dynamin) by using a recombinant adenovirus in the H4IIE hepatoma and 3T3L1 adipocyte cell lines. Expression of K44A/dynamin inhibited endocytosis of the insulin receptor as determined by both cell surface radioligand binding and trypsin protection analysis. The inhibition of the insulin receptor endocytosis had no effect on either the extent of insulin receptor autophosphorylation or insulin receptor substrate 1 (IRS1) tyrosine phosphorylation. In contrast, expression of K44A/dynamin partially inhibited insulin-stimulated Shc tyrosine phosphorylation and activation of the mitogen-activated protein kinases ERK1 and -2. Although there was an approximately 50% decrease in the insulin-stimulated activation of the phosphatidylinositol 3-kinase associated with IRS1, insulin-stimulated Akt kinase phosphorylation and activation were unaffected. The expression of K44A/dynamin increased the basal rate of amino acid transport, which was additive with the effect of insulin but had no effect on the basal or insulin-stimulated DNA synthesis. In 3T3L1 adipocytes, expression of K44A/dynamin increased the basal rate of glucose uptake, glycogen synthesis, and lipogenesis without any significant effect on insulin stimulation. Together, these data demonstrate that the acute actions of insulin are largely independent of insulin receptor endocytosis and are initiated by activation of the plasma membrane-localized insulin receptor. PMID:9632770

  16. Inhibition of Clathrin-Mediated Endocytosis Selectively Attenuates Specific Insulin Receptor Signal Transduction Pathways

    PubMed Central

    Ceresa, Brian P.; Kao, Aimee W.; Santeler, Scott R.; Pessin, Jeffrey E.

    1998-01-01

    To examine the role of clathrin-dependent insulin receptor internalization in insulin-stimulated signal transduction events, we expressed a dominant-interfering mutant of dynamin (K44A/dynamin) by using a recombinant adenovirus in the H4IIE hepatoma and 3T3L1 adipocyte cell lines. Expression of K44A/dynamin inhibited endocytosis of the insulin receptor as determined by both cell surface radioligand binding and trypsin protection analysis. The inhibition of the insulin receptor endocytosis had no effect on either the extent of insulin receptor autophosphorylation or insulin receptor substrate 1 (IRS1) tyrosine phosphorylation. In contrast, expression of K44A/dynamin partially inhibited insulin-stimulated Shc tyrosine phosphorylation and activation of the mitogen-activated protein kinases ERK1 and -2. Although there was an approximately 50% decrease in the insulin-stimulated activation of the phosphatidylinositol 3-kinase associated with IRS1, insulin-stimulated Akt kinase phosphorylation and activation were unaffected. The expression of K44A/dynamin increased the basal rate of amino acid transport, which was additive with the effect of insulin but had no effect on the basal or insulin-stimulated DNA synthesis. In 3T3L1 adipocytes, expression of K44A/dynamin increased the basal rate of glucose uptake, glycogen synthesis, and lipogenesis without any significant effect on insulin stimulation. Together, these data demonstrate that the acute actions of insulin are largely independent of insulin receptor endocytosis and are initiated by activation of the plasma membrane-localized insulin receptor. PMID:9632770

  17. Evidence against extrapancreatic insulin synthesis.

    PubMed Central

    Eng, J; Yalow, R S

    1981-01-01

    Labeled and unlabeled insulin in acid/ethanol tissue extracts can be concentrated up to 100-fold by using a hydrophobic adsorption technique. After adsorption to and elution from an octadecylsilyl silica column, insulin is recovered in yields greater than 75%. By using this method of concentration, insulin in brain tissues of three of four fed rats and one rabbit was found to be less than 20% of plasma concentration. The kidney is the only extrapancreatic organ in which insulin is observed to be markedly above plasma levels. Porcine-insulin-like material was not detectable in guinea pig tissues (less than 0.02 ng/g). It is concluded that insulin is not synthesized in brain or other extrapancreatic tissues and that other mammalian insulins are not found in guinea pig tissues. PMID:6270683

  18. Insulin degludec for diabetes mellitus.

    PubMed

    2013-07-01

    Over the last few years there has been a steady increase in the number of prescriptions dispensed in primary care for intermediate and long-acting insulin analogues and a reduction in prescriptions for biphasic isophane insulin. For example, in England, the volume of intermediate and long-acting insulin analogues in general practice has risen from approximately 650,000 prescriptions per quarter in 2007 to over 850,000 per quarter in 2012.(1) ▾Insulin degludec (Tresiba, Novo Nordisk) is a new long acting basal insulin analogue for the management of diabetes mellitus in adults.(2) Two strengths of insulin degludec (100 units/mL and 200 units/mL) were launched in the UK in February 2013. Here we discuss evidence for the effectiveness and safety of insulin degludec. PMID:23842634

  19. [Current concept of insulin therapy intensification, and the role of human regular insulin and rapid-acting insulin analogs in insulin treatment].

    PubMed

    Hamaguchi, Tomoya; Sadahiro, Katsuhiko; Satoh, Tomomi

    2015-03-01

    The evolution of insulin therapy from animal insulin to recombinant human regular insulin has improved diabetes treatment. Generating of rapid-acting insulin analogs, mimicking physiologic insulin action enables us to provide better control of post-prandial glucose level and lower incidence of hypoglycemia compared with human regular insulin. These rapid-acting insulin analogs show lower susceptibility of insulin precipitation and catheter occlusions, and are suitable for insulin pump therapy of continuous subcutaneous insulin infusion. Insulin lispro and insulin aspart are also applicable for diabetic patients with pregnancy, requiring excellent glycemic control. In some studies, stepwise addition of prandial insulin, as well as full basal-bolus regimen can improve glycemic control with less hypoglycemia. Treatment intensification with rapid-acting insulin analogs may offer a proper method to reach glycemic goals. PMID:25812371

  20. [Obesity and fatty acids in the etiology of insulin resistance].

    PubMed

    Galgani, J; Díaz, E

    2000-12-01

    Fatty acids, obesity and insulin resistance relationship are discussed. In the last decades fatty acids (FA) have been implicated in the etiology of insulin resistance. Initially, this process was related to FA inhibitory effects on glucose uptake mediated by the FA oxidation metabolites. This mechanism known as the Randle cycle has been presently discarded based on recent evidence for FA effects on glucose metabolism. Now is known that cytosolic lipid content and FA molecular structure determines higher or lower storage and oxidation capacity. Another factor is given by Tumor Necrosis Factor-alpha, which is overexpressed in animal and human obesity, producing insulin signaling and glucose uptake inhibition. This paper discuss the role played by FA and obesity on insulin resistance, mainly in relation to FA effects on glucose metabolism in the liver, muscle and adipose tissues. In the obesity condition adipose tissue releases higher levels of free FA which in turn stimulates hepatic glucose production. Adipose tissue also, increase TNF-alpha secretion impairing glucose utilization and insulin signaling. In muscle, cytosolic lipid content activate a Protein Kinase that inhibits the insulin signaling and reduce GLUT-4 translocation. The study of cellular and metabolic changes associated to weight gain and its relationship with insulin resistance etiology are encouraged. PMID:11227245

  1. Direct method for detection and characterization of cell surface receptors for insulin by means of 125I-labeled autoantibodies against the insulin receptor.

    PubMed Central

    Jarrett, D B; Roth, J; Kahn, C R; Flier, J S

    1976-01-01

    Autoantibodies directed against the cell surface receptors for insulin are found in some patients with extreme insulin resistance. These antibodies specifically inhibit the binding of insulin to its receptor. A purified IgG fraction from one patient's plasma was labeled with 125I. The 125I-labeled antireceptor antibody, which initially represented about 0.3% of the total 125I-IgG, was enriched by selective adsorption and subsequent elution from cells rich in insulin receptors. The 125I-antireceptor antibody bound to cells and the binding was inhibited by whole plasma and purified IgG from this patient, as well as whole plasma from another patient with autoantibodies to the insulin receptor. Insulins that differed 300-fold in biological potency and affinity inhibited binding of 125I-antireceptor antibody in direct proportion to their ability to bind to the insulin receptor. The binding of 125I-antireceptor antibody was closely correlated with the binding of 125I-insulin over a wide range of receptor concentrations on different cell types. Experimentally induced reduction of the insulin receptor concentration was associated with parallel decreases in the binding of 125I-antireceptor antibody and 125I-insulin. The preparation of 125I-antireceptor antibody with a high specific activity by cytoadsorption and elution has provided a sensitive method for the detection of receptors and autoantibodies to cell surface components. PMID:1069300

  2. Direct demonstration of insulin receptor internalization. A quantitative electron microscopic study of covalently bound /sup 125/I-photoreactive insulin incubated with isolated hepatocytes

    SciTech Connect

    Gorden, P.; Carpentier, J.L.; Moule, M.L.; Yip, C.C.; Orci, L.

    1982-07-01

    When /sup 125/I-insulin is incubated with isolated rodent hepatocytes at 37 degrees C, the ligand initially binds to the plasma membrane of the cell and is subsequently internalized by adsorptive endocytosis. To confirm directly that the insulin receptor is internalized with the ligand, we covalently linked photoreactive /sup 125/I-N sigma B29 (azidobenzoyl) insulin to its specific hepatocyte receptor and followed its fate by quantitative electron microscopic autoradiography. We found that the covalently linked photoreactive insulin is internalized by the cell in fashion analogous to the internalization of ordinary /sup 125/I-insulin, indicating that, at least under these conditions, the insulin receptor is internalized with the ligand.

  3. Detection of surreptitious administration of analog insulin to an 8-week-old infant.

    PubMed

    Green, Rebecca P; Hollander, Abby S; Thevis, Mario; Thomas, Andreas; Dietzen, Dennis J

    2010-05-01

    An 8-week-old infant presented to the emergency department with lethargy, tachycardia, and a blood glucose concentration of 1.8 mmol/L. After admission, hypoglycemia recurred on 3 additional occasions. Initial urinalysis results were negative for ketones, and the results of additional laboratory tests did not support the diagnosis of cortisol or growth hormone deficiency, oral hypoglycemic ingestion, or an inborn error of metabolism. Difficulty restoring and maintaining glucose concentrations along with a transient response to glucagon during 1 hypoglycemic episode suggested hyperinsulinism. In 1 hypoglycemic episode, elevated insulin and low C-peptide concentrations suggested exogenous insulin administration, but 2 subsequent blood samples obtained during hypoglycemia contained appropriately decreased concentrations of insulin. The insulin immunoassay initially used in this case (Roche ElecSys/cobas [Roche Diagnostics, Indianapolis, IN]) was insensitive to insulin analogs. Two additional immunoassays, 1 with intermediate (Immulite [Siemens, Deerfield, IL]) and 1 with broad (radioimmunoassay [Millipore, Inc, Billerica, MA]) reactivity to insulin analogs were used to characterize insulin in each of the critical blood samples. Samples obtained during hypoglycemia displayed a graded reactivity similar to that observed in type 1 diabetic patients prescribed insulin analogs, whereas a sample obtained from the patient and a control subject during euglycemia showed equal reactivity among the 3 assays. These data suggested administration of insulin analog to the child, and further characterization of insulin by using tandem mass spectrometry confirmed the presence of Humalog. The child was subsequently placed in foster care with no further recurrence of hypoglycemia. PMID:20385635

  4. Insulin receptor binding and protein kinase activity in muscles of trained rats

    SciTech Connect

    Dohm, G.L.; Sinha, M.K.; Caro, J.F.

    1987-02-01

    Exercise has been shown to increase insulin sensitivity, and muscle is quantitatively the most important tissue of insulin action. Since the first step in insulin action is the binding to a membrane receptor, the authors postulated that exercise training would change insulin receptors in muscle and in this study they have investigated this hypothesis. Female rats initially weighing approx. 100 g were trained by treadmill running for 2 h/day, 6 days/wk for 4 wk at 25 m/min (0 grade). Insulin receptors from vastus intermedius muscles were solubilized by homogenizing in a buffer containing 1% Triton X-100 and then partially purified by passing the soluble extract over a wheat germ agglutinin column. The 4 wk training regimen resulted in a 65% increase in citrate synthase activity in red vastus lateralis muscle, indicating an adaptation to exercise ( SVI). Insulin binding by the partially purified receptor preparations was approximately doubled in muscle of trained rats at all insulin concentrations, suggesting an increase in the number of receptors. Training did not alter insulin receptor structure as evidenced by electrophoretic mobility under reducing and nonreducing conditions. Basal insulin receptor protein kinase activity was higher in trained than untrained animals and this was likely due to the greater number of receptors. However, insulin stimulation of the protein kinase activity was depressed by training. These results demonstrate that endurance training does alter receptor number and function in muscle and these changes may be important in increasing insulin sensitivity after exercise training.

  5. Digital time delay

    DOEpatents

    Martin, A.D.

    1986-05-09

    Method and apparatus are provided for generating an output pulse following a trigger pulse at a time delay interval preset with a resolution which is high relative to a low resolution available from supplied clock pulses. A first lumped constant delay provides a first output signal at predetermined interpolation intervals corresponding to the desired high resolution time interval. Latching circuits latch the high resolution data to form a first synchronizing data set. A selected time interval has been preset to internal counters and corrected for circuit propagation delay times having the same order of magnitude as the desired high resolution. Internal system clock pulses count down the counters to generate an internal pulse delayed by an internal which is functionally related to the preset time interval. A second LCD corrects the internal signal with the high resolution time delay. A second internal pulse is then applied to a third LCD to generate a second set of synchronizing data which is complementary with the first set of synchronizing data for presentation to logic circuits. The logic circuits further delay the internal output signal with the internal pulses. The final delayed output signal thereafter enables the output pulse generator to produce the desired output pulse at the preset time delay interval following input of the trigger pulse.

  6. Inhibition of insulin synthesis by cyproheptadine: effects on translation.

    PubMed

    Hawkins, Belinda S; Fischer, Lawrence J

    2004-06-01

    The antihistaminic, antiserotonergic drug cyproheptadine (CPH) is known to inhibit insulin synthesis in vivo and in vitro. This inhibition of insulin synthesis occurs without a commensurate decrease in preproinsulin mRNA (PPImRNA) levels, suggesting a post-transcriptional mechanism of action. The goal of the present study was to investigate the direct effects of CPH on translation of PPImRNA in RINm5F cells. Results produced using a subcellular fractionation technique followed by real-time RT-PCR indicated that a 2-h 10 microM CPH treatment resulted in a decrease in the percentage of cellular PPImRNA associated with endoplasmic reticulum (ER) bound polysomes and increases in the percentages of translationally uninitiated and monoribosome-associated PPImRNA. These alterations in PPImRNA distribution were found to be concentration-dependent, chemical structure-specific, and reversible with a time course consistent with a previously reported CPH-induced inhibition of insulin synthesis. Further investigations to examine the possible effect of CPH on translation initiation were then undertaken by examining the phosphorylation state of the translation initiation factors eIF2alpha, eIF4E, and 4E-BP1 after CPH treatment. CPH (10 microM) treatment resulted in increased phosphorylation of eIF2alpha, and decreased phosphorylation of both eIF4E and 4E-BP1. These changes are all consistent with decreased initiation of translation. Taken together, these results suggest that the inhibition of insulin synthesis known to be elicited by CPH treatment of RINm5F cells and intact animals involves alterations of initiation factor phosphorylation leading to a decrease in insulin synthesis and of stored insulin in insulin-producing cells. PMID:15056814

  7. Current european regulatory perspectives on insulin analogues.

    PubMed

    Enzmann, Harald G; Weise, Martina

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  8. Insulin receptor in Drosophila melanogaster

    SciTech Connect

    Petruzzelli, L.; Herrera, R.; Rosen, O.

    1986-05-01

    A specific, high affinity insulin receptor is present in both adult Drosophila and in Drosophila embryos. Wheat germ lectin-enriched extracts of detergent-solubilized membranes from embryos and adults bind insulin with a K/sub d/ of 15 nM. Binding is specific for insulin; micromolar concentrations of proinsulin, IGFI, and IGFII are required to displace bound /sup 125/I-insulin. Insulin-dependent protein tyrosine kinase activity appears during embryogenesis. It is evident between 6 and 12 hours of development, peaks between 12 and 18 hours and falls in the adult. During 0-6 hours of embryogenesis, and in the adult, a specific protein band (Mr = 135,000) is crosslinked to /sup 125/I-insulin. During 6-12 and 12-18 hours of embryogenesis stages in which insulin-dependent protein tyrosine kinase is high, an additional band (Mr = 100,000) becomes crosslinked to /sup 125/I-insulin. Isolation and DNA sequence analysis of genomic clones encoding the Drosophila insulin receptor will be presented as will the characterization of insulin receptor mRNA's during development.

  9. Variability of NPH Insulin Preparations

    PubMed Central

    Belmonte, M. M.; Colle, E.; deBelle, R.; Murthy, D. Y. N.

    1971-01-01

    In 1968-69 certain juvenile diabetics receiving NPH insulin began having pre-breakfast glucosuria and mid-morning hypoglycemic reactions. A mail survey of our clinic population and a study done at the Quebec camp for diabetic children in 1969 revealed that certain lot numbers were associated with poor control and that a change to new lot numbers or alternate insulin preparations resulted in better control. “Suspect” insulin preparations and non-suspect insulins were given to newly diagnosed diabetics, and plasma insulin and glucose levels were measured over a 24-hour period. The data confirmed that the “suspect” insulins were causing early hypoglycemia and failing to control hyperglycemia during the latter hours of the 24-hour period. The lower glucose levels were associated with higher plasma insulin levels. The “suspect” insulins were further found to have elevated levels of free insulin in the supernatant fluid. The requirements for quality control of modified insulin preparations are reviewed and suggestions are offered for their improvement. PMID:5539004

  10. AFREZZA® (insulin human) Inhalation Powder: A Review in Diabetes Mellitus.

    PubMed

    Kim, Esther S; Plosker, Greg L

    2015-09-01

    Afrezza® (insulin human) inhalation powder is a rapid-acting Technosphere® insulin (TI) administered via a breath-powered oral inhaler to patients with diabetes requiring prandial insulin. TI, a dry powdered formulation of recombinant human insulin adsorbed onto a proprietary carrier, is designed to deliver insulin to the deep lung, at the level of the alveoli, where it is absorbed into the systemic circulation. In a randomized, open-label, multinational, phase III trial (trial 171) in type 1 diabetes (T1DM) patients, prandial TI via the Gen2 inhaler provided noninferior glycated haemoglobin (HbA1c) lowering compared with prandial subcutaneous insulin aspart. Although TI was associated with less HbA1c lowering, it provided significantly lower fasting plasma glucose levels and significantly less hypoglycaemia and bodyweight gain compared with insulin aspart. In a randomized, double-blind, placebo-controlled, multinational, phase III trial (trial 175) in type 2 diabetes (T2DM) patients, prandial TI via the Gen2 inhaler provided superior HbA1c lowering compared with inhaled placebo. Cough was the most commonly occurring non-hypoglycaemia adverse event across both studies. In a pooled analysis of tolerability data from phase II and III studies, the most commonly occurring non-hypoglycaemia adverse events in T1DM and T2DM patients were cough and throat pain/irritation. However, cough was generally mild, dry and decreased over time. In addition, treatment with TI was associated with positive patient-reported outcomes. Insulin human inhalation powder is an effective and generally well-tolerated agent for the prandial treatment of hyperglycaemia in T1DM and T2DM patients and may provide a solution to insulin initiation barriers such as injection phobia, concerns of bodyweight gain and concerns of hypoglycaemia. PMID:26384673

  11. Insulin resistance in young, lean male subjects with essential hypertension.

    PubMed

    Penesova, A; Cizmarova, E; Belan, V; Blazicek, P; Imrich, R; Vlcek, M; Vigas, M; Selko, D; Koska, J; Radikova, Z

    2011-06-01

    Impaired insulin action, frequently found in essential hypertension (HT), is modified by other factors, such as higher age, accumulation of body fat, dyslipidaemia, impaired glucose metabolism and endothelial dysfunction. In addition, antihypertensive and insulin-sensitizing medication itself may significantly affect cardiovascular and metabolic milieu. The aim of this study was to assess insulin sensitivity, acute insulin response, lipidaemic status and the adipokines' concentrations with regard to abdominal fat distribution in young, lean male subjects with treatment-naïve essential HT and in matched healthy normotensive (NT) subjects. We studied 27 HT patients (age: 19.9±0.6 years; body mass index (BMI): 22.9±0.5 kg m(-2)) and 15 NT controls (age: 22.3±1.0 years; BMI: 23.7±0.6 kg m(-2)). The subjects underwent an oral and an intravenous glucose tolerance test (OGTT, IVGTT) on separate days in random order. Higher fasting insulin (P<0.001), non-esterified fatty acids (P<0.05) and plasminogen activator inhibitor factor 1 concentrations (P<0.05) were found in HT patients when compared with NT patients. Despite comparable anthropometric parameters and body fat distribution assessed by magnetic resonance imaging in both groups, newly diagnosed untreated young hypertensive male subjects showed decreased insulin sensitivity, augmented insulin response to both oral and intravenous glucose load (P<0.01; P<0.05 respectively) and 'higher still normal' 2-h plasma glucose levels during OGTT. Untreated, young, lean hypertensive male subjects, with distribution of abdominal adipose tissue and lipid profile comparable with their healthy NT matched counterparts, showed considerable signs of insulin resistance and hyperinsulinaemia. We hypothesize that insulin resistance is the initial feature, which is influenced by several environmental factors, and HT is one of their common consequences. PMID:20631738

  12. Effect of insulin immunization on glucose tolerance in normal rats.

    PubMed

    Froguel, P; Reach, G

    1987-01-01

    Normal rats were immunized with insulin and Freund's adjuvant and submitted to an intravenous glucose tolerance test. Plasma glucose and free and total IRI levels were determined and compared to those observed in untreated rats, and in animals injected with the Freund's adjuvant used for the immunization procedure. In six of the 15 insulin injected animals, a significant amount of IRI (more than 100 mU/l) was found to circulate in bound form. In these animals, the fasting plasma glucose concentrations, and glucose disappearance rates were not different from those observed in all the other groups. However, the rise in their free IRI level was delayed, as was the return to basal level: 45 min after glucose injection, the free IRI concentration was still 98 +/- 29 mU/l in the six immunized rats vs 14 +/- 6 mU/l in those treated with Freund's adjuvant (p less than 0.01). Furthermore, the secondary nadir in the plasma glucose concentration observed at 60 min after glucose injection, was lower in the immunized rats (5.4 +/- 0.5 vs 6.8 +/- 0.3 mmol/l, p less than 0.05). It is concluded that in normal animals, IRI binding in proportions similar to those commonly observed in insulin-treated diabetic patients does not alter glucose tolerance but might lead to abnormal insulin kinetics and secondary hypoglycemia. These results might have implications for the use of closed-loop insulin delivery systems in type 1 (insulin-dependent) diabetic patients with insulin antibodies. PMID:3123287

  13. Insulin binding to plastic bags: a methodologic study.

    PubMed

    Twardowski, Z J; Nolph, K D; McGary, T J; Moore, H L; Collin, P; Ausman, R K; Slimack, W S

    1983-04-01

    A radiotracer method to assess insulin binding to commercially available plastic peritoneal dialysis solution containers was developed. A peritoneal dialysis bag (bag 2) was emptied and attached to another full bag (bag 1) of the same kind. In the syringe-to-bag method, bag 1 was symmetrically injected through the bag wall with four syringes containing dialysis solution and radioactive insulin, with or without regular insulin. The radioactivity in each syringe was measured with a gamma counter before injection, and all of the samples were counted afterwards directly in the syringes. Using a bag-to-bag transfer method, bag 1 was agitated, eight samples were taken from different parts through the wall, and then the contents were transferred to bag 2. Bag 2 was then agitated and eight samples were taken and counted. In the bag-pieces method, pieces of bag wall were cut and the radioactivity on the walls was measured to determine the amount of binding. The syringe-to-bag method gave negative results, severely underestimating the amount of insulin binding. The bag-to-bag transfer method yielded positive results in all instances. Increasing the amounts of regular insulin had no demonstrable impact on percent of binding. When the bag-to-bag method was compared with the bag-pieces method, it gave only slightly higher values; however, the bag-to-bag method was considered more reliable because the counting can be controlled more effectively. A 15-minute delay in sampling was not found to influence insulin binding. A reliable method of assessing insulin binding must be based on the following two principles: (1) The transfer of samples to intermediate containers should be avoided, and (2) radiotracer concentrations in the samples should be similar. PMID:6342377

  14. Pitfalls of Insulin Pump Clocks

    PubMed Central

    Reed, Amy J.

    2014-01-01

    The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

  15. One-Year Outcomes of Out-of-Hospital Administration of Intravenous Glucose, Insulin, and Potassium (GIK) in Patients with Suspected Acute Coronary Syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care] Trial)

    PubMed Central

    Selker, Harry P.; Udelson, James E.; Massaro, Joseph M.; Ruthazer, Robin; D’Agostino, Ralph B.; Griffith, John L.; Sheehan, Patricia R.; Desvigne-Nickens, Patrice; Rosenberg, Yves; Tian, Xin; Vickery, Ellen M.; Atkins, James M.; Aufderheide, Tom P.; Sayah, Assaad J.; Pirrallo, Ronald G.; Levy, Michael K.; Richards, Michael E.; Braude, Darren A.; Doyle, Delanor D.; Frascone, Ralph J.; Kosiak, Donald J.; Leaming, James M.; Van Gelder, Carin M.; Walter, Gert-Paul; Wayne, Marvin A.; Woolard, Robert H.; Beshansky, Joni R.

    2014-01-01

    The IMMEDIATE Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefit. Here we report 1-year outcomes. Pre-specified 1-year endpoints of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality, and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Among 871 participants randomized to GIK vs. placebo, respectively, death occurred within 1 year in 11.6% vs. 13.5% (unadjusted hazard ratio [HR] 0.83; 95% CI 0.57, 1.23, P=0.36). The composite of cardiac arrest or 1-year mortality was 12.8% vs. 17.0% (HR 0.71; 95% CI 0.50, 1.02, P=0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% vs. 17.2% (HR 0.98; 95% CI 0.70, 1.37, P=0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% vs. 20.4% (HR 0.85; 95% CI 0.62, 1.16, P=0.30). Among patients presenting with suspected ST elevation myocardial infarction (STEMI), hazard ratios for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33, 1.27, P=0.21); 0.52 (95% CI 0.30, 0.92, P=0.03); 0.63 (95% CI 0.35, 1.16, P=0.14); and 0.51 (95% CI 0.30, 0.87, P=0.01). Among patients with suspected ACS, serious endpoints generally were lower with GIK than placebo, but the differences were not statistically significant. However, among those with STEMI, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced. PMID:24792735

  16. Oral insulin (human, murine, or porcine) does not prevent diabetes in the non-obese diabetic mouse.

    PubMed

    Pham, Minh N; Gibson, Claire; Rydén, Anna K E; Perdue, Nikole; Boursalian, Tamar E; Pagni, Philippe P; Coppieters, Ken; Skonberg, Christian; Porsgaard, Trine; von Herrath, Matthias; Vela, Jose Luis

    2016-03-01

    Studies have shown oral insulin prevents type 1 diabetes (T1D) in mouse models, however human trials were inconclusive. We tested the ability of different insulins to prevent T1D in non-obese diabetic mice. Mice received oral insulin or PBS twice weekly and disease was monitored. Contrary to previous studies, no insulin tested showed significant ability to prevent T1D, nor did testing of linked suppression in a delayed type hypersensitivity model have reproducible effect. To investigate delivery of antigen within the GI tract, blue dye was fed to mice. Dye traveled 5-8 cm from stomach to small intestine within 10s, suggesting orally administered antigen may not get digested in the stomach in mice. Insulin incubated with jejunum extracts was instantly digested. Thus, in humans large doses of insulin may be required to achieve tolerance as antigen may be more vulnerable to digestion in the stomach even before reaching the small intestine. PMID:26821303

  17. Delayed Geodynamo in Hadean

    NASA Astrophysics Data System (ADS)

    Arkani-Hamed, J.

    2014-12-01

    Paleointensity measurements of Archean rocks reveal a strong geodynamo at ~3.45 Ga, while excess nitrogen content of lunar soil samples implies no geodynamo at ~3.9 Ga. Here I propose that initiation of a strong geodynamo is delayed due to accretion style of Earth, involving collision and merging of a few dozen Moon to Mars size planetary embryos. Two accretion scenarios consisting of 25 and 50 embryos are investigated. The collision of an embryo heats the proto-Earth's core differentially and the rotating low-viscosity core stably stratifies, creating a spherically symmetric and radially increasing temperature distribution. Convection starts in the outer core after each impact but is destroyed by the next impact. The iron core of an impacting embryo descends in the mantle and merges to the proto-Earth's core. Both adiabatic and non-adiabatic merging cases are studied. A major part of the gravitational energy released due to core merging is used to lift up the upper portion of the core to emplace the impactor core material at the neutrally buoyant level in the proto-Earth's core. The remaining energy is converted to heat. In the adiabatic case the merging embryo's core retains all of the remaining energy, while in the non-adiabatic merging 50% of the remaining energy is shared with the outer part of the proto-Earth's core where the embryo's core descends. The two merging models result in significantly different temperature distributions in the core at the end of accretion. After the accretion, the convecting shell in the outer core grows monotonically and generates geodynamo gradually. It takes about 50-100 Myr for the convecting shell to generate a strong dipole field at the surface, 50,000 to 100,000 nT, in the presence of a large stably stratified liquid inner core when the convecting outer core thickness exceeds about one half the radius of the Earth's core.

  18. [Intensified insulin therapy and insulin micro-pumps during pregnancy].

    PubMed

    Galuppi, V

    1994-06-01

    Before conception and during pregnancy in diabetic patients, every possible effort should be made in order to obtain a good, if not perfect, metabolic control and to warrant maternal and fetal health. Multiple daily injections are required to achieve a very strict glucose regulation in pregnant patients with insulin-dependent diabetes mellitus. The most usual intensive insulin administration patterns require 3 premeal doses of short-acting insulin and 1 (at bedtime) or 2 (one in the morning and one at bedtime) injections of intermediate or slow-acting insulin. As an alternative choice, insulin pumps allow a continuous subcutaneous infusion with short-acting insulin according to a basal rate which cover the insulin need during the night and between meals. Premeal and presnack surges of insulin are administrated by the patient herself. Home glucose monitoring must be used to adjust insulin doses. Target glucose levels every diabetic pregnant woman should try to achieve are lower than in non-pregnant women: fasting glycaemia should be below 100 mg/dl, 1 hour post-prandial value below 140 mg/dl and 2 hour post-prandial level below 120 mg/dl. The stricter the control and treatment goals are, the more frequently hypoglycaemia may occur. Hypoglycaemia may be harmful especially for patients with severe diabetic complications and may affect the fetus. Therefore, every pregnant diabetic woman should receive individualized treatment and glycaemic goals according to her clinical features, her compliance and her social and cultural background. PMID:7968932

  19. Clinical Use and Evaluation of Insulin Pens.

    PubMed

    Ginsberg, Barry H

    2016-01-01

    Insulin pens are more accurate and easier to teach than other methods of insulin delivery. They also do not suffer from the risk of mismatch of insulin concentration and type of insulin syringe. The ISO standard used to test insulin pens, however, needs to be updated to reflect their clinical use. PMID:26323484

  20. Options for intensification of basal insulin in type 2 diabetes: Premeal insulin or short-acting GLP-1 receptor agonists?

    PubMed

    Darmon, P; Raccah, D

    2015-12-01

    Type 2 diabetes is an evolutive disease with a progressive defect of beta-cell insulin secretion. This characteristic points to a need for treatment that takes into account such a natural history. When oral antidiabetic drugs fail to achieve the patient's target HbA1c level, basal insulin treatment is usually initiated and titrated in association with oral drugs to manage fasting hyperglycaemia. Over a period of time, it is enough to simply achieve the HbA1c target. However, when even a good fasting blood glucose level is no longer sufficient to control overall glycaemia, then prandial treatment must be combined with the titrated basal insulin to deal with the postprandial hyperglycaemia responsible for the elevation of HbA1c. Of the different therapeutic options now available for this, rapid-acting insulins and GLP-1 receptor agonists (RAs) can be used. Rapid-acting insulins can be added either at each meal, achieving full insulin supplementation with a basal-bolus regimen, or at the main meal only as a "basal-plus" regimen. Compared with the full basal-bolus, the basal-plus strategy is associated with fewer injections, yet provides similar efficacy in terms of HbA1c improvement, but with less weight gain and lower hypoglycaemic risk. As for GLP-1 RAs, numerous studies, and especially those using short-acting GLP-1 RAs, have demonstrated more pronounced effects on postprandial hyperglycaemia, good complementary effects with basal insulin, and significant improvement of HbA1c with no weight gain and a low risk of hypoglycaemia. Similarly, direct and indirect comparisons of the use of rapid-acting insulins and GLP-1 RAs to intensify basal insulin have shown comparable efficacy in terms of HbA1c control, but with less weight gain and fewer hypoglycaemic episodes with GLP-1 RAs. PMID:26774016

  1. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    PubMed

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates. PMID:25509050

  2. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    PubMed

    Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates. PMID:25490849

  3. Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?

    PubMed

    Nasrallah, Sami N; Reynolds, L Raymond

    2012-01-01

    The advances in recombinant DNA technology have led to an improvement in the properties of currently available long-acting insulin analogs. Insulin degludec, a new generation ultra-long-acting basal insulin, currently in phase 3 clinical trials, has a promising future in clinical use. When compared to its rival basal insulin analogs, a longer duration of action and lower incidence of hypoglycemic events in both type 1 and type 2 diabetic patients has been demonstrated.1,2 Its unique mechanism of action is based on multihexamer formation after subcutaneous injection. This reportedly allows for less pharmacodynamic variability and within-subject variability than currently available insulin analogs, and a duration of action that is over 24 hours.3 The lack of proof of carcinogenicity with insulin degludec is yet another factor that would be taken into consideration when choosing the optimal basal insulin for a diabetic individual.4 A formulation of insulin degludec with insulin aspart, Insulin degludec 70%/aspart 30%, may permit improved flexibly of dosing without compromising glycemic control or safety.5. PMID:22879797

  4. Pharmacokinetic Model of the Transport of Fast-Acting Insulin From the Subcutaneous and Intradermal Spaces to Blood.

    PubMed

    Lv, Dayu; Kulkarni, Sandip D; Chan, Alice; Keith, Stephen; Pettis, Ron; Kovatchev, Boris P; Farhi, Leon S; Breton, Marc D

    2015-07-01

    Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models. To develop the model we compare 9 insulin transport PK models which describe hypothetical insulin delivery pathways potentially capable of approximating biphasic appearance of exogenous insulin. The models are tested with respect to their ability to describe clinical data from 10 healthy volunteers which received 1 subcutaneous and 2 intradermal insulin injections on 3 different occasions. The optimal model, selected based on information and posterior identifiability criteria, assumes that insulin is delivered at the administrative site and is then transported to the bloodstream via 2 independent routes (1) diffusion-like process to the blood and (2) combination of diffusion-like processes followed by an additional compartment before entering the blood. This optimal model accounts for biphasic appearance and delayed clearance of exogenous insulin. It agrees better with the clinical data as compared to commonly used models and is expected to improve the in silico development and testing of insulin treatment strategies, including artificial pancreas systems. PMID:25759184

  5. Pharmacokinetic Model of the Transport of Fast-Acting Insulin From the Subcutaneous and Intradermal Spaces to Blood

    PubMed Central

    Lv, Dayu; Kulkarni, Sandip D.; Chan, Alice; Keith, Stephen; Pettis, Ron; Kovatchev, Boris P.; Farhi, Leon S.; Breton, Marc D.

    2015-01-01

    Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models. To develop the model we compare 9 insulin transport PK models which describe hypothetical insulin delivery pathways potentially capable of approximating biphasic appearance of exogenous insulin. The models are tested with respect to their ability to describe clinical data from 10 healthy volunteers which received 1 subcutaneous and 2 intradermal insulin injections on 3 different occasions. The optimal model, selected based on information and posterior identifiability criteria, assumes that insulin is delivered at the administrative site and is then transported to the bloodstream via 2 independent routes (1) diffusion-like process to the blood and (2) combination of diffusion-like processes followed by an additional compartment before entering the blood. This optimal model accounts for biphasic appearance and delayed clearance of exogenous insulin. It agrees better with the clinical data as compared to commonly used models and is expected to improve the in silico development and testing of insulin treatment strategies, including artificial pancreas systems. PMID:25759184

  6. Protein Crystal Recombinant Human Insulin

    NASA Technical Reports Server (NTRS)

    1994-01-01

    The comparison of protein crystal, Recombiant Human Insulin; space-grown (left) and earth-grown (right). On STS-60, Spacehab II indicated that space-grown crystals are larger and of greater optical clarity than their earth-grown counterparts. Recombiant Human Insulin facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  7. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes

    PubMed Central

    McNay, Ewan C.; Recknagel, Andrew K.

    2011-01-01

    Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cogntive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients. PMID:21907815

  8. Delayed emergence after anesthesia.

    PubMed

    Tzabazis, Alexander; Miller, Christopher; Dobrow, Marc F; Zheng, Karl; Brock-Utne, John G

    2015-06-01

    In most instances, delayed emergence from anesthesia is attributed to residual anesthetic or analgesic medications. However, delayed emergence can be secondary to unusual causes and present diagnostic dilemmas. Data from clinical studies is scarce and most available published material is comprised of case reports. In this review, we summarize and discuss less common and difficult to diagnose reasons for delayed emergence and present cases from our own experience or reference published case reports/case series. The goal is to draw attention to less common reasons for delayed emergence, identify patient populations that are potentially at risk and to help anesthesiologists identifying a possible cause why their patient is slow to wake up. PMID:25912729

  9. Time delay spectrum conditioner

    DOEpatents

    Greiner, Norman R.

    1980-01-01

    A device for delaying specified frequencies of a multiple frequency laser beam. The device separates the multiple frequency beam into a series of spatially separated single frequency beams. The propagation distance of the single frequency beam is subsequently altered to provide the desired delay for each specific frequency. Focusing reflectors can be utilized to provide a simple but nonadjustable system or, flat reflectors with collimating and focusing optics can be utilized to provide an adjustable system.

  10. Delayed voice communication

    NASA Astrophysics Data System (ADS)

    Love, Stanley G.; Reagan, Marcum L.

    2013-10-01

    We present results from simulated deep-space exploration missions that investigated voice communication with significant time delays. The simulations identified many challenges: confusion of sequence, blocked calls, wasted crew time, impaired ability to provide relevant information to the other party, losing track of which messages have reached the other party, weakened rapport between crew and ground, slow response to rapidly changing situations, and reduced situational awareness. These challenges were met in part with additional training; greater attention and foresight; longer, less frequent transmissions; meticulous recordkeeping and timekeeping; and specific alerting and acknowledging calls. Several simulations used both delayed voice and text messaging. Text messaging provided a valuable record of transmissions and allowed messages to be targeted to subsets of the flight and ground crew, but it was a poor choice for high-workload operators such as vehicle drivers and spacewalkers. Even with the foregoing countermeasures, delayed voice communication is difficult. Additional aids such as automatic delay timers and voice-to-text transcription would help. Tests comparing delays of 50 and 300 s unexpectedly revealed that communicating with the shorter delay was just as challenging as with the longer one.

  11. Insulin Glulisine (rDNA origin) Injection

    MedlinePlus

    ... oral medication(s) for diabetes. Insulin glulisine is a short-acting, man-made version of human insulin. Insulin ... contraceptives (birth control pills, patches, rings, injections, or implants); octreotide (Sandostatin); oral medications for diabetes; oral steroids ...

  12. Future prospect of insulin inhalation for diabetic patients: The case of Afrezza versus Exubera.

    PubMed

    Al-Tabakha, Moawia M

    2015-10-10

    The current review was designed to compare between the insulin inhalation systems Exubera and Afrezza and to investigate the reasons why Exubera was unsuccessful, when Afrezza maker is expecting their product to be felicitous. In January 2006, Pfizer secured FDA and EC approval for the first of its kind, regular insulin through Exubera inhaler device for the management of types 1 and 2 diabetes mellitus (DM) in adults. The product was no longer available to the market after less than two years from its approval triggering a setback for competitive new inhalable insulins that were already in various clinical development phases. In contrary, MannKind Corporation started developing its ultra-rapid-acting insulin Afrezza in a bold bid, probably by managing the issues in which Exubera was not successful. Afrezza has been marketed since February, 2015 by Sanofi after getting FDA approval in June 2014. The results from this systematic review indicate the effectiveness of insulin inhalation products, particularly for patients initiating insulin therapy. Pharmaceutical companies should capitalize on the information available from insulin inhalation to produce competitive products that are able to match the bioavailability of subcutaneous (SC) insulin injection and to deal with the single insulin unit increments and basal insulin requirements in some diabetic patients or extending the horizon to inhalable drug products with completely different drug entities for other indications. PMID:26222134

  13. [Insulin therapy in type 2 diabetes: a review of "when" over "how" up to "why"].

    PubMed

    Laimer, Markus; Jenni, Stefan; Stettler, Christoph

    2015-02-11

    Type 2 Diabetes is characterized by its progressive character. An intensification of the therapy is necessary in most cases over the years and insulin is typically used as an add-on agent when oral antidiabetic regimes are judged to be no longer sufficient. However, insulin can also be used in the initial phase of the disease directly after diagnosis of diabetes. Intermittent worsening of glycemic control (e.g. due to infectious diseases or corticosteroids) may be additional indications for an insulin treatment at an earlier stage. Noticeably, insulin can often be stopped if the triggering event or treatment is reversible, thereby countering the widely spread fear of dependency on insulin. We recommend a rather cautious starting dose of insulin and individual adaptations thereafter. Well-informed patients can also perform such adaptations themselves. PMID:25669222

  14. Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.

    PubMed

    Tseng, Huey-Ling; Yang, Shu-Chuan; Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  15. Hepatic Circadian-Clock System Altered by Insulin Resistance, Diabetes and Insulin Sensitizer in Mice

    PubMed Central

    Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  16. SIRT2 regulates insulin sensitivity in insulin resistant neuronal cells.

    PubMed

    Arora, Amita; Dey, Chinmoy Sankar

    2016-06-10

    Insulin resistance in brain is well-associated with pathophysiology of deficits in whole-body energy metabolism, neurodegenerative diseases etc. Among the seven sirtuins, SIRT2 is the major deacetylase expressed in brain. Inhibition of SIRT2 confers neuroprotection in case of Parkinson's disease (PD) and Huntington's disease (HD). However, the role of this sirtuin in neuronal insulin resistance is not known. In this study, we report the role of SIRT2 in regulating insulin-sensitivity in neuronal cells in vitro. Using approaches like pharmacological inhibition of SIRT2, siRNA mediated SIRT2 knockdown and over-expression of wild-type and catalytically-mutated SIRT2, we observed that downregulation of SIRT2 ameliorated the reduced activity of AKT and increased insulin-stimulated glucose uptake in insulin resistant neuro-2a cells. The data was supported by over expression of catalytically-inactive SIRT2 in insulin-resistant human SH-SY5Y neuronal cells. Data highlights a crucial role of SIRT2 in regulation of neuronal insulin sensitivity under insulin resistant condition. PMID:27163642

  17. Insulin stimulation of hepatic triacylglycerol secretion and the etiology of insulin resistance.

    PubMed

    Zammit, V A; Waterman, I J; Topping, D; McKay, G

    2001-08-01

    The recent observations that insulin can either stimulate or inhibit triacylglycerol secretion by the liver, depending on prior metabolic (possibly insulinemic) state, have rationalized the many apparently contradictory observations, obtained over the past three decades, on the effects of the hormone on this aspect of hepatic metabolism. Extrapolation to the situation in vivo suggests that frequent stimulation of insulin secretion may result in a chronic stimulation of VLDL secretion, and increased delivery of acyl moieties to muscle, where they induce insulin resistance if provided in excess of the oxidative needs (mostly due to exercise) of the tissue. High fructose/sucrose diets, which also stimulate hepatic VLDL secretion, will have the same effect, especially if consumed frequently during the diurnal cycle. Due to the quantitative importance of muscle as a site for insulin-sensitive glucose metabolism, these effects may initiate the metabolic vicious cycle that results in the development of the metabolic syndrome, well in advance of overt obesity or the diagnosis of type-2 diabetes. PMID:11481396

  18. Insulin sensitivity and complications in type 1 diabetes: New insights

    PubMed Central

    Bjornstad, Petter; Snell-Bergeon, Janet K; Nadeau, Kristen J; Maahs, David M

    2015-01-01

    Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials. PMID:25685274

  19. A novel method for simulating insulin mediated GLUT4 translocation.

    PubMed

    Jezewski, Andrew J; Larson, Joshua J; Wysocki, Beata; Davis, Paul H; Wysocki, Tadeusz

    2014-12-01

    Glucose transport in humans is a vital process which is tightly regulated by the endocrine system. Specifically, the insulin hormone triggers a cascade of intracellular signals in target cells mediating the uptake of glucose. Insulin signaling triggers cellular relocalization of the glucose transporter protein GLUT4 to the cell surface, which is primarily responsible for regulated glucose import. Pathology associated with the disruption of this pathway can lead to metabolic disorders, such as type II diabetes mellitus, characterized by the failure of cells to appropriately uptake glucose from the blood. We describe a novel simulation tool of the insulin intracellular response, incorporating the latest findings regarding As160 and GEF interactions. The simulation tool differs from previous computational approaches which employ algebraic or differential equations; instead, the tool incorporates statistical variations of kinetic constants and initial molecular concentrations which more accurately mimic the intracellular environment. Using this approach, we successfully recapitulate observed in vitro insulin responses, plus the effects of Wortmannin-like inhibition of the pathway. The developed tool provides insight into transient changes in molecule concentrations throughout the insulin signaling pathway, and may be employed to identify or evaluate potentially critical components of this pathway, including those associated with insulin resistance. In the future, this highly tractable platform may be useful for simulating other complex cell signaling pathways. Biotechnol. Bioeng. 2014;111: 2454-2465. © 2014 Wiley Periodicals, Inc. PMID:24917169

  20. Insulin sensitivity and complications in type 1 diabetes: New insights.

    PubMed

    Bjornstad, Petter; Snell-Bergeon, Janet K; Nadeau, Kristen J; Maahs, David M

    2015-02-15

    Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials. PMID:25685274

  1. Teaching Speech to Your Language Delayed Child.

    ERIC Educational Resources Information Center

    Rees, Roger J.; Pryor, Jan, Ed.

    1980-01-01

    Intended for parents, the booklet focuses on the speech and language development of children with language delays. The following topics are among those considered: the parent's role in the initial diagnosis of deafness, intellectual handicap, and neurological difficulties; diagnoses and single causes of difficultiy with speech; what to say to…

  2. [The discovery of insulin].

    PubMed

    Lestradet, H

    1996-02-01

    When a medical problem is intensively studied by many teams in the world, it is frequent to see the solution found simultaneously in different countries. However that was not exactly the case concerning the extraction of a potent insulin able to cure Diabetes Mellitus. It seems necessary, seventy five years later, when passions are quenched, to reconsider the chronology of the history and put Paolesco but also Collip at the right places much before Banting and Best to whom, by a curious misinterpretation of facts, was attributed the priority of this fundamental discovery. PMID:8705382

  3. [Medication of the month. Insulin glargine (Lantus)].

    PubMed

    Scheen, A J

    2004-02-01

    Insulin glargine (Lantus) is a human insulin analogue produced by recombinant DNA technology and recently launched by Aventis. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue (pH > 7,4) from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant over 24 hours as compared to conventional human insulins, especially NPH. This allows once-daily injection as basal insulin therapy, at any moment of the clock time (but if possible at the same time from day to day). Reproducibility of plasma insulin levels is also improved with insulin glargine as compared to human NPH insulin. Insulin glargine administration should be combined to rapid insulin injections, before each meal in order to control postprandial hyperglycaemia, or with oral antidiabetic agents in type 2 diabetes. The pharmacokinetic properties of insulin glargine allow an easier titration of basal insulin dose, which should facilitate adequate blood glucose control while decreasing the risk of hypoglycaemia, especially during night time. Insulin glargine use is safe with no increased antigenicity, immunogenicity or mitogenicity reactions as compared to human insulin. Optimal use of this new insulin analogue should be integrated in a global management of the diabetic patient as well as in a new culture of insulin therapy. PMID:15112902

  4. Problems in diabetes mellitus management. Insulin resistance.

    PubMed

    Wolfsheimer, K J

    1990-12-01

    Insulin resistance is a cause for morning hyperglycemia seen in diabetic patients. Other reasons for morning hyperglycemia should be eliminated by performing an insulin response test. Once insulin resistance has been established as the cause of hyperglycemia, a step-by-step process should be used to establish the cause of the insulin resistance. Common causes of insulin resistance include hyperadrenocorticism, acromegaly, hyperthyroidism, and obesity. Hepatic disease, renal insufficiency, and sepsis are other causes of insulin resistance in practice. Less common causes include insulin antibodies, pregnancy, neoplasia, hyperandrogenism, and pheochromocytoma. If the underlying cause cannot be found or resolved, then increased doses of insulin are required to manage the hyperglycemia. PMID:2134077

  5. Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation

    PubMed Central

    Stuart, Charles A.; Howell, Mary E. A.; Cartwright, Brian M.; McCurry, Melanie P.; Lee, Michelle L.; Ramsey, Michael W.; Stone, Michael H.

    2014-01-01

    Abstract Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin‐responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate‐1 (IRS‐1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS‐1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS‐1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS‐1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS‐1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c‐Jun N‐terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS‐1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS‐1 diminishes the transmission of the insulin signal and thereby decreases the insulin‐stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS‐1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss. PMID:25472611

  6. Methimazole-induced insulin autoimmune syndrome

    PubMed Central

    Jain, Nidhi; Savani, Malvi; Agarwal, Manyoo; Kadaria, Dipen

    2016-01-01

    Background: Hypoglycemia in a critical care setting is often multifactorial with iatrogenic insulin use, sulfonylurea (SU) use, sepsis, adrenal insufficiency and insulinoma among the common causes. Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin-binding autoantibodies to the sulfhydryl group-containing agents. We report a case of methimazole-induced IAS managed in the intensive care unit. Case presentation: A 76-year-old woman with a history of primary hyperthyroidism was sent from a nursing home for unresponsiveness. Vital signs were significant for hypotension (74/46) and low blood sugars. Fluid resuscitations with normal saline and 50% dextrose stabilized the blood pressure (BP) to 135/75 and her blood glucose to 264. Due to respiratory distress and septic appearance, she required emergency intubation. Nursing home medications were noted for methimazole and absence of any insulin or SU use. Empiric antibiotic treatment was started and fluid resuscitation was continued while home medications were held. Her laboratory values were significant for elevated creatinine, lactic acid, serum cortisol, C-peptide, and insulin. Her cultures, SU screen and computerized tomography (CT) scan were negative for significant findings. On day 2, in addition to 10% dextrose, octreotide was initiated for recurrent hypoglycemia. Her blood glucose (BG) continued to drop throughout the day for which she required glucagon support and a D20 infusion. By day 4, the rate of infusion was titrated up and her BG continued to drop to <60 mg/dl despite D20, octreotide and tube feeds with concentrated calories (1.5 cal/ml). Due to her declining health, her family endorsed palliative care and she was extubated. After day 11, her hypoglycemic episodes resolved and she remained endogenously euglycemic. Conclusions: IAS is associated with methimazole use due to formation of autoantibodies to insulin after its interaction with Sulfhydryl (SH

  7. Resource guide 2004. Insulin delivery.

    PubMed

    2004-01-01

    Syringes...pumps...jet infectors...pens...infusers...they all do the same basic thing--deliver insulin. These items carry insulin through the outermost layer of skin and into fatty tissue so it can be used by the body. This section will also cover injection aids, products designed to make infecting easier. PMID:14976945

  8. [Endogenous hyperlactatemia and insulin secretion].

    PubMed

    Ribes, G; Valette, G; Lignon, F; Loubatières-Mariani, M M

    1978-01-01

    In the normal anesthetized dog, the endogenous hyperlactatemia induced either by intense muscular work or by a high dose of phenformin (20 mg/kg subtucaneously) is followed by an increase in the pancreaticoduodenal insulin output. A previous perfusion of sodium dichloroacetate (50 mg/kg. h) opposes the hyperlactatemia, and reduces or suppresses the increase in insulin output. PMID:150887

  9. Insulin Signaling and Heart Failure.

    PubMed

    Riehle, Christian; Abel, E Dale

    2016-04-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

  10. Relationship between Weather, Traffic and Delay Based on Empirical Methods

    NASA Technical Reports Server (NTRS)

    Sridhar, Banavar; Swei, Sean S. M.

    2006-01-01

    The steady rise in demand for air transportation over the years has put much emphasis on the need for sophisticated air traffic flow management (TFM) within the National Airspace System (NAS). The NAS refers to hardware, software and people, including runways, radars, networks, FAA, airlines, etc., involved in air traffic management (ATM) in the US. One of the metrics that has been used to assess the performance of NAS is the actual delays provided through FAA's Air Traffic Operations Network (OPSNET). The OPSNET delay data includes those reportable delays, i.e. delays of 15 minutes or more experienced by Instrument Flight Rule (IFR) flights, submitted by the FAA facilities. These OPSNET delays are caused by the application of TFM initiatives in response to, for instance, weather conditions, increased traffic volume, equipment outages, airline operations, and runway conditions. TFM initiatives such as, ground stops, ground delay programs, rerouting, airborne holding, and miles-in-trail restrictions, are actions which are needed to control the air traffic demand to mitigate the demand-capacity imbalance due to the reduction in capacity. Consequently, TFM initiatives result in NAS delays. Of all the causes, weather has been identified as the most important causal factor for NAS delays. Therefore, in order to accurately assess the NAS performance, it has become necessary to create a baseline for NAS performance and establish a model which characterizes the relation between weather and NAS delays.

  11. The Vernier delay unit

    SciTech Connect

    Pierce, W.B.

    1985-02-01

    One of the most critical timing specifications for the SLC machine occurs at the injector and ejector magnets for the Damping Ring. It has been determined that the trigger pulses to the magnets must be controlled to 0.1 ns. The primary source for all trigger pulses for the SLC machine is the Programmable Delay Unit (PDU). The PDU generates a 67.2 ns wide pulse with delay increments of 8.7 ns. The gap between the required accuracy and that available from the PDU requires the design of a new module that is called the Vernier Delay Unit (VDU). This module accepts the 67.2 ns pulse from the PDU and is capable of increasing the delay in steps of 0.1 ns from 0 to 10.7 ns plus the minimum 9 ns delay. The module has two totally independent channels. The pulse input to the module is software selectable from either the auxiliary backplane or a front panel Lemo connector. The auxiliary backplane pulses are to be the 67 ns differential ECL pulses from the PDU. The front panel input is to be a NIM level (-0.7 V 50 termination).

  12. Insulin Neuroprotection and the Mechanisms

    PubMed Central

    Yu, Li-Yun; Pei, Yu

    2015-01-01

    Objective: To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action. Data Sources: The study is based on the data from PubMed. Study Selection: Articles were selected with the search terms “insulin”, “blood glucose”, “neuroprotection”, “brain”, “glycogen”, “cerebral ischemia”, “neuronal necrosis”, “glutamate”, “γ-aminobutyric acid”. Results: Insulin has neuroprotection. The mechanisms include the regulation of neurotransmitter, promoting glycogen synthesis, and inhibition of neuronal necrosis and apoptosis. Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia. Conclusions: Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6–9 mmol/L. PMID:25836621

  13. On the stability of the telegraph equation with time delay

    NASA Astrophysics Data System (ADS)

    Ashyralyev, Allaberen; Agirseven, Deniz; Turk, Koray

    2016-08-01

    In this study, the initial value problem for telegraph equations with delay in a Hilbert space is considered. Theorem on stability estimates for the solution of this problem is established. As a test problem, one-dimensional delay telegraph equation with Dirichlet boundary conditions is considered. Numerical solutions of this problem are obtained by first and second order of accuracy difference schemes.

  14. Human Insulin from Recombinant DNA Technology

    NASA Astrophysics Data System (ADS)

    Johnson, Irving S.

    1983-02-01

    Human insulin produced by recombinant DNA technology is the first commercial health care product derived from this technology. Work on this product was initiated before there were federal guidelines for large-scale recombinant DNA work or commercial development of recombinant DNA products. The steps taken to facilitate acceptance of large-scale work and proof of the identity and safety of such a product are described. While basic studies in recombinant DNA technology will continue to have a profound impact on research in the life sciences, commercial applications may well be controlled by economic conditions and the availability of investment capital.

  15. Insulin and insulin like growth factor II endocytosis and signaling via insulin receptor B

    PubMed Central

    2013-01-01

    Background Insulin and insulin-like growth factors (IGFs) act on tetrameric tyrosine kinase receptors controlling essential functions including growth, metabolism, reproduction and longevity. The insulin receptor (IR) binds insulin and IGFs with different affinities triggering different cell responses. Results We showed that IGF-II induces cell proliferation and gene transcription when IR-B is over-expressed. We combined biotinylated ligands with streptavidin conjugated quantum dots and visible fluorescent proteins to visualize the binding of IGF-II and insulin to IR-B and their ensuing internalization. By confocal microscopy and flow cytometry in living cells, we studied the internalization kinetic through the IR-B of both IGF-II, known to elicit proliferative responses, and insulin, a regulator of metabolism. Conclusions IGF-II promotes a faster internalization of IR-B than insulin. We propose that IGF-II differentially activates mitogenic responses through endosomes, while insulin-activated IR-B remains at the plasma membrane. This fact could facilitate the interaction with key effector molecules involved in metabolism regulation. PMID:23497114

  16. The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity

    PubMed Central

    Hinoi, Eiichi; Gao, Nan; Jung, Dae Young; Yadav, Vijay; Yoshizawa, Tatsuya; Myers, Martin G.; Chua, Streamson C.; Kim, Jason K.; Kaestner, Klaus H.; Karsenty, Gerard

    2008-01-01

    The osteoblast-secreted molecule osteocalcin favors insulin secretion, but how this function is regulated in vivo by extracellular signals is for now unknown. In this study, we show that leptin, which instead inhibits insulin secretion, partly uses the sympathetic nervous system to fulfill this function. Remarkably, for our purpose, an osteoblast-specific ablation of sympathetic signaling results in a leptin-dependent hyperinsulinemia. In osteoblasts, sympathetic tone stimulates expression of Esp, a gene inhibiting the activity of osteocalcin, which is an insulin secretagogue. Accordingly, Esp inactivation doubles hyperinsulinemia and delays glucose intolerance in ob/ob mice, whereas Osteocalcin inactivation halves their hyperinsulinemia. By showing that leptin inhibits insulin secretion by decreasing osteocalcin bioactivity, this study illustrates the importance of the relationship existing between fat and skeleton for the regulation of glucose homeostasis. PMID:19103808

  17. When Intensive Insulin Therapy (MDI) Fails in Patients With Type 2 Diabetes: Switching to GLP-1 Receptor Agonist Versus Insulin Pump.

    PubMed

    Cohen, Ohad; Filetti, Sebastiano; Castañeda, Javier; Maranghi, Marianna; Glandt, Mariela

    2016-08-01

    Treatment with insulin, alone or with oral or injectable hypoglycemic agents, is becoming increasingly common in patients with type 2 diabetes. However, approximately 40% of patients fail to reach their glycemic targets with the initially prescribed regimen and require intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia. Many of these patients eventually reach a state in which further increases in the insulin dosage fail to improve glycemic control while increasing the risks of weight gain and hypoglycemia. The recently completed OpT2mise clinical trial showed that continuous subcutaneous insulin infusion (CSII) is more effective in reducing glycated hemoglobin (HbA1c) than intensification of multiple daily injection (MDI) insulin therapy in patients with type 2 diabetes who do not respond to intensive insulin therapy. CSII therapy may also be useful in patients who do not reach glycemic targets despite multidrug therapy with basal-bolus insulin and other agents, including glucagon-like peptide (GLP)-1 receptor agonists; current guidelines offer no recommendations for the treatment of such patients. Importantly, insulin and GLP-1 receptor agonists have complementary effects on glycemia and, hence, can be used either sequentially or in combination in the initial management of diabetes. Patients who have not previously failed GLP-1 receptor agonist therapy may show reduction in weight and insulin dose, in addition to moderate improvement in HbA1c, when GLP-1 receptor agonist therapy is added to MDI regimens. In subjects with long-standing type 2 diabetes who do not respond to intensive insulin therapies, switching from MDI to CSII and/or the addition of GLP-1 receptor agonists to MDI have the potential to improve glycemic control without increasing the risk of adverse events. PMID:27440831

  18. PHENYLMETHYLSULFONYL FLUORIDE PROTECTS RATS FROM MIPAFOX-INDUCED DELAYED NEUROPATHY

    EPA Science Inventory

    Initiation of organophosphorus-induced delayed neuropathy (OPIDN) is thought to consist of two molecular events involving the phosphorylation of the target enzyme, neurotoxic esterase or neuropathy target enzyme (NTE), and a subsequent 'aging' reaction which transforms the inhibi...

  19. Autoantibodies to Insulin Receptor Spontaneously Develop as Anti-Idiotypes in Mice Immunized with Insulin

    NASA Astrophysics Data System (ADS)

    Shechter, Yoram; Maron, Ruth; Elias, Dana; Cohen, Irun R.

    1982-04-01

    Mice immunized with insulin developed antibodies to both insulin and the insulin receptor. The antibodies to insulin receptor displaced labeled insulin from insulin receptors and mimicked the actions of insulin in stimulating the oxidation of glucose and its incorporation into lipids, and in inhibiting lipolysis. The antibodies to insulin receptor could be blocked by or bound to the antibodies to insulin, and therefore were identified as anti-idiotypes. Thus, immunization against a hormone may activate spontaneously an idiotype-anti-idiotype network resulting in antibodies to the hormone receptor.

  20. Cell factories for insulin production.

    PubMed

    Baeshen, Nabih A; Baeshen, Mohammed N; Sheikh, Abdullah; Bora, Roop S; Ahmed, Mohamed Morsi M; Ramadan, Hassan A I; Saini, Kulvinder Singh; Redwan, Elrashdy M

    2014-01-01

    The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Manufacturing of therapeutic recombinant proteins require an appropriate host organism with efficient machinery for posttranslational modifications and protein refolding. Recombinant human insulin has been produced predominantly using E. coli and Saccharomyces cerevisiae for therapeutic use in human. We would focus in this review, on various approaches that can be exploited to increase the production of a biologically active insulin and its analogues in E. coli and yeast. Transgenic plants are also very attractive expression system, which can be exploited to produce insulin in large quantities for therapeutic use in human. Plant-based expression system hold tremendous potential for high-capacity production of insulin in very cost-effective manner. Very high level of expression of biologically active proinsulin in seeds or leaves with long-term stability, offers a low-cost technology for both injectable as well as oral delivery of proinsulin. PMID:25270715

  1. Delayed flowering and global warming

    NASA Astrophysics Data System (ADS)

    Cook, B. I.; Wolkovich, E. M.; Parmesan, C.

    2011-12-01

    Within general trends toward earlier spring, observed cases of species and ecosystems that have not advanced their phenology, or have even delayed it, appear paradoxical, especially when made in temperate regions experiencing significant warming. The typical interpretation of this pattern has been that non-responders are insensitive to relatively small levels of warming over the past 40 years, while species showing delays are often viewed as statistical noise or evidence for unknown confounding factors at play. However, plant physiology studies suggest that when winter chilling (vernalization) is required to initiate spring development, winter warming may retard spring events, masking expected advances caused by spring warming. Here, we analyzed long-term data on phenology and seasonal temperatures from 490 species on two continents and demonstrate that 1) apparent non-responders are indeed responding to warming, but their responses to winter and spring warming are opposite in sign, 2) observed trends in first flowering date depend strongly on the magnitude of a given species' response to autumn/winter versus spring warming, and 3) inclusion of these effects strongly improves hindcast predictions of long-term flowering trends. With a few notable exceptions, climate change research has focused on the overall mean trend towards phenological advance, minimizing discussion of apparently non-responding species. Our results illuminate an under-studied source of complexity in wild species responses and support the need for models incorporating diverse environmental cues in order to improve predictability of species responses to anthropogenic climate change.

  2. Differences in the sites of phosphorylation of the insulin receptor in vivo and in vitro

    SciTech Connect

    White, M.F.; Takayama, S.; Kahn, C.R.

    1985-08-05

    Phosphorylation of the insulin receptor was studied in intact well differentiated hepatoma cells (Fao) and in a solubilized and partially purified receptor preparation obtained from these cells by affinity chromatography on wheat germ agglutinin agarose. Tryptic peptides containing the phosphorylation sites of the beta-subunit of the insulin receptor were analyzed by reverse-phase high performance liquid chromatography. Phosphoamino acid content of these peptides was determined by acid hydrolysis and high voltage electrophoresis. Separation of the phosphopeptides from unstimulated Fao cells revealed one major and two minor phosphoserine-containing peptides and a single minor phosphothreonine-containing peptide. Insulin (10(-7) M) increased the phosphorylation of the beta-subunit of the insulin receptor 3- to 4-fold in the intact Fao cell. After insulin stimulation, two phosphotyrosine-containing peptides were identified. Tyrosine phosphorylation reached a steady state within 20 s after the addition of insulin and remained nearly constant for 1 h. Under our experimental conditions, no significant change in the amount of (TSP)phosphoserine or (TSP)phosphothreonine associated with the beta-subunit was found during the initial response of cells to insulin. When the insulin receptor was extracted from the Fao cells and incubated in vitro with (gamma-TSP)ATP and MnS , very little phosphorylation occurred in the absence of insulin.

  3. Contingencies promote delay tolerance.

    PubMed

    Ghaemmaghami, Mahshid; Hanley, Gregory P; Jessel, Joshua

    2016-09-01

    The effectiveness of functional communication training as treatment for problem behavior depends on the extent to which treatment can be extended to typical environments that include unavoidable and unpredictable reinforcement delays. Time-based progressive delay (TBPD) often results in the loss of acquired communication responses and the resurgence of problem behavior, whereas contingency-based progressive delay (CBPD) appears to be effective for increasing tolerance for delayed reinforcement. No direct comparison of TBPD and CBPD has, however, been conducted. We used single-subject designs to compare the relative efficacy of TBPD and CBPD. Four individuals who engaged in problem behavior (e.g., aggression, vocal and motor disruptions, self-injury) participated. Results were consistent across all participants, and showed lower rates of problem behavior and collateral responses during CBPD than during TBPD. The generality of CBPD treatment effects, including optimal rates of communication and compliance with demands, was demonstrated across a small but heterogeneous group of participants, reinforcement contingencies, and contexts. PMID:27449401

  4. Estimating Delays In ASIC's

    NASA Technical Reports Server (NTRS)

    Burke, Gary; Nesheiwat, Jeffrey; Su, Ling

    1994-01-01

    Verification is important aspect of process of designing application-specific integrated circuit (ASIC). Design must not only be functionally accurate, but must also maintain correct timing. IFA, Intelligent Front Annotation program, assists in verifying timing of ASIC early in design process. This program speeds design-and-verification cycle by estimating delays before layouts completed. Written in C language.

  5. Effect of glyburide on in vivo recycling of the hepatic insulin receptor

    SciTech Connect

    Frank, H.J.; Donohoe, M.T.; Morris, W.L.

    1985-09-20

    Sulfonylureas affect insulin action at both receptor and post-receptor sites, but their exact mechanism is poorly understood. In these studies, a novel technique was used to examine the influence of glyburide on in vivo cycling of the hepatic insulin receptor. Rats were gavage-fed with 5 mg/kg per day of glyburide solubilized in 60 percent polyethylene glycol and 40 percent phosphate buffer. Control rats were fed polyethylene glycol and buffer alone. After seven days, each rat was anesthetized, the abdomen was surgically exposed, and the animal was given a saturating bolus of 30 micrograms of unlabeled insulin via the portal vein. At seven specified times from 10 seconds to 45 minutes later, a second portal vein injection of a mixture of 1.5 microCi (0.015 micrograms) SVI-labeled insulin and 15 microCi THOH (a highly diffusible internal reference marker) was administered; 18 seconds later (time for one circulation), the right lobe of the liver was removed, and SVI and TH values were counted. The liver uptake index and the turnover half-time were then calculated. Glyburide caused a doubling of the turnover half-time for the receptor. This suggests that sulfonylureas potentiate the action of insulin either by increasing the dwell time of insulin on its receptor or by affecting an intracellular event that delays the recycling of the insulin receptor back to the cell surface plasma membrane.

  6. Factors influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a qualitative exploration

    PubMed Central

    2013-01-01

    Background Many Type 2 Diabetes Mellitus (T2DM) patients refuse insulin therapy even when they require this modality of treatment. However, some eventually accept insulin. This study aimed to explore the T2DM patients’ reasons for accepting insulin therapy and their initial barriers to use insulin. Methods This qualitative study interviewed twenty-one T2DM patients at a primary care clinic who had been on insulin for more than a year through three in-depth interviews and three focus group discussions. A semi structured interview protocol was used and the sessions were audio-recorded. Subsequently, thematic analysis was conducted to identify major themes. Results The participants’ acceptance of insulin was influenced by their concerns and beliefs about diabetes and insulin. Concerns about complications of poorly controlled diabetes and side effects of other treatment regime had resulted in insulin acceptance among the participants. They also had a strong belief in insulin benefits and effectiveness. These concerns and beliefs were the results of having good knowledge about the diabetes and insulin, experiential learning, as well as doctors’ practical and emotional support that helped them to accept insulin therapy and become efficient in self-care management. These factors also allayed their negative concerns and beliefs towards diabetes and insulin, which were their barriers for insulin acceptance as it caused fear to use insulin. These negative concerns were related to injection (self-injection, needle phobia, injection pain), and insulin use (inconvenience, embarrassment, lifestyle restriction, negative social stigma, and poor self-efficacy), whereas the negative beliefs were 'insulin could cause organ damage’, 'their diabetes was not serious enough’, 'insulin is for life-long’, and 'insulin is for more severe disease only’. Conclusions Exploring patients’ concerns and beliefs about diabetes and insulin is crucial to assist physicians in

  7. Biologically active insulin-derived peptides.

    PubMed

    Fawcett, Janet

    2014-06-01

    Insulin has many actions within cells many of which are dependent on the cell type. For example, insulin stimulates glucose uptake in adipose tissue and skeletal muscle but not in liver. In liver glucose influx will increase as insulin stimulates the phosphorylation of glucose and eventual storage in the form of glycogen. Insulin also increases glucose oxidation, decreases glucose production, decreases lipolysis, increases protein synthesis and inhibits protein degradation in addition to others. Many actions have been related to insulin binding to its receptor and subsequent phosphorylation cascades, but insulin action on protein degradation has been shown to be linked to insulin degradation, specifically insulin degradation by the insulin-degrading enzyme (IDE). This activity has been shown to be due to an interaction of IDE with the proteasome, which is responsible for degradation of ubiquitin-tagged proteins. Smaller fragments of insulin that are produced by the action of IDE that do not bind to the insulin receptor show a small effect on protein degradation and a modest effect on mitogenesis. These small fragments do however inhibit lipolysis in a similar manner to insulin. If fragments are larger and can bind to the receptor they have been shown to increase glucose oxidation. Studies show that fragments of the insulin molecule have cellular activity, and that the varied actions of insulin are not completely controlled by insulin binding to the insulin receptor, even though the mechanisms may not be mutually exclusive. PMID:24559166

  8. Insulin receptor binding motif tagged with IgG4 Fc (Yiminsu) works as an insulin sensitizer to activate Akt signaling in hepatocytes.

    PubMed

    Wang, J; Zou, T; Yang, H X; Gong, Y Z; Xie, X J; Liu, H Y; Liao, D F

    2015-01-01

    Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose- and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer. PMID:26345813

  9. Lipid signals and insulin resistance.

    PubMed

    Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A

    2013-12-01

    The metabolic syndrome, a cluster of metabolic derangements that include obesity, glucose intolerance, dyslipidemia and hypertension, is a major risk factor for cardiovascular disease. Insulin resistance has been proposed to be the common feature that links obesity to the metabolic syndrome, but the mechanism remains obscure. Although the excess content of triacylglycerol in muscle and liver is highly associated with insulin resistance in these tissues, triacylglycerol itself is not causal but merely a marker. Thus, attention has turned to the accumulation of cellular lipids known to have signaling roles. This review will discuss recent progress in understanding how glycerolipids and related lipid intermediates may impair insulin signaling. PMID:24533033

  10. Insulin Receptor Signaling in Normal and Insulin-Resistant States

    PubMed Central

    Boucher, Jérémie; Kleinridders, André; Kahn, C. Ronald

    2014-01-01

    In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications. PMID:24384568

  11. Interferometric Propagation Delay

    NASA Technical Reports Server (NTRS)

    Goldstein, Richard

    1999-01-01

    Radar interferometry based on (near) exact repeat passes has lately been used by many groups of scientists, worldwide, to achieve state of the art measurements of topography, glacier and ice stream motion, earthquake displacements, oil field subsidence, lava flows, crop-induced surface decorrelation, and other effects. Variations of tropospheric and ionospheric propagation delays limit the accuracy of all such measurements. We are investigating the extent of this limitation, using data from the Shuttle radar flight, SIR-C, which is sensitive to the troposphere, and the Earth Resources Satellites, ERS-1/2, which are sensitive to both the troposphere and the ionosphere. We are presently gathering statistics of the delay variations over selected, diverse areas to determine the best accuracy possible for repeat track interferometry. The phases of an interferogram depend on both the topography of the scene and variations in propagation delay. The delay variations can be caused by movement of elements in the scene, by changes in tropospheric water vapor and by changes of the charge concentrations in the ionosphere. We plan to separate these causes by using the data from a third satellite visit (three-pass interferometry). The figure gives the geometry of the three-pass observations. The page of the figure is taken to be perpendicular to the spacecraft orbits. The three observational locations are marked on the figure, giving baselines B-12 and B-13, separated by the angle alpha. These parameters are almost constant over the whole scene. However, each pixel has an individual look angle, theta, which is related to the topography, rho is the slant range. A possible spurious time delay is shown. Additional information is contained in the original.

  12. Alterations in insulin binding accompanying differentiation of 3T3-L1 preadipocytes.

    PubMed Central

    Reed, B C; Kaufmann, S H; Mackall, J C; Student, A K; Lane, M D

    1977-01-01

    Expression of the adipocyte phenotype by differentiating 3T3-L1 preadipocytes occurs upon exposure of the cells to insulin. Differentiation-linked changes in 125I-labeled insulin binding to 3T3-L1 cells were monitored and compared with those in nondifferentiating 3T3-C2 controls treated similarly. Without chronic insulin treatment, 3T3-L1 cells failed to express the adipocyte phenotype but maintained a level of 25,000-35,000 insulin-binding sites per cell. Treatment of 3T3-L1 cells with insulin resulted in an initial suppression of insulin binding followed by a 12-fold increase that paralleled the appearance of differentiated cells. A maximum of 170,000 insulin-binding sites per cell was attained for a population in which greater than 75% of the cells had differentiated. The increase of insulin receptor level appears to be differentiation-dependent and is not a general response of cells to the culture conditions. 3T3-C2 cells maintained in the presence of insulin for 30 days exhibited the undifferentiated phenotype and suppressed levels of insulin binding (35,000 sites per cell). The binding capacity of 3T3-L1 cells for epidermal growth factor remained unchanged between 25,000 and 40;000 sites per cell and was independent of the state of differentiation. Thus, induction by insulin in receptor-specific changes. Insulin receptors increase in number but epidermal growth factor receptors remain constant. PMID:303773

  13. Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

    PubMed Central

    Masser, Dustin R.; VanGuilder Starkey, Heather D.; Bixler, Georgina V.; Dunton, Wendy; Bronson, Sarah K.; Freeman, Willard M.

    2014-01-01

    Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition. PMID:24931083

  14. Cutaneous allergy to human (recombinant DNA) insulin.

    PubMed

    Grammer, L C; Metzger, B E; Patterson, R

    1984-03-16

    p6 report two cases of cutaneous allergy to human (recombinant DNA) insulin. Each patient had a history of systemic allergic reactions to porcine insulin and was at least as reactive to human as to porcine insulin by end-point cutaneous titration. Both patients' insulin allergy was managed with animal insulins and both have done well. Our experience with these two patients indicates that human insulin (rDNA) should not be expected to be efficacious in all patients with systemic allergy to insulin. PMID:6366262

  15. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2010-02-01

    When Exubera (EXU), the first inhaled insulin formulation to make it through the clinical development process, was introduced to the market some years ago it was hoped that this would be the first in a series of novel insulin formulations applied by this route. In addition, it was hoped that inhaled insulin would pave the way for other alternative routes of insulin administration (ARIA), i.e. oral insulin, nasal insulin or transdermal insulin to mention only some of the different attempts that have been studied in the last 90 years. The failure of EXU, i.e. its withdrawal from the market due to insufficient market success, was followed by the cessation of nearly all other attempts to develop inhaled insulin formulations. Currently there is only one company (MannKind) which moves sturdily ahead with their Technosphere insulin. This company has submitted an NDA for their product recently and hopes to bring it to the market by the end of 2010 or early 2011. Even if the product is able to pass the approval hurdles in the USA and Europe, this does not guarantee that it will become a market success. Many diabetologists were sceptical about the need/advantages of inhaled insulin/EXU from the start and the introduction of this product has raised even more scepticism. Reports about 'side effects' (development of lung cancer in patients treated with EXU) of inhaled insulin are also not helpful, even if the causality of the appearance of cancer with this type of insulin therapy is not proven. One of the very negative consequences of stopping EXU are the huge financial losses to Pfizer. The managers in charge in other pharmaceutical companies and also most venture capitalists are reluctant to invest in ARIA nowadays. This in turn means that many of the small companies that try to develop new forms of insulin administration have issues when they try to find a big brother and/or sufficient financial support. Clearly the economic crisis has further aggravated this issue. One can

  16. Diagnostic delay in progressive multifocal leukoencephalopathy.

    PubMed

    Miskin, Dhanashri P; Ngo, Long H; Koralnik, Igor J

    2016-05-01

    We investigated delay in diagnosing progressive multifocal leukoencephalopathy (PML). The median time from initial symptom to diagnosis was 74 days (range 1-1643) in 111 PML patients seen at our institution from 1993 to 2015. Another diagnosis was considered before PML in nearly two-thirds, and more than three-quarters of patients suffered from diagnostic delay greater than 1 month, irrespective of their underlying immunosuppressive condition. Extended diagnostic delay occurred more frequently in patients with possible PML, and among HIV (+) patients with higher CD4(+) T-cell counts at symptom onset. Prompt diagnosis may improve survival of PML in so far as immune reconstitution can be effected, and prevent unnecessary interventions. PMID:27231708

  17. Delayed gamma technique for fissile material assay

    SciTech Connect

    Mozin, Vladimir; Tobin, Stephen; Vujie, Jasmina; Hunt, Alan

    2010-01-01

    Research sponsored by the Next Generation Safeguards Initiative are investigating several non-destructive assay techniques for the quantification of fissile plutonium mass in spent nuclear fuel assemblies. AppHcation of the delayed gamma signatures is investigated in this context. The objective of the research is to assess whether the delayed gamma assay instrument can provide sufficient sensitivity, isotope specificity and accuracy as required in nuclear material safeguards. This effort includes theoretical and experimental components for the optimal combination of interrogation parameters. A new modeling algorithm offering a high level of detail was developed specifically for this purpose and was validated in series of benchmark experiments. Preliminary modeling of the delayed gamma response from spent fuel assemblies was accomplished offering a future direction for the design process.

  18. Do long delay conditioned stimuli develop inhibitory properties?

    PubMed Central

    Escobar, Martha; Suits, W. T.; Rahn, Elizabeth J.; Arcediano, Francisco

    2015-01-01

    In long-delay conditioning, a long conditioned stimulus (CS) is paired in its final segments with an unconditioned stimulus. With sufficient training, this procedure usually results in conditioned responding being delayed until the final segment of the CS, a pattern of responding known as inhibition of delay. However, there have been no systematic investigations of the associative structure of long delay conditioning, and whether the initial segment of a long delay CS actually becomes inhibitory is debatable. In an appetitive preparation with rat subjects, the initial segment of long delay CS A passed a retardation (Experiment 1a) but not a summation (Experiment 1b) test for conditioned inhibition. Furthermore, retardation was observed only if long delay conditioning and retardation training occurred in the same context (Experiment 2). Thus, the initial segment of a long delay CS appears to share more characteristics with a latent inhibitor than a conditioned inhibitor. Componential theories of conditioning appear best suited to account for these results. PMID:26557103

  19. In utero origins of adult insulin resistance and vascular dysfunction.

    PubMed

    Thompson, Jennifer A; Regnault, Timothy R H

    2011-05-01

    The metabolic syndrome (or syndrome X) is a constellation of risk factors including insulin resistance, hypertension, dyslipidemia, and central obesity that predispose to the development of cardiovascular disease and type 2 diabetes in adult life. Insulin resistance is believed to be a critical pathophysiological event early in the disease process, impacting both skeletal muscle metabolic function and vascular responses. Adverse changes in insulin sensitivity have been found to originate in utero; for instance, prenatal events such as placental insufficiency/oxidative stress leading to altered fetal growth trajectories are associated with increased rates of metabolic syndrome in adult life. Such intrauterine insults result in reduced skeletal muscle mass in conjunction with altered insulin signaling, decreased oxidative fibers, and impaired mitochondrial function. These developmental disturbances set the stage for development of muscle triglyceride accumulation and depressed insulin sensitivity in childhood. Abnormalities of vascular structure and function arising from deprived intrauterine conditions that are exacerbated by insulin resistance account for the progression of hypertension from childhood to adulthood. Arterial changes initiated in utero include reduced endothelial nitric oxide (NO) bioavailability, vascular smooth muscle cell proliferation and inflammation, events leading to endothelial dysfunction, and atherosclerosis that are present in those destined for metabolic syndrome. In addition, the hypertensive phenotype that is a hallmark of metabolic syndrome may also be traced to blunted kidney development and renin-angiotensin system activation in growth-restricted offspring. The summative impact of these intrauterine programmed changes in terms of influencing adult health and disease encompasses dietary and lifestyle factors introduced postnatally. Establishing novel therapeutic interventions aimed at preventing and/or reducing in utero

  20. Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity.

    PubMed

    Eckel, Robert H; Depner, Christopher M; Perreault, Leigh; Markwald, Rachel R; Smith, Mark R; McHill, Andrew W; Higgins, Janine; Melanson, Edward L; Wright, Kenneth P

    2015-11-16

    Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration. PMID:26549253

  1. Therapeutic alteration of insulin-dependent diabetes mellitus progression by T cell tolerance to glutamic acid decarboxylase 65 peptides in vitro and in vivo.

    PubMed

    Wilson, S S; White, T C; DeLuca, D

    2001-07-01

    We have reported previously that nonobese diabetic (NOD) fetal pancreas organ cultures lose the ability to produce insulin when maintained in contact with NOD fetal thymus organ cultures (FTOC). Initial studies indicated that exposure to glutamic acid decarboxylase (GAD65) peptides in utero resulted in delay or transient protection from insulin-dependent diabetes mellitus (IDDM) in NOD mice. We also found that exposure of young adult NOD mice to the same peptides could result in acceleration of the disease. To more closely examine the effects of early and late exposure to diabetogenic Ags on T cells, we applied peptides derived from GAD65 (GAD AA 246-266, 509-528, and 524-543), to our "in vitro IDDM" (ivIDDM) model. T cells derived from NOD FTOC primed during the latter stages of organ culture, when mature T cell phenotypes are present, had the ability to proliferate to GAD peptides. ivIDDM was exacerbated under these conditions, suggesting that GAD responsiveness correlates with the ivIDDM phenotype, and parallels the acceleration of IDDM we had seen in young adult NOD mice. When GAD peptides were present during the initiation of FTOC, GAD proliferative responses were inhibited, and ivIDDM was reduced. This result suggests that tolerance to GAD peptides may reduce the production of diabetogenic T cells or their capacity to respond, as suggested by the in utero therapies studied in NOD mice. PMID:11418696

  2. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2011-02-01

    The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is

  3. Alternative Devices for Taking Insulin

    MedlinePlus

    ... the day. Pumps can also give "bolus" doses—one-time larger doses—of insulin at meals and at times when blood glucose is too high based on the programming set by the user. Frequent blood glucose monitoring ...

  4. [Alternative routes for insulin administration].

    PubMed

    Lassmann-Vague, V

    1994-01-01

    Ideally, insulin administration should be done through portal route, with a precise kinetic. It should also lead to a reproducible biologic effect, with minimal side-effects and be acceptable for the majority of diabetic patients. Many alternative routes of insulin administration try to fulfill one or more of these criteria. Intraperitoneal route is already used with implantable pumps. It has proven safety and metabolic efficacy, particularly upon the reduction of severe hypoglycaemia. Nasal route could provide a rapid kinetic, but its long-term utilisation depends on improvement of bioavailability and studies of local toxicity. Results concerning intrabronchic insulin seem promising, but are still preliminary. In the future, the choice among these alternative routes of insulin administration will be guided by the development of a closed-loop system. PMID:8001707

  5. Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation.

    PubMed

    Mayer, Christopher M; Belsham, Denise D

    2010-01-01

    Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR. PMID:19887566

  6. Insulin delivery methods: Past, present and future

    PubMed Central

    Shah, Rima B.; Patel, Manhar; Maahs, David M.; Shah, Viral N.

    2016-01-01

    Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development. PMID:27014614

  7. Insulin delivery methods: Past, present and future.

    PubMed

    Shah, Rima B; Patel, Manhar; Maahs, David M; Shah, Viral N

    2016-01-01

    Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development. PMID:27014614

  8. Atomic delay in helium, neon, argon and krypton

    NASA Astrophysics Data System (ADS)

    Palatchi, Caryn; Dahlström, J. M.; Kheifets, A. S.; Ivanov, I. A.; Canaday, D. M.; Agostini, P.; DiMauro, L. F.

    2014-12-01

    Photoionization by an eXtreme UltraViolet (XUV) attosecond pulse train (APT) in the presence of an infrared pulse (RABBITT method) conveys information about the atomic photoionization delay. By taking the difference of the spectral delays between pairs of rare gases (Ar,He), (Kr,He) and (Ne,He) it is possible to eliminate in each case the larger group delay (‘attochirp’) associated with the APT itself and obtain the Ar, Kr and Ne Wigner delays referenced to model calculations of the He delay. In this work we measure how the delays vary as a function of XUV photon energy but we cannot determine the absolute delay difference between atoms due to lack of precise knowledge of the initial conditions. The extracted delays are compared with several theoretical predictions and the results are consistent within 30 as over the energy range from 10 to 50 eV. An ‘effective’ Wigner delay over all emission angles is found to be more consistent with our angle-integrated measurement near the Cooper minimum in Ar. We observe a few irregular features in the delay that may be signatures of resonances. .

  9. Recursive delay calculation unit for parametric beamformer

    NASA Astrophysics Data System (ADS)

    Nikolov, Svetoslav I.; Jensen, Jørgen A.; Tomov, Borislav

    2006-03-01

    This paper presents a recursive approach for parametric delay calculations for a beamformer. The suggested calculation procedure is capable of calculating the delays for any image line defined by an origin and arbitrary direction. It involves only add and shift operations making it suitable for hardware implementation. One delaycalculation unit (DCU) needs 4 parameters, and all operations can be implemented using fixed-point arithmetics. An N-channel system needs N+ 1 DCUs per line - one for the distance from the transmit origin to the image point and N for the distances from the image point to each of the receivers. Each DCU recursively calculates the square of the distance between a transducer element and a point on the beamformed line. Then it finds the approximate square root. The distance to point i is used as an initial guess for point i + 1. Using fixed-point calculations with 36-bit precision gives an error in the delay calculations on the order of 1/64 samples, at a sampling frequency of f s = 40 MHz. The circuit has been synthesized for a Virtex II Pro device speed grade 6 in two versions - a pipelined and a non-pipelined producing 150 and 30 million delays per second, respectively. The non-pipelined circuit occupies about 0.5 % of the FPGA resources and the pipelined one about 1 %. When the square root is found with a pipelined CORDIC processor, 2 % of the FPGA slices are used to deliver 150 million delays per second.

  10. Active inference, eye movements and oculomotor delays.

    PubMed

    Perrinet, Laurent U; Adams, Rick A; Friston, Karl J

    2014-12-01

    This paper considers the problem of sensorimotor delays in the optimal control of (smooth) eye movements under uncertainty. Specifically, we consider delays in the visuo-oculomotor loop and their implications for active inference. Active inference uses a generalisation of Kalman filtering to provide Bayes optimal estimates of hidden states and action in generalised coordinates of motion. Representing hidden states in generalised coordinates provides a simple way of compensating for both sensory and oculomotor delays. The efficacy of this scheme is illustrated using neuronal simulations of pursuit initiation responses, with and without compensation. We then consider an extension of the generative model to simulate smooth pursuit eye movements-in which the visuo-oculomotor system believes both the target and its centre of gaze are attracted to a (hidden) point moving in the visual field. Finally, the generative model is equipped with a hierarchical structure, so that it can recognise and remember unseen (occluded) trajectories and emit anticipatory responses. These simulations speak to a straightforward and neurobiologically plausible solution to the generic problem of integrating information from different sources with different temporal delays and the particular difficulties encountered when a system-like the oculomotor system-tries to control its environment with delayed signals. PMID:25128318

  11. Time Delay for the Dirac Equation

    NASA Astrophysics Data System (ADS)

    Naumkin, Ivan; Weder, Ricardo

    2016-07-01

    We consider time delay for the Dirac equation. A new method to calculate the asymptotics of the expectation values of the operator {intlimits0 ^{∞}e^{iH0t}ζ(\\vert x\\vert /R) e^{-iH0t}dt} , as {R → ∞} , is presented. Here, H 0 is the free Dirac operator and {ζ(t)} is such that {ζ(t) = 1} for {0 ≤ t ≤ 1} and {ζ(t) = 0} for {t > 1} . This approach allows us to obtain the time delay operator {δ {T}(f)} for initial states f in {{H} 2^{3/2+ɛ}({R}3;{C}4)} , {ɛ > 0} , the Sobolev space of order {3/2+ɛ} and weight 2. The relation between the time delay operator {δ{T}(f)} and the Eisenbud-Wigner time delay operator is given. In addition, the relation between the averaged time delay and the spectral shift function is presented.

  12. Biosimilar insulins: a European perspective.

    PubMed

    DeVries, J H; Gough, S C L; Kiljanski, J; Heinemann, L

    2015-05-01

    Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins. PMID:25376600

  13. Cardiovascular effects of basal insulins.

    PubMed

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  14. Cardiovascular effects of basal insulins

    PubMed Central

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  15. Biosimilar insulins: a European perspective

    PubMed Central

    DeVries, J H; Gough, S C L; Kiljanski, J; Heinemann, L

    2015-01-01

    Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins. PMID:25376600

  16. Pluronic P85/poly(lactic acid) vesicles as novel carrier for oral insulin delivery.

    PubMed

    Xiong, Xiang Yuan; Li, Qi Han; Li, Yu Ping; Guo, Liang; Li, Zi Ling; Gong, Yan Chun

    2013-11-01

    Poly(lactic acid)-b-Pluronic-b-poly(lactic acid) (PLA-P85-PLA) vesicles were developed as novel carrier for oral insulin delivery. PLA-P85-PLA block copolymer was synthesized by ring opening polymerization of the monomer l-lactide using Pluronic copolymer P85 as the initiator. Insulin-loaded PLA-P85-PLA vesicles were prepared by dialysis method and the mean diameter of insulin-loaded PLA-P85-PLA vesicles was determined to be 178 nm. The cytotoxicity studies using human ovarian cancer cells OVCAR-3 indicate that PLA-P85-PLA block copolymer has good biocompatibility. Both in vitro and in vivo release behavior of insulin loaded in PLA-P85-PLA vesicles were studied. It was observed that insulin was released out gradually from PLA-P85-PLA vesicles and almost all insulin was released out 7.5h later. More importantly, for the oral administration of insulin-loaded PLA-P85-PLA vesicles at insulin doses of 200 IU/kg, the minimum blood glucose concentration was observed in the diabetic mice test after 2.5h, which was 15% of initial glucose level. Furthermore, the blood glucose concentration increased slowly to 31.8% of initial blood glucose concentration after 10.5h and was maintained at this level for at least an additional 14h (32.5% of initial blood glucose concentration at 24.5h). These results proved that PLA-P85-PLA vesicles could be promising polymeric carriers for oral insulin delivery application due to their sustained and enhanced hypoglycemic effect. PMID:23838194

  17. [Acromegaly: reducing diagnostic delay].

    PubMed

    Giustina, Andrea

    2016-08-01

    Diagnostic delay of acromegaly is still very relevant (6-8 years on average) without substantial changes in last twenty years. Clinical impact of this diagnostic delay is significant: tumor growth (2/3 of the patients at diagnosis bear a pituitary macroadenoma), development of irreversible complications (arthropathy, sleep apnea) and in all increased mortality. Reasons for this delay are related to the disease itself (facial and acral changes are very slow and subtle) but also to medical unawareness. Simple tools based on a few sufficiently sensitive and specific signs and symptoms which can trigger the diagnostic suspect would be useful in clinical practice. Global evaluation during follow-up (tumor volume, signs and symptoms, complications, circulating levels of growth hormone and its peripheral mediator IGF-I) has become crucial for the therapeutic decision making. In this regard, tools like SAGIT are now under validation and are expected to improve management of acromegaly. In fact, in the last 30 years there has been a relevant growth of the medical options to treat acromegaly and in the near future there will be an expansion of the medical options. This will greatly help the needed personalization of treatment which necessarily should consider patient convenience and preference and control of complications such as diabetes mellitus. PMID:27571562

  18. Time-Delay Interferometry

    NASA Astrophysics Data System (ADS)

    Dhurandhar, Sanjeev V.; Tinto, Massimo

    2005-07-01

    Equal-arm interferometric detectors of gravitational radiation allow phase measurements many orders of magnitude below the intrinsic phase stability of the laser injecting light into their arms. This is because the noise in the laser light is common to both arms, experiencing exactly the same delay, and thus cancels when it is differenced at the photo detector. In this situation, much lower level secondary noises then set the overall performance. If, however, the two arms have different lengths (as will necessarily be the case with space-borne interferometers), the laser noise experiences different delays in the two arms and will hence not directly cancel at the detector. In order to solve this problem, a technique involving heterodyne interferometry with unequal arm lengths and independent phase-difference readouts has been proposed. It relies on properly time-shifting and linearly combining independent Doppler measurements, and for this reason it has been called Time-Delay Interferometry (TDI). This article provides an overview of the theory and mathematical foundations of TDI as it will be implemented by the forthcoming space-based interferometers such as the Laser Interferometer Space Antenna (LISA) mission. We have purposely left out from this first version of our "Living Review" article on TDI all the results of more practical and experimental nature, as well as all the aspects of TDI that the data analysts will need to account for when analyzing the LISA TDI data combinations. Our forthcoming "second edition" of this review paper will include these topics.

  19. The Effect of Diagnostic Delays on the Drop-Out Rate and the Total Delay to Diagnosis of Tuberculosis

    PubMed Central

    Millen, Stephen J.; Uys, Pieter W.; Hargrove, John; van Helden, Paul D.; Williams, Brian G.

    2008-01-01

    Background Numerous patient and healthcare system-related delays contribute to the overall delay experienced by patients from onset of TB symptoms to diagnosis and treatment. Such delays are critical as infected individuals remain untreated in the community, providing more opportunities for transmission of the disease and adversely affecting the epidemic. Methodology/Principal Findings We present an analysis of the factors that contribute to the overall delay in TB diagnosis and treatment, in a resource-poor setting. Impact on the distribution of diagnostic delay times was assessed for various factors, the sensitivity of the diagnostic method being found to be the most significant. A linear relationship was found between the sensitivity of the test and the predicted mean delay time, with an increase in test sensitivity resulting in a reduced mean delay time and a reduction in the drop-out rate. Conclusions/Significance The results show that in a developing country a number of delay factors, particularly the low sensitivity of the initial sputum smear microscopy test, potentially increase total diagnostic delay times experienced by TB patients significantly. The results reinforce the urgent need for novel diagnostic methods, both for smear positive and negative TB, that are highly sensitive, accessible and point of care, in order to reduce mean delay times. PMID:18398459

  20. Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock.

    PubMed

    Dang, Fabin; Sun, Xiujie; Ma, Xiang; Wu, Rong; Zhang, Deyi; Chen, Yaqiong; Xu, Qian; Wu, Yuting; Liu, Yi

    2016-01-01

    Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms. PMID:27576939

  1. Insulin Restores Gestational Diabetes Mellitus–Reduced Adenosine Transport Involving Differential Expression of Insulin Receptor Isoforms in Human Umbilical Vein Endothelium

    PubMed Central

    Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Puebla, Carlos; Guzmán-Gutiérrez, Enrique; Cifuentes, Fredi; Leiva, Andrea; Casanello, Paola; Sobrevia, Luis

    2011-01-01

    OBJECTIVE To determine whether insulin reverses gestational diabetes mellitus (GDM)–reduced expression and activity of human equilibrative nucleoside transporters 1 (hENT1) in human umbilical vein endothelium cells (HUVECs). RESEARCH DESIGN AND METHODS Primary cultured HUVECs from full-term normal (n = 44) and diet-treated GDM (n = 44) pregnancies were used. Insulin effect was assayed on hENT1 expression (protein, mRNA, SLC29A1 promoter activity) and activity (initial rates of adenosine transport) as well as endothelial nitric oxide (NO) synthase activity (serine1177 phosphorylation, l-citrulline formation). Adenosine concentration in culture medium and umbilical vein blood (high-performance liquid chromatography) as well as insulin receptor A and B expression (quantitative PCR) were determined. Reactivity of umbilical vein rings to adenosine and insulin was assayed by wire myography. Experiments were in the absence or presence of l-NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) or ZM-241385 (an A2A-adenosine receptor antagonist). RESULTS Umbilical vein blood adenosine concentration was higher, and the adenosine- and insulin-induced NO/endothelium-dependent umbilical vein relaxation was lower in GDM. Cells from GDM exhibited increased insulin receptor A isoform expression in addition to the reported NO–dependent inhibition of hENT1-adenosine transport and SLC29A1 reporter repression, and increased extracellular concentration of adenosine and NO synthase activity. Insulin reversed all these parameters to values in normal pregnancies, an effect blocked by ZM-241385 and l-NAME. CONCLUSIONS GDM and normal pregnancy HUVEC phenotypes are differentially responsive to insulin, a phenomenon where insulin acts as protecting factor for endothelial dysfunction characteristic of this syndrome. Abnormal adenosine plasma levels, and potentially A2A-adenosine receptors and insulin receptor A, will play crucial roles in this phenomenon in GDM. PMID:21515851

  2. Assessing delay discounting in mice

    PubMed Central

    Mitchell, Suzanne H.

    2014-01-01

    Delay discounting (also intertemporal choice or impulsive choice) is the process by which delayed outcomes, such as delayed food delivery, are valued less than the same outcomes delivered immediately or with a shorter delay. This process is of interest because many psychopathologies, including substance dependence, pathological gambling, attention deficit hyperactivity disorder and conduct disorder, are characterized by heightened levels of delay discounting. Some of these disorders are heritable, and data indicate that delay discounting also has a genetic component. To identify the genes underlying the delay discounting decision-making process and genetic correlates of heightened discounting, researchers have used mouse models. This unit describes a protocol for generating delay discounting behavior in mice and discusses analysis techniques for such behavior. PMID:24510779

  3. Delayed Speech or Language Development

    MedlinePlus

    ... to Know About Zika & Pregnancy Delayed Speech or Language Development KidsHealth > For Parents > Delayed Speech or Language ... your child is right on schedule. Normal Speech & Language Development It's important to discuss early speech and ...

  4. Tooth formation - delayed or absent

    MedlinePlus

    Delayed or absent tooth formation; Teeth - delayed or absent formation ... The age at which the tooth comes in varies. Most infants get their first tooth between 6 and 9 months, but it may be earlier or later. ...

  5. Novel method demonstrates differential ligand activation and phosphatase-mediated deactivation of insulin receptor tyrosine-specific phosphorylation.

    PubMed

    Cieniewicz, Anne M; Cooper, Philip R; McGehee, Jennifer; Lingham, Russell B; Kihm, Anthony J

    2016-08-01

    Insulin receptor signaling is a complex cascade leading to a multitude of intracellular functional responses. Three natural ligands, insulin, IGF1 and IGF2, are each capable of binding with different affinities to the insulin receptor, and result in variable biological responses. However, it is likely these affinity differences alone cannot completely explain the myriad of diverse cellular outcomes. Ligand binding initiates activation of a signaling cascade resulting in phosphorylation of the IR itself and other intracellular proteins. The direct catalytic activity along with the temporally coordinated assembly of signaling proteins is critical for insulin receptor signaling. We hypothesized that determining differential phosphorylation among individual tyrosine sites activated by ligand binding or dephosphorylation by phosphatases could provide valuable insight into insulin receptor signaling. Here, we present a sensitive, novel immunoassay adapted from Meso Scale Discovery technology to quantitatively measure changes in site-specific phosphorylation levels on endogenous insulin receptors from HuH7 cells. We identified insulin receptor phosphorylation patterns generated upon differential ligand activation and phosphatase-mediated deactivation. The data demonstrate that insulin, IGF1 and IGF2 elicit different insulin receptor phosphorylation kinetics and potencies that translate to downstream signaling. Furthermore, we show that insulin receptor deactivation, regulated by tyrosine phosphatases, occurs distinctively across specific tyrosine residues. In summary, we present a novel, quantitative and high-throughput assay that has uncovered differential ligand activation and site-specific deactivation of the insulin receptor. These results may help elucidate some of the insulin signaling mechanisms, discriminate ligand activity and contribute to a better understanding of insulin receptor signaling. We propose this methodology as a powerful approach to characterize

  6. Insulin therapy: going the "smarter" way.

    PubMed

    Kalra, Sanjay; Joshi, Ameya; Parmar, Girish

    2014-01-01

    Insulin pharmacology has evolved from nonhuman source based extraction of insulin, to use of recombinant technologies for human insulin production, to tailor made synthetic insulin analogues. The delivery techniques of insulin have also improved, from injections to pumps, and to pumps with sensors. However, to achieve the final goal of a closed loop insulin delivery is far from achieved. One of the researches in this direction includes synthetic smart insulins. These are systems with chemical sensors for glucose, linked to reactions that trigger glucose mediated insulin delivery. Interest in this field is high and recent publications and patents show promise. The current review tries to summarize the basic concept of smart insulin as well as cater the recent developments and patents in this direction. PMID:24975640

  7. Treatment of insulin resistance in uremia.

    PubMed

    Stefanović, V; Nesić, V; Stojimirović, B

    2003-02-01

    Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms. PMID:12653342

  8. Human insulin: DNA technology's first drug.

    PubMed

    The, M J

    1989-11-01

    The history, biologic activity, and immunogenicity of human insulin are described. Recombinant human insulin first entered clinical trials in humans in 1980. At that time, the A and B chains of the insulin molecule were produced separately and then combined by chemical techniques. Since 1986, a different recombinant process has been used. The human genetic coding for proinsulin is inserted into Escherichia coli cells, which are then grown by fermentation to produce proinsulin. The connecting peptide is cleaved enzymatically from proinsulin to produce human insulin. Studies indicate that there are no important differences between pork insulin and human insulin in terms of therapeutic efficacy and disposition after intravenous administration. Recombinant human insulin has a faster onset of action and lower immunogenicity than pork or beef insulin. Diabetic patients may have an improvement in glucose concentrations when their therapy is switched from animal-source insulin to human insulin. Such a change usually requires a dosage adjustment, which must be determined by a physician. Pharmacists are responsible for educating patients concerning all insulin products and for preventing patients from interchanging insulin products. The availability of human insulin as the first pharmaceutical product manufactured through recombinant DNA technology, however, has had little effect on the pharmacist's role in the care of such patients. The production of human insulin through recombinant DNA technology represents an important advance in the treatment of patients with diabetes. PMID:2690608

  9. Molecular mechanisms for the control of translation by insulin.

    PubMed Central

    Proud, C G; Denton, R M

    1997-01-01

    Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5'-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5'-untranslated regions (5'-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5'-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general

  10. Acquisition of Cocaine Self-Administration with Unsignaled Delayed Reinforcement in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Galuska, Chad M.; Woods, James H.

    2005-01-01

    Six experimentally naive rhesus monkeys produced 0.01 mg/kg/infusion cocaine by lever pressing under a tandem fixed-ratio 1 differential-reinforcement-of-other- behavior schedule. One lever press initiated an unsignaled 15- or 30-s delay culminating in cocaine delivery. Each press made during the delay reset the delay interval. With two…

  11. Reducing Unnecessary Delay: Innovations in Case Processing. Pathways to Juvenile Detention Reform 5.

    ERIC Educational Resources Information Center

    Henry, D. Alan

    This report discusses how to reduce unnecessary delay in the juvenile justice system, presenting data from the Juvenile Detention Alternatives Initiative (JDAI). Chapter 1, "Why Focus on Unnecessary Delay?" explains the negative effects of unnecessary delays. Chapter 2, "Guiding Principles," examines principles inherent in all case processing…

  12. The Design and Development of a Computer Game on Insulin Injection

    PubMed Central

    Ebrahimpour, Fatemeh; Najafi, Mostafa; Sadeghi, Narges

    2014-01-01

    Background: Insulin therapy is of high importance in glycemic control and prevention of complications in type 1 diabetes in children. However, this treatment is unpleasant and stressful for many children, and it is difficult for them to accept. The purpose of the study was to design and develop an educational computer game for diabetic children to familiarize them with insulin injections. Methods: After a review of the literature and the collection of basic information, we discussed the purpose of this research with some diabetic children, their parents, and nurses. The findings that we acquired from the discussion were considered in designing and developing the game. Then, following the principles associated with the development of computer games, we developed seven different games that related to insulin injections, and the games were evaluated in a pilot study. Results: The games developed through the design and programming environment of Adobe Flash Player and stored on a computer disk (CD). The seven games were a pairs game, a puzzle game, a question and answer game, an insulin kit game, a drawing room game, a story game, and an insulin injection-room game). The idea was that diabetic children could become acquainted with insulin injections and the injection toolkit by playing a variety of entertaining and fun games. They also learned about some of the issues associated with insulin and experienced insulin injection in a simulated environment. Conclusions: It seems that the use of new technologies, such as computer games, can influence diabetic children’s acquaintance with the correct method of insulin injection, psychological readiness to initiate insulin therapy, reduction in stress, anxiety, and fear of insulin injection. PMID:25763157

  13. Programmable Differential Delay Circuit With Fine Delay Adjustment

    DOEpatents

    DeRyckere, John F.; Jenkins, Philip Nord; Cornett, Frank Nolan

    2002-07-09

    Circuitry that provides additional delay to early arriving signals such that all data signals arrive at a receiving latch with same path delay. The delay of a forwarded clock reference is also controlled such that the capturing clock edge will be optimally positioned near quadrature (depending on latch setup/hold requirements). The circuitry continuously adapts to data and clock path delay changes and digital filtering of phase measurements reduce errors brought on by jittering data edges. The circuitry utilizes only the minimum amount of delay necessary to achieve objective thereby limiting any unintended jitter. Particularly, this programmable differential delay circuit with fine delay adjustment is designed to allow the skew between ASICS to be minimized. This includes skew between data bits, between data bits and clocks as well as minimizing the overall skew in a channel between ASICS.

  14. A digitizer based on reflections in delay lines

    NASA Astrophysics Data System (ADS)

    Hristoforou, E.; Reilly, R. E.

    1991-10-01

    A new type of digitizer is proposed, based on the generation of an acoustic pulse reflection in a magnetostrictive delay line (MDL), at a point where a force is applied. A conductor wire C crosses an array of MDL positioned at a distance close to their end and carries a pulsed current. The measuring portion of the delay lines is under a flexible mat, so that they are not pressed at any point if no force is applied. The initial acoustic pulse in the line is detected by short coils between C and the end of each line. If a force is applied on the flexible mat above a delay line, the position and the amplitude of the applied force are respectively defined by the delay and the amplitude of the reflected pulse, with respect to the initial one. Experimental results are given for the function of the peak value of the reflected signal with respect to the applied input force under various values of pulsed current and dc bias field, for a 1-mm-wide and 150-cm-long Metglas 2605SC delay line. The resolution of this type of digitizer along the length of the delay line can be 0.1 mm, while in the other dimension it depends on the pitch of the flexible array channels (i.e., on the width of the delay lines) and can be improved by using two arrays of delay lines, orthogonal to each other.

  15. A digitizer based on reflections in delay lines (abstract)

    NASA Astrophysics Data System (ADS)

    Hristoforou, E.; Reilly, R. E.

    1991-04-01

    A new type of digitizer is proposed, based on the generation of an acoustic pulse reflection in a magnetostrictive delay line (MDL), at a point where a force is applied. A conductor wire C crosses an array of MDL positioned at a distance close to their end and carries a pulsed current. The measuring portion of the delay lines is under a flexible mat, so that they are not pressed at any point if no force is applied. The initial acoustic pulse in the line is detected by short coils between C and the end of each line. If a force is applied on the flexible mat above a delay line, the position and the amplitude of the applied force are respectively defined by the delay and the amplitude of the reflected pulse, with respect to the initial one. Experimental results are given for the function of the peak value of the reflected signal with respect to the applied input force under various values of pulsed current and dc bias field, for a 1-mm-wide and 150-cm-long Metglas 2605SC delay line. The resolution of this type of digitizer along the length of the delay line can be 0.1 mm, while in the other dimension it depends on the pitch of the flexible array channels (i.e., on the width of the delay lines) and can be improved by using two arrays of delay lines, orthogonal to each other.

  16. Insulin is protein-anabolic in chronic renal failure patients.

    PubMed

    Lim, Victoria S; Yarasheski, Kevin E; Crowley, Jan R; Fangman, Jerry; Flanigan, Michael

    2003-09-01

    To examine the protein anabolic actions of insulin in chronic renal failure, the authors measured four sets of whole body leucine fluxes during insulin alone and insulin with amino acid infusion in nine uremic patients before hemodialysis (B-HD). Seven were restudied 8 wk after initiation of maintenance hemodialysis (HD). Six normal subjects served as control (N). All values ( micro mol/kg/h, mean +/- SEM) are presented in the sequence of B-HD, HD, and N, and only P < 0.05 are listed. During Flux 1 (baseline), D (leucine release from body protein degradation) were 114 +/- 7, 126 +/- 4, and 116 +/- 6, respectively. C (leucine oxidation rates) were 18 +/- 2, 17 +/- 2, and 21 +/- 3, respectively. S (leucine disappearance into body protein [index of protein synthesis]) were 96 +/- 6, 107 +/- 4, and 94 +/- 4, respectively, and balances (net leucine flux into protein [values were negative during fasting]) were -18 +/- 2, -17 +/- 2, and -21 +/- 3, respectively. During Flux 2 (low-dose insulin infusion), D were 89 +/- 3, 98 +/- 6, and 94 +/- 5, respectively; C were 12 +/- 1, 11 +/- 2, and 18 +/- 1, respectively (P = 0.02); S were 77 +/- 4, 87 +/- 5, and 76 +/- 5, respectively, and balances were -12 +/- 1, -11 +/- 2, and -18 +/- 1, respectively (P = 0.02). During Flux 3 (high-dose insulin infusion): D were 77 +/- 3, 82 +/- 7, and 84 +/- 5, respectively; C were 9 +/- 1, 8 +/- 1, and 14 +/- 1, respectively (P = 0.005); S were 68 +/- 4, 74 +/- 6, and 70 +/- 5, respectively, and balances were -9 +/- 1, -8 +/- 1, and -14 +/- 1, respectively (P = 0.005). In Flux 4 (insulin infused with amino acids): D were 73 +/- 3, 107 +/- 18, and 85 +/- 7, respectively; C were 35 +/- 4, 29 +/- 5, and 39 +/- 3, respectively; S were 105 +/- 5, 145 +/- 15, and 113 +/- 6, respectively (P = 0.02), and balances were 32 +/- 4, 38 +/- 5, and 27 +/- 3, respectively. These data show that B-HD and HD patients were as sensitive as normal subjects to the protein anabolic actions of insulin. Insulin alone

  17. Insulin Secretory Defect and Insulin Resistance in Isolated Impaired Fasting Glucose and Isolated Impaired Glucose Tolerance

    PubMed Central

    Aoyama-Sasabe, Sae; Fukushima, Mitsuo; Xin, Xin; Taniguchi, Ataru; Nakai, Yoshikatsu; Mitsui, Rie; Takahashi, Yoshitaka; Tsuji, Hideaki; Yabe, Daisuke; Yasuda, Koichiro; Kurose, Takeshi; Inagaki, Nobuya; Seino, Yutaka

    2016-01-01

    Objective. To investigate the characteristics of isolated impaired glucose tolerance (IGT) and isolated impaired fasting glucose (IFG), we analyzed the factors responsible for elevation of 2-hour postchallenge plasma glucose (2 h PG) and fasting plasma glucose (FPG) levels. Methods. We investigated the relationship between 2 h PG and FPG levels who underwent 75 g OGTT in 5620 Japanese subjects at initial examination for medical check-up. We compared clinical characteristics between isolated IGT and isolated IFG and analyzed the relationships of 2 h PG and FPG with clinical characteristics, the indices of insulin secretory capacity, and insulin sensitivity. Results. In a comparison between isolated IGT and isolated IFG, insulinogenic index was lower in isolated IGT than that of isolated IFG (0.43 ± 0.34 versus 0.50 ± 0.47, resp.; p < 0.01). ISI composite was lower in isolated IFG than that of isolated IGT (6.87 ± 3.38 versus 7.98 ± 4.03, resp.; p < 0.0001). In isolated IGT group, insulinogenic index showed a significant correlation with 2 h PG (r = −0.245, p < 0.0001) and had the strongest correlation with 2 h PG (β = −0.290). In isolated IFG group, ISI composite showed a significant correlation with FPG (r = −0.162, p < 0.0001) and had the strongest correlation with FPG (β = −0.214). Conclusions. We have elucidated that decreased early-phase insulin secretion is the most important factor responsible for elevation of 2 h PG levels in isolated IGT subjects, and decreased insulin sensitivity is the most important factor responsible for elevation of FPG levels in isolated IFG subjects. PMID:26788515

  18. Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production.

    PubMed

    Tran, Thi Thu Trang; Postal, Bárbara Graziela; Demignot, Sylvie; Ribeiro, Agnès; Osinski, Céline; Pais de Barros, Jean-Paul; Blachnio-Zabielska, Agnieszka; Leturque, Armelle; Rousset, Monique; Ferré, Pascal; Hajduch, Eric; Carrière, Véronique

    2016-07-29

    The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure. PMID:27255710

  19. pH sensitive N-succinyl chitosan grafted polyacrylamide hydrogel for oral insulin delivery.

    PubMed

    Mukhopadhyay, Piyasi; Sarkar, Kishor; Bhattacharya, Sourav; Bhattacharyya, Aditi; Mishra, Roshnara; Kundu, P P

    2014-11-01

    pH sensitive PAA/S-chitosan hydrogel was prepared using ammonium persulfate (APS) as an initiator and methylenebisacrylamide (MBA) as a crosslinker for oral insulin delivery. The synthesized copolymer was characterized by Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) study; morphology was observed under scanning electron microscope (SEM). The PAA/S-chitosan with ∼ 38% of insulin loading efficiency (LE) and ∼ 76% of insulin encapsulation efficiency (EE), showed excellent pH sensitivity, retaining ∼ 26% of encapsulated insulin in acidic stomach pH 1.2 and releasing of ∼ 98% of insulin in the intestine (pH 7.4), providing a prolonged attachment with the intestinal tissue. The oral administration of insulin loaded PAA/S-chitosan hydrogel was successful in lowering the blood glucose level of diabetic mice. The bioavailability of insulin was ∼ 4.43%. Furthermore, no lethality or toxicity was documented after its peroral administration. Thus, PAA/S-chitosan hydrogel could serve as a promising oral insulin carrier in future. PMID:25129792

  20. Mammalian exocyst complex is required for the docking step of insulin vesicle exocytosis.

    PubMed

    Tsuboi, Takashi; Ravier, Magalie A; Xie, Hao; Ewart, Marie-Ann; Gould, Gwyn W; Baldwin, Stephen A; Rutter, Guy A

    2005-07-01

    Glucose stimulates insulin secretion from pancreatic beta cells by inducing the recruitment and fusion of insulin vesicles to the plasma membrane. However, little is currently known about the mechanism of the initial docking or tethering of insulin vesicles prior to fusion. Here, we examined the role of the SEC6-SEC8 (exocyst) complex, implicated in trafficking of secretory vesicles to fusion sites in the plasma membrane in yeast and in regulating glucose-stimulated insulin secretion from pancreatic MIN6 beta cells. We show first that SEC6 is concentrated on insulin-positive vesicles, whereas SEC5 and SEC8 are largely confined to the cytoplasm and the plasma membrane, respectively. Overexpression of truncated, dominant-negative SEC8 or SEC10 mutants decreased the number of vesicles at the plasma membrane, whereas expression of truncated SEC6 or SEC8 inhibited overall insulin secretion. When single exocytotic events were imaged by total internal reflection fluorescence microscopy, the fluorescence of the insulin surrogate, neuropeptide Y-monomeric red fluorescent protein brightened, diffused, and then vanished with kinetics that were unaffected by overexpression of truncated SEC8 or SEC10. Together, these data suggest that the exocyst complex serves to selectively regulate the docking of insulin-containing vesicles at sites of release close to the plasma membrane. PMID:15878854

  1. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism

    PubMed Central

    Redwan, Elrashdy M.; Linjawi, Moustafa H.; Uversky, Vladimir N.

    2016-01-01

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein? PMID:26983499

  2. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism.

    PubMed

    Redwan, Elrashdy M; Linjawi, Moustafa H; Uversky, Vladimir N

    2016-01-01

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein? PMID:26983499

  3. Adaptive Phase Delay Generator

    NASA Technical Reports Server (NTRS)

    Greer, Lawrence

    2013-01-01

    There are several experimental setups involving rotating machinery that require some form of synchronization. The adaptive phase delay generator (APDG) the Bencic-1000 is a flexible instrument that allows the user to generate pulses synchronized to the rising edge of a tachometer signal from any piece of rotating machinery. These synchronized pulses can vary by the delay angle, pulse width, number of pulses per period, number of skipped pulses, and total number of pulses. Due to the design of the pulse generator, any and all of these parameters can be changed independently, yielding an unparalleled level of versatility. There are two user interfaces to the APDG. The first is a LabVIEW program that has the advantage of displaying all of the pulse parameters and input signal data within one neatly organized window on the PC monitor. Furthermore, the LabVIEW interface plots the rpm of the two input signal channels in real time. The second user interface is a handheld portable device that goes anywhere a computer is not accessible. It consists of a liquid-crystal display and keypad, which enable the user to control the unit by scrolling through a host of command menus and parameter listings. The APDG combines all of the desired synchronization control into one unit. The experimenter can adjust the delay, pulse width, pulse count, number of skipped pulses, and produce a specified number of pulses per revolution. Each of these parameters can be changed independently, providing an unparalleled level of versatility when synchronizing hardware to a host of rotating machinery. The APDG allows experimenters to set up quickly and generate a host of synchronizing configurations using a simple user interface, which hopefully leads to faster results.

  4. Vehicle barrier with access delay

    DOEpatents

    Swahlan, David J; Wilke, Jason

    2013-09-03

    An access delay vehicle barrier for stopping unauthorized entry into secure areas by a vehicle ramming attack includes access delay features for preventing and/or delaying an adversary from defeating or compromising the barrier. A horizontally deployed barrier member can include an exterior steel casing, an interior steel reinforcing member and access delay members disposed within the casing and between the casing and the interior reinforcing member. Access delay members can include wooden structural lumber, concrete and/or polymeric members that in combination with the exterior casing and interior reinforcing member act cooperatively to impair an adversarial attach by thermal, mechanical and/or explosive tools.

  5. Delayed Recompression for Decompression Sickness: Retrospective Analysis

    PubMed Central

    Hadanny, Amir; Fishlev, Gregori; Bechor, Yair; Bergan, Jacob; Friedman, Mony; Maliar, Amit; Efrati, Shai

    2015-01-01

    Introduction Most cases of decompression sickness (DCS) occur soon after surfacing, with 98% within 24 hours. Recompression using hyperbaric chamber should be administrated as soon as feasible in order to decrease bubble size and avoid further tissue injury. Unfortunately, there may be a significant time delay from surfacing to recompression. The time beyond which hyperbaric treatment is non effective is unclear. The aims of the study were first to evaluate the effect of delayed hyperbaric treatment, initiated more than 48h after surfacing for DCS and second, to evaluate the different treatment protocols. Methods From January 2000 to February 2014, 76 divers had delayed hyperbaric treatment (≥48h) for DCS in the Sagol center for Hyperbaric medicine and Research, Assaf-Harofeh Medical Center, Israel. Data were collected from their medical records and compared to data of 128 patients treated earlier than 48h after surfacing at the same hyperbaric institute. Results There was no significant difference, as to any of the baseline characteristics, between the delayed and early treatment groups. With respect to treatment results, at the delayed treatment divers, complete recovery was achieved in 76% of the divers, partial recovery in 17.1% and no improvement in 6.6%. Similar results were achieved when treatment started early, where 78% of the divers had complete recovery, 15.6% partial recovery and 6.2% no recovery. Delayed hyperbaric treatment using US Navy Table 6 protocol trended toward a better clinical outcome yet not statistically significant (OR=2.786, CI95%[0.896-8.66], p=0.07) compared to standard hyperbaric oxygen therapy of 90 minutes at 2 ATA, irrespective of the symptoms severity at presentation. Conclusions Late recompression for DCS, 48 hours or more after surfacing, has clinical value and when applied can achieve complete recovery in 76% of the divers. It seems that the preferred hyperbaric treatment protocol should be based on US Navy Table 6. PMID

  6. The Strong Lensing Time Delay Challenge (2014)

    NASA Astrophysics Data System (ADS)

    Liao, Kai; Dobler, G.; Fassnacht, C. D.; Treu, T.; Marshall, P. J.; Rumbaugh, N.; Linder, E.; Hojjati, A.

    2014-01-01

    Time delays between multiple images in strong lensing systems are a powerful probe of cosmology. At the moment the application of this technique is limited by the number of lensed quasars with measured time delays. However, the number of such systems is expected to increase dramatically in the next few years. Hundred such systems are expected within this decade, while the Large Synoptic Survey Telescope (LSST) is expected to deliver of order 1000 time delays in the 2020 decade. In order to exploit this bounty of lenses we needed to make sure the time delay determination algorithms have sufficiently high precision and accuracy. As a first step to test current algorithms and identify potential areas for improvement we have started a "Time Delay Challenge" (TDC). An "evil" team has created realistic simulated light curves, to be analyzed blindly by "good" teams. The challenge is open to all interested parties. The initial challenge consists of two steps (TDC0 and TDC1). TDC0 consists of a small number of datasets to be used as a training template. The non-mandatory deadline is December 1 2013. The "good" teams that complete TDC0 will be given access to TDC1. TDC1 consists of thousands of lightcurves, a number sufficient to test precision and accuracy at the subpercent level, necessary for time-delay cosmography. The deadline for responding to TDC1 is July 1 2014. Submissions will be analyzed and compared in terms of predefined metrics to establish the goodness-of-fit, efficiency, precision and accuracy of current algorithms. This poster describes the challenge in detail and gives instructions for participation.

  7. Circadian photoentrainment: parameters of phase delaying.

    PubMed

    DeCoursey, P J

    1986-01-01

    Experiments were carried out using simulated den cages to delineate specific characteristics of phase delaying in circadian photoentrainment of a nocturnal rodent, the flying squirrel. The principal experiments entailed presentation of one to five consecutive 15-min white-light pulses per activity cycle at activity onset to animals free-running in darkness, in order to determine the immediate and final phase-shifting effect. Auxiliary experiments recorded entrainment patterns on light-dark (LD) schedules in the den cages. Phase response curves (PRCs) based on 15-min white-light pulses in standard wheel cages were also constructed for these animals as background information for interpreting the phase-delaying experiments. Exposure of a den animal to light by light sampling at the time of initial arousal from the rest state at circadian time (CT) 12, either by an LD schedule or by a 15-min light pulse, resulted in a return to the nest box for a short rest period. The phase delay occurring after a single light exposure at activity onset was equal to the induced rest, thus suggesting an immediate phase shift. The maximum delay was about 1 1/2 hr/cycle, with the amount of delay related to the number of light exposures. During the photoentrained state on an LD schedule, the activity rhythm of a den-housed animal was essentially free-running on the days following a phase delay. The data are used to expand current models for photoentrainment of circadian activity rhythms in nocturnal rodents. PMID:2979583

  8. Choice and the Initial Delay to a Reinforcer

    ERIC Educational Resources Information Center

    Moore, J.

    2008-01-01

    Pigeons were trained in two experiments that used the concurrent-chains procedure. These experiments sought to identify the variables controlling the preference of pigeons for a constant duration over a variable duration of exposure to an aperiodic, time-based, terminal-link schedule. The results indicated that two variables correlated with the…

  9. Combined therapy of insulin-producing cells and haematopoietic stem cells offers better diabetic control than only haematopoietic stem cells’ infusion for patients with insulin-dependent diabetes

    PubMed Central

    Dave, Shruti D; Trivedi, Hargovind L; Gopal, Saroj C; Chandra, Tulika

    2014-01-01

    Insulin-dependent diabetes mellitus (IDDM) is a chronic condition characterised by impaired blood sugar metabolism and autoimmunity. We report two children: a 5-year-old girl on exogenous insulin therapy of 30 IU/day and a 9-year-old boy on short-acting insulin 30 IU/day, long-acting insulin 70 IU/day, with IDDM since 4 and 7 years, respectively. We infused in vitro-generated donor bone marrow (BM)-derived haematopoietic stem cells (HSC) in patient 1 and insulin-secreting cells trans-differentiated from autologous adipose tissue-derived mesenchymal stem cells along with BM-HSC in patient 2 under non-myeloablative conditioning. Patient 1 improved during the initial 6 months, but then again lost metabolic control with increased blood sugar levels and insulin requirement of 32 IU/day; we lost her to follow-up after 18 months. Patient 2, over follow-up of 24.87 months, has stable blood sugar levels with glycosylated haemoglobin of 6.4% and present insulin requirement of 15 IU/day. PMID:25199184

  10. Patient Perspectives on Biosimilar Insulin.

    PubMed

    Wilkins, Alasdair R; Venkat, Manu V; Brown, Adam S; Dong, Jessica P; Ran, Nina A; Hirsch, James S; Close, Kelly L

    2014-01-01

    Given that a new wave of biosimilar insulins will likely enter the market in coming years, it is important to understand patient perspectives on these biosimilars. A survey (N = 3214) conducted by the market research company dQ&A, which maintains a 10 000-patient panel of people with type 1 or type 2 diabetes in roughly equal measure, investigated these perspectives. The survey asked whether patients would switch to a hypothetical less expensive biosimilar insulin that was approved by their provider. Approximately 66% of respondents reported that they would "definitely" or "likely" use a biosimilar insulin, while 17% reported that they were "unlikely" to use or would "definitely not use" such a product. Type 2 diabetes patients demonstrated slightly more willingness to use biosimilars than type 1 diabetes patients. Common patient concerns included whether biosimilars would be as effective as reference products (~650 respondents), whether side effect profiles would deviate from those of reference products (~220 respondents), and the design of the delivery device (~50 respondents). While cost savings associated with biosimilar insulins could increase patient uptake, especially among patients without health insurance (some recent estimates suggest that biosimilars will come at a substantial discount), patients may still need assurance that a cheaper price tag is not necessarily associated with substandard quality. Overall, the dQ&A survey indicates that the majority of patients are willing to consider biosimilar insulins, but manufacturers will need to work proactively to address and assuage patient concerns regarding efficacy, safety, drug administration, and other factors. PMID:24876533

  11. Oxidative Stress and Insulin Resistance

    PubMed Central

    Park, Kyong; Gross, Myron; Lee, Duk-Hee; Holvoet, Paul; Himes, John H.; Shikany, James M.; Jacobs, David R.

    2009-01-01

    OBJECTIVE Although cumulative evidence suggests that increased oxidative stress may lead to insulin resistance in vivo or in vitro, community-based studies are scarce. This study examined the longitudinal relationships of oxidative stress biomarkers with the development of insulin resistance and whether these relationships were independent of obesity in nondiabetic young adults. RESEARCH DESIGN AND METHODS Biomarkers of oxidative stress (F2-isoprostanes [F2Isop] and oxidized LDL [oxLDL]), insulin resistance (the homeostasis model assessment of insulin resistance [HOMA-IR]), and various fatness measures (BMI, waist circumference, and estimated percent fat) were obtained in a population-based observational study (Coronary Artery Risk Development in Young Adults) and its ancillary study (Young Adult Longitudinal Trends in Antioxidants) during 2000–2006. RESULTS There were substantial increases in estimated mean HOMA-IR over time. OxLDL and F2Isop showed little association with each other. Mean evolving HOMA-IR increased with increasing levels of oxidative stress markers (P < 0.001 for oxLDL and P = 0.06 for F2Isop), measured in 2000–2001. After additional adjustment for adiposity, a positive association between oxLDL and HOMA-IR was strongly evident, whereas the association between F2Isop and HOMA-IR was not. CONCLUSIONS We observed positive associations between each of two oxidative stress markers and insulin resistance. The association with oxidized LDL was independent of obesity, but that with F2Isop was not. PMID:19389821

  12. How to achieve a predictable basal insulin?

    PubMed

    Kurtzhals, P

    2005-09-01

    The development of insulin analogues over the last two decades have aimed at optimising the pharmacokinetic profile of subcutaneously injected insulin for therapeutic use in diabetes mellitus. Rapid acting analogues were successfully engineered and marketed in the late 1990's. In engineering long-acting analogues it has been a particular challenge to obtain action profiles that would be predictable from day to day in the same person. The most recent approach has been to acylate the insulin molecule with a fatty acid which provides the insulin molecule with a specific affinity for albumin. The first clinically available agent of this type is insulin detemir. Pharmacological studies have shown that reversible albumin binding will protract absorption following subcutaneous injection but still allow the insulin molecule to be recognised by the insulin receptor following dissociation from the carrier protein. Moreover, the molecular features of insulin detemir are attractive in that the molecule can be formulated as a neutral aqueous solution and does not precipitate after injection. Together with an important buffering mechanism effected by plasma albumin binding, this explains a highly significant reduction of within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. No safety considerations have been identified in using albumin as an insulin carrier to protract and buffer insulin action. In assessing the clinical attractiveness of insulin analogues, it is furthermore critically important to consider how the molecular modifications impact efficacy and safety. A number of pharmacological studies have shown that insulin detemir overall retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Taken together, insulin detemir provides an attractive novel approach for

  13. Insulin receptors in the mammary gland

    SciTech Connect

    Smith, D.H.

    1986-01-01

    Insulin binding studies were conducted using mammary membrane preparations to further the authors understanding of insulin's role in regulating mammary metabolism, particularly ruminant mammary metabolism. Specific objectives were to: (1) characterize insulin binding to bovine mammary microsomes and determine if the specificity and kinetics of binding indicate the presence of insulin receptors in bovine mammary gland; (2) examine and compare insulin binding by liver and mammary microsomes of the pig and dairy cow; (3) examine insulin binding to bovine milk fat globule membranes (MFGM) and evaluate this model's usefulness in assessing insulin receptor regulation in the mammary gland of the cow; (4) examine the effect of dietary fat in insulin binding by rat mammary and liver microsomes. The specificity and kinetics of /sup 125/I-insulin binding of bovine mammary microsomes indicated the presence of insulin receptors in bovine mammary gland. Bovine liver and mammary microsomes specifically bound less /sup 125/I-insulin than did the corresponding porcine microsomes, and mammary microsomes, regardless of species, specifically bound less /sup 125/I-insulin than did liver microsomes. These differences in binding suggest differences in insulin responsiveness between pigs and cattle, as well as between the liver and mammary glands.

  14. Characterization of the chicken muscle insulin receptor

    SciTech Connect

    Adamo, M.; Simon, J.; Rosebrough, R.W.; McMurtry, J.P.; Steele, N.C.; LeRoith, D.

    1987-12-01

    Insulin receptors are present in chicken skeletal muscle. Crude membrane preparations demonstrated specific /sup 125/I-insulin binding. The nonspecific binding was high (36-55% of total binding) and slightly lower affinity receptors were found than are typically observed for crude membrane insulin binding in other chicken tissues. Affinity crosslinking of /sup 125/I-insulin to crude membranes revealed insulin receptor alpha-subunits of Mr 128K, intermediate between those of liver (134K) and brain (124K). When solubilized and partially purified on wheat germ agglutinin (WGA) affinity columns, chicken muscle insulin receptors exhibited typical high affinity binding, with approximately 10(-10) M unlabeled insulin producing 50% inhibition of the specific /sup 125/I-insulin binding. WGA purified chicken muscle insulin receptors also exhibited insulin-stimulated autophosphorylation of the beta-subunit, which appeared as phosphorylated bands of 92- and 81K. Both bands were immunoprecipitated by anti-receptor antiserum (B10). WGA purified membranes also demonstrated dose-dependent insulin-stimulated phosphorylation of the exogenous substrate poly(Glu,Tyr)4:1. However, unlike chicken liver, chicken muscle insulin receptor number and tyrosine kinase activity were unaltered by 48 hr of fasting or 48 hr of fasting and 24 hr of refeeding. Thus, despite the presence of insulin receptors in chicken muscle showing normal coupling to receptor tyrosine kinase activity, nutritional alterations modulate these parameters in a tissue-specific manner in chickens.

  15. Transplacental passage of insulin complexed to antibody.

    PubMed Central

    Bauman, W A; Yalow, R S

    1981-01-01

    The passage of plasma proteins across the placental barrier in humans is known to be highly selective. Thus, free maternal insulin has been reported not to cross the normal maternofetal barrier, although insulin-binding antibodies have been detected in newborn infants whose diabetic mothers received insulin therapy. In this report we demonstrate, with the use of a human antiserum that permits distinction between human and animal insulins, that insulin in the cord blood of each of two neonates of insulin-treated diabetic mothers was, in part, animal insulin. The higher the antibody titer of the mother the greater was the total insulin in the cord plasma and the greater was the fraction that was animal insulin. In case 1 cord plasma insulin was 0.7 unit/liter, of which 10% was animal insulin; in case 2 cord plasma insulin was 3.5 units/liter, of which 25% was animal insulin. The demonstration that antigen restricted from transplacental passage can be transferred while complexed to antibody raises the question whether such fetal exposure would induce partial or total immunologic unresponsiveness subsequently if the fetus were rechallenged with the same antigen. PMID:7027265

  16. In vivo peripheral nervous system insulin signaling

    PubMed Central

    Grote, Caleb W.; Ryals, Janelle M.; Wright, Douglas E.

    2014-01-01

    Alterations in peripheral nervous system (PNS) insulin support may contribute to diabetic neuropathy (DN); yet, PNS insulin signaling is not fully defined. Here, we investigated in vivo insulin signaling in the PNS and compared the insulin-responsiveness to that of muscle, liver, and adipose. Nondiabetic mice were administered increasing doses of insulin to define a dose response relationship between insulin and Akt activation in the DRG and sciatic nerve. Resulting EC50 doses were used to characterize the PNS insulin signaling time course and make comparisons between insulin signaling in the PNS and other peripheral tissues (i.e., muscle, liver, adipose). The results demonstrate that the PNS is responsive to insulin and that differences in insulin signaling pathway activation exist between PNS compartments. At a therapeutically relevant dose, Akt was activated in the muscle, liver, and adipose at 30 minutes, correlating with the changes in blood glucose levels. Interestingly, the sciatic nerve showed a similar signaling profile as insulin-sensitive tissues, however there was not a comparable activation in the DRG or spinal cord. These results present new evidence regarding PNS insulin signaling pathways in vivo and provide a baseline for studies investigating the contribution of disrupted PNS insulin signaling to DN pathogenesis. PMID:24028189

  17. Delayed rule following

    PubMed Central

    Schmitt, David R.

    2001-01-01

    Although the elements of a fully stated rule (discriminative stimulus [SD], some behavior, and a consequence) can occur nearly contemporaneously with the statement of the rule, there is often a delay between the rule statement and the SD. The effects of this delay on rule following have not been studied in behavior analysis, but they have been investigated in rule-like settings in the areas of prospective memory (remembering to do something in the future) and goal pursuit. Discriminative events for some behavior can be event based (a specific setting stimulus) or time based. The latter are more demanding with respect to intention following and show age-related deficits. Studies suggest that the specificity with which the components of a rule (termed intention) are stated has a substantial effect on intention following, with more detailed specifications increasing following. Reminders of an intention, too, are most effective when they refer specifically to both the behavior and its occasion. Covert review and written notes are two effective strategies for remembering everyday intentions, but people who use notes appear not to be able to switch quickly to covert review. By focusing on aspects of the setting and rule structure, research on prospective memory and goal pursuit expands the agenda for a more complete explanation of rule effects. PMID:22478363

  18. Treatment Approach to Patients With Severe Insulin Resistance.

    PubMed

    Church, Timothy J; Haines, Stuart T

    2016-04-01

    In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin. PMID:27092020

  19. Human Insulin Does Not Increase Bladder Cancer Risk

    PubMed Central

    Tseng, Chin-Hsiao

    2014-01-01

    Background Whether human insulin can induce bladder cancer is rarely studied. Methods The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2004 and a total of 785,234 patients with type 2 diabetes were followed up for bladder cancer incidence until the end of 2009. Users of pioglitazone were excluded and the period since the initiation of insulin glargine (marketed after the entry date in Taiwan) was not included in the calculation of follow-up. Incidences for ever-users, never-users and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin, duration of therapy and cumulative dose) were calculated and the hazard ratios were estimated by Cox regression. Results There were 87,940 ever-users and 697,294 never-users, with respective numbers of incident bladder cancer of 454 (0.52%) and 3,330 (0.48%), and respective incidence of 120.49 and 94.74 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) indicated a significant association with insulin in the age-sex-adjusted models [1.238 (1.122–1.366)], but not in the model adjusted for all covariates [1.063 (0.951–1.187)]. There was also a significant trend for the hazard ratios for the different categories of the dose-response parameters in the age-sex-adjusted models, which became insignificant when all covariates were adjusted. Conclusions This study relieves the concern of a bladder cancer risk associated with human insulin. Appropriate adjustment for confounders is important in the evaluation of cancer risk associated with a medication. PMID:24466131

  20. Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential. PMID:22201977

  1. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... be used with another type of insulin (a short-acting insulin). In patients with type 2 diabetes, ... contraceptives (birth control pills, patches, rings, injections, or implants); medications for mental illness and nausea; monoamine oxidase ( ...

  2. Insulin Glargine (rDNA origin) Injection

    MedlinePlus

    ... be used with another type of insulin (a short-acting insulin). In patients with type 2 diabetes, ... therapy (birth control pills, patches, rings, injections, or implants); isoniazid (Laniazid, in Rifamate, in Rifater); lithium (Lithobid); ...

  3. Quantification of adipose tissue insulin sensitivity.

    PubMed

    Søndergaard, Esben; Jensen, Michael D

    2016-06-01

    In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses. PMID:27073214

  4. Metabolic inflammation: connecting obesity and insulin resistance.

    PubMed

    Dali-Youcef, Nassim; Mecili, Mustapha; Ricci, Roméo; Andrès, Emmanuel

    2013-05-01

    Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. PMID:22834949

  5. Metabolism A higher power for insulin

    NASA Astrophysics Data System (ADS)

    Gribble, Fiona M.

    2005-04-01

    Glucose output from the liver is tightly regulated by insulin. But insulin holds sway over more than the liver - an unappreciated circuit in glucose control involves the opening of ion channels in the brain.

  6. Emerging Trends in Noninvasive Insulin Delivery

    PubMed Central

    Verma, Arun; Kumar, Nitin; Malviya, Rishabha; Sharma, Pramod Kumar

    2014-01-01

    This paper deals with various aspects of oral insulin delivery system. Insulin is used for the treatment of diabetes mellitus, which is characterized by the elevated glucose level (above the normal range) in the blood stream, that is, hyperglycemia. Oral route of administration of any drug is the most convenient route. Development of oral insulin is still under research. Oral insulin will cause the avoidance of pain during the injection (in subcutaneous administration), anxiety due to needle, and infections which can be developed. Different types of enzyme inhibitors, like sodium cholate, camostat, mesilate, bacitracin, leupeptin, and so forth, have been used to prevent insulin from enzymatic degradation. Subcutaneous route has been used for administration of insulin, but pain and itching at the site of administration can occur. That is why various alternative routes of insulin administration like oral route are under investigation. In this paper authors summarized advancement in insulin delivery with their formulation aspects. PMID:26556194

  7. Coordinate phosphorylation of insulin-receptor kinase and its 175,000-Mr endogenous substrate in rat hepatocytes

    SciTech Connect

    Okamoto, M.; Karasik, A.; White, M.F.; Kahn, C.R. )

    1991-01-01

    To investigate the early events in insulin signal transmission in liver, isolated rat hepatocytes were labeled with {sup 32}P, and proteins phosphorylated in response to insulin were detected by immunoprecipitation with anti-phosphotyrosine and anti-receptor antibodies and analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and autoradiography. In these cells, insulin rapidly stimulated tyrosine phosphorylation of the 95,000-Mr beta-subunit of the insulin receptor and a 175,000-Mr phosphoprotein (pp175). Both proteins were precipitated by anti-phosphotyrosine antibody, whereas only the insulin receptor was recognized with anti-insulin-receptor antibody. In the insulin-stimulated state, both pp175 and the receptor beta-subunit were found to be phosphorylated on tyrosine and serine residues. Based on precipitation by the two antibodies, receptor phosphorylation was biphasic with an initial increase in tyrosine phosphorylation followed by a more gradual increase in serine phosphorylation over the first 30 min of stimulation. The time course of phosphorylation of pp175 was rapid and paralleled that of the beta-subunit of the insulin receptor. The pp175 was clearly distinguished from the insulin receptor, because it was detected only when boiling SDS was used to extract cellular phosphoproteins, whereas the insulin receptor was extracted with either Triton X-100 or SDS. In addition, the tryptic peptide maps of the two proteins were distinct. The dose-response curve for insulin stimulation was shifted slightly to the left of the insulin receptor, suggesting some signal amplification at this step. These data suggest that pp175 is a major endogenous substrate of the insulin receptor in liver and may be a cytoskeletal-associated protein.

  8. Hypersensitivity Reaction to Insulin Glargine and Insulin Detemir in a Pediatric Patient: A Case Report.

    PubMed

    Badik, Jennifer; Chen, Jimmy; Letvak, Kira; So, Tsz-Yin

    2016-01-01

    Allergy to human insulin or its analogs is rare, but it is still a significant issue in current diabetes care. Allergic reactions can range from localized injection site reactions to generalized anaphylaxis, and they can be caused by excipients or the insulin molecules themselves. We presented a case of a 14-year-old male patient with generalized allergic reactions to insulin glargine and insulin detemir. The patient was successfully managed by being switched to a continuous subcutaneous insulin infusion with insulin aspart. Allergic reactions to insulin detemir and insulin glargine have both been well described, with insulin detemir allergy appearing to be more common. There are several potential mechanisms for insulin allergy, and immunologic characteristics vary among different insulin analogs. After confirming insulin allergy in practice, management involves treating symptoms and switching insulin preparations. This is the first documented case of allergies to both insulin glargine and insulin detemir in a pediatric patient. Exact mechanism of insulin allergy is unknown, and management strategies must be individualized for each patient. PMID:26997933

  9. Hypersensitivity Reaction to Insulin Glargine and Insulin Detemir in a Pediatric Patient: A Case Report

    PubMed Central

    Badik, Jennifer; Chen, Jimmy; Letvak, Kira

    2016-01-01

    Allergy to human insulin or its analogs is rare, but it is still a significant issue in current diabetes care. Allergic reactions can range from localized injection site reactions to generalized anaphylaxis, and they can be caused by excipients or the insulin molecules themselves. We presented a case of a 14-year-old male patient with generalized allergic reactions to insulin glargine and insulin detemir. The patient was successfully managed by being switched to a continuous subcutaneous insulin infusion with insulin aspart. Allergic reactions to insulin detemir and insulin glargine have both been well described, with insulin detemir allergy appearing to be more common. There are several potential mechanisms for insulin allergy, and immunologic characteristics vary among different insulin analogs. After confirming insulin allergy in practice, management involves treating symptoms and switching insulin preparations. This is the first documented case of allergies to both insulin glargine and insulin detemir in a pediatric patient. Exact mechanism of insulin allergy is unknown, and management strategies must be individualized for each patient. PMID:26997933

  10. Stability and delay sensitivity of neutral fractional-delay systems

    NASA Astrophysics Data System (ADS)

    Xu, Qi; Shi, Min; Wang, Zaihua

    2016-08-01

    This paper generalizes the stability test method via integral estimation for integer-order neutral time-delay systems to neutral fractional-delay systems. The key step in stability test is the calculation of the number of unstable characteristic roots that is described by a definite integral over an interval from zero to a sufficient large upper limit. Algorithms for correctly estimating the upper limits of the integral are given in two concise ways, parameter dependent or independent. A special feature of the proposed method is that it judges the stability of fractional-delay systems simply by using rough integral estimation. Meanwhile, the paper shows that for some neutral fractional-delay systems, the stability is extremely sensitive to the change of time delays. Examples are given for demonstrating the proposed method as well as the delay sensitivity.

  11. Stability and delay sensitivity of neutral fractional-delay systems.

    PubMed

    Xu, Qi; Shi, Min; Wang, Zaihua

    2016-08-01

    This paper generalizes the stability test method via integral estimation for integer-order neutral time-delay systems to neutral fractional-delay systems. The key step in stability test is the calculation of the number of unstable characteristic roots that is described by a definite integral over an interval from zero to a sufficient large upper limit. Algorithms for correctly estimating the upper limits of the integral are given in two concise ways, parameter dependent or independent. A special feature of the proposed method is that it judges the stability of fractional-delay systems simply by using rough integral estimation. Meanwhile, the paper shows that for some neutral fractional-delay systems, the stability is extremely sensitive to the change of time delays. Examples are given for demonstrating the proposed method as well as the delay sensitivity. PMID:27586618

  12. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine

    PubMed Central

    Belhekar, Mahesh N.; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  13. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine.

    PubMed

    Belhekar, Mahesh N; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  14. [Chronic insulin urticaria. Therapeutic efficacy and good tolerability of human insulins].

    PubMed

    Mirouze, J; Monnier, L; Rodier, M; Balducchi, J P; Orsetti, A; Clot, J

    1982-10-23

    A case of type III (Arthus') hypersensitivity to insulin which occurred several years after insulin treatment was instituted is described. Its persistence even with highly purified insulins of bovine or porcine origin was suggestive of a direct reaction against insulin itself. The patient had no history of allergy and, contrary to most similar cases published, had not received intermittent insulin therapy. Using stimulation of lymphocyte blastogenesis, the authors were able to demonstrate the presence of specific antigen-mediated hypersensitivity to all insulins tested, including human insulins. The circulating immune complexes did not appear to be pathogenic, since the patient only had minimal retinopathy after 22 years of insulin-dependent diabetes. Human insulin was tolerated and proved effective in controlling both blood glucose levels and skin rashes in response to conventional insulins. PMID:6757860

  15. Qualitative analysis of subcutaneous Lispro and regular insulin injections for stress hyperglycemia: a pilot numerical study.

    PubMed

    Strilka, Richard J; Armen, Scott B; Indeck, Matthew C

    2014-09-01

    Increased glucose variability (GV) is an independent risk factor for mortality in the critically ill; unfortunately, the optimal insulin therapy that minimizes GV is not known. We simulate the glucose-insulin feedback system to study how stress hyperglycemia (SH) states, taken to be a non-uniform group of physiologic disorders with varying insulin resistance (IR) and similar levels of hyperglycemia, respond to the type and dose of subcutaneous (SQ) insulin. Two groups of 100 virtual patients are studied: those receiving and those not receiving continuous enteral feeds. Stress hyperglycemia was facilitated by doubling the gluconeogenesis rate and IR was stepwise varied from a borderline to a high value. Lispro and regular insulin were simulated with dosages that ranged from 0 to 6 units; the resulting GV was analyzed after each insulin injection. The numerical model used consists of a set of non-linear differential equations with two time delays and five adjustable parameters. The results show that regular insulin decreased GV in both patient groups and rarely caused hypoglycemia. With continuous enteral feeds and borderline to mild IR, Lispro showed minimal effect on GV; however, rebound hyperglycemia that increased GV occurred when the IR was moderate to high. Without a nutritional source, Lispro worsened GV through frequent hypoglycemia episodes as the injection dose increased. The inferior performance of Lispro is a result of its rapid absorption profile; half of its duration of action is similar to the glucose ultradian period. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units, and if such dynamics are present, their clinical effects should be evaluated. PMID:24769252

  16. Impact on mortality of the timing of renal replacement therapy in patients with severe acute kidney injury in septic shock: the IDEAL-ICU study (initiation of dialysis early versus delayed in the intensive care unit): study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background One of the most dreaded complications of septic shock is acute kidney injury. It occurs in around 50% of patients, with a mortality rate of about 60% at 3 months. There is no consensus on the optimal time to initiate renal replacement therapy. Retrospective and observational studies suggest that early implementation of renal replacement therapy could improve the prognosis for these patients. Methods/design This protocol summarizes the rationale and design of a randomized, controlled, multicenter trial investigating the effect of early versus delayed renal replacement therapy in patients with severe acute kidney injury in early septic shock. In total, 864 critically ill adults with septic shock and evidence of acute kidney injury, defined as the failure stage of the RIFLE classification, will be enrolled. The primary outcome is mortality at 90 days. Secondary outcomes include safety, number of days free of mechanical ventilation, number of days free of renal replacement therapy, intensive care length of stay, in-hospital length of stay, quality of life as evaluated by the EQ-5D and renal replacement therapy dependence at hospital discharge. The primary analysis will be intention to treat. Recruitment started in March 2012 and will be completed by March 2015. Discussion This protocol for a randomized controlled study investigating the impact of the timing of renal replacement therapy initiation should provide an answer to a key question for the management of patients with acute kidney injury in the context of septic shock, for whom the mortality rate remains close to 60% despite improved understanding of physiopathology and recent therapeutic advances. Trial registration ClinicalTrials.gov identifier NCT01682590, registered on 10 September 2012. PMID:24998258

  17. Oral Insulin Delivery: How Far Are We?

    PubMed Central

    Fonte, Pedro; Araújo, Francisca; Reis, Salette; Sarmento, Bruno

    2013-01-01

    Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The main barriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized. PMID:23567010

  18. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units...

  19. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units...

  20. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units...

  1. [Resistance to the action of insulin].

    PubMed

    Azevedo, M da S

    1993-06-01

    The author analyses the insulin and glucagon effect on glycaemia regulation. The structure of glucose transporters and insulin receptors is described in some detail. Finally the author attempts to explain the insulin resistance mechanism based on a post receptor alteration that would be advantageous in traditional nutrition, but is noxious in a western type society, due to excessive caloric intake. PMID:8368096

  2. Oral insulin delivery: how far are we?

    PubMed

    Fonte, Pedro; Araújo, Francisca; Reis, Salette; Sarmento, Bruno

    2013-01-01

    Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The mainbarriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized. PMID:23567010

  3. Soviet delays raise prices

    SciTech Connect

    Young, I.

    1992-01-15

    The breakup of the Soviet Union is causing massive disruptions to methanol exports. The changeover to a Commonwealth of independent States has created logistical problems which have led some shipments of Russian methanol to be cancelled and delayed other deliveries by up to two weeks. In recent years the Soviet Union has exported 700,000 m.t./year-900,000 m.t./year of methanol, mainly to Western Europe. The product is made at 750,000-m.t./year plants at Tomsk and Gubakha in Russia and transported by rail for shipment from the ports of Ventspils, Latvia, on the Baltic Sea and Yuzhnyy in Ukraine, on the Black Sea. The exports were handled by state export agency Soyuzagrochim, mainly under contract to West European traders and consumers in areas like Scandinavia and France.

  4. Delayed cure bismaleimide resins

    DOEpatents

    Adams, Johnnie E.; Jamieson, Donald R.

    1984-08-07

    Polybismaleimides prepared by delayed curing of bis-imides having the formula ##STR1## wherein R.sub.1 and R.sub.2 each independently is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, Cl or Br, or R.sub.1 and R.sub.2 together form a fused 6-membered hydrocarbon aromatic ring, with the proviso that R.sub.1 and R.sub.2 are not t-butyl or t-butoxy; X is O, S or Se; n is 1-3; and the --(CH.sub.2).sub.n -- group, optionally, is substituted by 1-3 methyl groups or by fluorine.

  5. Combining GLP-1 receptor agonists with insulin: therapeutic rationales and clinical findings.

    PubMed

    Holst, J J; Vilsbøll, T

    2013-01-01

    Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose-dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP-1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP-1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined. PMID:22646532

  6. Insulin requirements in patients with diabetes and declining kidney function: differences between insulin analogues and human insulin?

    PubMed Central

    Kulozik, Felix

    2013-01-01

    Objectives: In diabetic nephropathy the decline of renal function causes modifications of the insulin and carbohydrate metabolism resulting in changed insulin requirements. The aim of the present study was to identify potential differences in the requirements of human insulin and various insulin analogues in patients with type 1 diabetes mellitus and renal dysfunction. Methods: The insulin requirements of 346 patients with type 1 diabetes mellitus under everyday life circumstances were assessed in an observational study. Simultaneously, laboratory parameters were measured and the estimated glomerular filtration rate (eGFR) was calculated using the formula by Cockcroft–Gault. Medical history and concomitant medication were recorded. The insulin requirements of long- and short-acting insulin were tested for a relationship with the eGFR and laboratory parameters. Results: The dosage of long-acting human insulin did not show any relation to eGFR. In contrast, a strong positive relation between dosage and renal function was found for insulin glargine and insulin detemir. After classification according to renal function, the insulin dosage at eGFR less than 60 ml/min was 29.7% lower in glargine-treated and 27.3% lower in detemir-treated patients compared with eGFR greater than 90 ml/min. Considering the whole range of eGFR, short-acting human insulin did not show a relation with renal function. Only after classification according to renal function was a dose reduction found for human insulin at eGFR less than 60 ml/min. In contrast, requirements of insulin lispro were significantly related to eGFR over the whole range of eGFR. At eGFR less than 60 ml/min the insulin dosage was 32.6% lower than at eGFR greater than 90 ml/min. The requirements of insulin aspart did not show any association with the eGFR. Conclusions: Patients with type 1 diabetes mellitus show different insulin requirements according to the renal function depending on the applied insulin. This finding is

  7. Toward Closing the Loop: An Update on Insulin Pumps and Continuous Glucose Monitoring Systems

    PubMed Central

    Aye, Tandy; Block, Jen; Buckingham, Bruce

    2010-01-01

    Synoposis In this paper we review current pump and continuous glucose monitoring therapy and what will be required to integrate these systems into closed-loop control. Issues with sensor accuracy, lag time and calibration are discussed as well as issues with insulin pharmacodynamics which result in a delayed onset of insulin action in a closed-loop system. A stepwise approach to closed-loop therapy is anticipated where the first systems will suspend insulin delivery based on actual or predicted hypoglycemia. Subsequent systems may “control-to-range” limiting the time spent in hyperglycemia by mitigating the effects of a missed food bolus or underestimate of consumed carbohydrates while minimizing the risk of hypoglycemia. PMID:20723823

  8. Modeling delay in genetic networks: From delay birth-death processes to delay stochastic differential equations

    PubMed Central

    Gupta, Chinmaya; López, José Manuel; Azencott, Robert; Bennett, Matthew R.; Josić, Krešimir; Ott, William

    2014-01-01

    Delay is an important and ubiquitous aspect of many biochemical processes. For example, delay plays a central role in the dynamics of genetic regulatory networks as it stems from the sequential assembly of first mRNA and then protein. Genetic regulatory networks are therefore frequently modeled as stochastic birth-death processes with delay. Here, we examine the relationship between delay birth-death processes and their appropriate approximating delay chemical Langevin equations. We prove a quantitative bound on the error between the pathwise realizations of these two processes. Our results hold for both fixed delay and distributed delay. Simulations demonstrate that the delay chemical Langevin approximation is accurate even at moderate system sizes. It captures dynamical features such as the oscillatory behavior in negative feedback circuits, cross-correlations between nodes in a network, and spatial and temporal information in two commonly studied motifs of metastability in biochemical systems. Overall, these results provide a foundation for using delay stochastic differential equations to approximate the dynamics of birth-death processes with delay. PMID:24880267

  9. Modeling delay in genetic networks: From delay birth-death processes to delay stochastic differential equations

    SciTech Connect

    Gupta, Chinmaya; López, José Manuel; Azencott, Robert; Ott, William; Bennett, Matthew R.; Josić, Krešimir

    2014-05-28

    Delay is an important and ubiquitous aspect of many biochemical processes. For example, delay plays a central role in the dynamics of genetic regulatory networks as it stems from the sequential assembly of first mRNA and then protein. Genetic regulatory networks are therefore frequently modeled as stochastic birth-death processes with delay. Here, we examine the relationship between delay birth-death processes and their appropriate approximating delay chemical Langevin equations. We prove a quantitative bound on the error between the pathwise realizations of these two processes. Our results hold for both fixed delay and distributed delay. Simulations demonstrate that the delay chemical Langevin approximation is accurate even at moderate system sizes. It captures dynamical features such as the oscillatory behavior in negative feedback circuits, cross-correlations between nodes in a network, and spatial and temporal information in two commonly studied motifs of metastability in biochemical systems. Overall, these results provide a foundation for using delay stochastic differential equations to approximate the dynamics of birth-death processes with delay.

  10. High fasting serum insulin level due to autoantibody interference in insulin immunoassay discloses autoimmune insulin syndrome: a case report.

    PubMed

    Lamy, Pierre-Jean; Sault, Corinne; Renard, Eric

    2016-08-01

    Insulin-antibodies are a cause of misleading results in insulin immunoassays. They may also mediate deleterious blood glucose variations. A patient presented with overtiredness, recurrent episodes of sweating, dizziness and fainting fits. A fasting serum insulin assay performed on a Modular platform (Modular analytic E170, Roche Diagnostic, Meylan, France) showed a highly elevated value of 194.7 mIU/L, whereas on the same sample glucose and C-peptide levels were normal. Other immunometric insulin assays were performed, as well as antibodies anti-insulin radiobinding assay (RBA) and gel filtration chromatography (GFC). While complementary insulin assays yielded closer to normal fasting levels, the free insulin concentration assessed after PEG precipitation was 14.0 mIU/L and the RBA was positive. GFC revealed that most of the insulin was complexed with a 150 kDa molecule, corresponding to an immunoglobulin G (IgG). A high fasting serum insulin level in a patient with neuroglucopenic symptoms was related to a high insulin-antibody level, suggesting an insulin autoimmune syndrome. PMID:27492703

  11. Globular Adiponectin Enhances Muscle Insulin Action via Microvascular Recruitment and Increased Insulin Delivery

    PubMed Central

    Zhao, Lina; Chai, Weidong; Fu, Zhuo; Dong, Zhenhua; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong; Liu, Zhenqi

    2014-01-01

    Rationale Adiponectin enhances insulin action and induces nitric oxide–dependent vasodilatation. Insulin delivery to muscle microcirculation and transendothelial transport are 2 discrete steps that limit insulin's action. We have shown that expansion of muscle microvascular surface area increases muscle insulin delivery and action. Objective To examine whether adiponectin modulates muscle microvascular recruitment thus insulin delivery and action in vivo. Methods and Results Overnight fasted adult male rats were studied. We determined the effects of adiponectin on muscle microvascular recruitment, using contrast-enhanced ultrasound, on insulin-mediated microvascular recruitment and whole-body glucose disposal, using contrast-enhanced ultrasound and insulin clamp, and on muscle insulin clearance and uptake with 125I-insulin. Globular adiponectin potently increased muscle microvascular blood volume without altering microvascular blood flow velocity, leading to a significantly increased microvascular blood flow. This was paralleled by a ≈30% to 40% increase in muscle insulin uptake and clearance, and ≈30% increase in insulin-stimulated whole-body glucose disposal. Inhibition of endothelial nitric oxide synthase abolished globular adiponectin-mediated muscle microvascular recruitment and insulin uptake. In cultured endothelial cells, globular adiponectin dose-dependently increased endothelial nitric oxide synthase phosphorylation but had no effect on endothelial cell internalization of insulin. Conclusions Globular adiponectin increases muscle insulin uptake by recruiting muscle microvasculature, which contributes to its insulin-sensitizing action. PMID:23459195

  12. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes.

    PubMed

    Manowsky, Julia; Camargo, Rodolfo Gonzalez; Kipp, Anna P; Henkel, Janin; Püschel, Gerhard P

    2016-06-01

    Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. PMID:27094035

  13. Time Delay of CGM Sensors

    PubMed Central

    Schmelzeisen-Redeker, Günther; Schoemaker, Michael; Kirchsteiger, Harald; Freckmann, Guido; Heinemann, Lutz; del Re, Luigi

    2015-01-01

    Background: Continuous glucose monitoring (CGM) is a powerful tool to support the optimization of glucose control of patients with diabetes. However, CGM systems measure glucose in interstitial fluid but not in blood. Rapid changes in one compartment are not accompanied by similar changes in the other, but follow with some delay. Such time delays hamper detection of, for example, hypoglycemic events. Our aim is to discuss the causes and extent of time delays and approaches to compensate for these. Methods: CGM data were obtained in a clinical study with 37 patients with a prototype glucose sensor. The study was divided into 5 phases over 2 years. In all, 8 patients participated in 2 phases separated by 8 months. A total number of 108 CGM data sets including raw signals were used for data analysis and were processed by statistical methods to obtain estimates of the time delay. Results: Overall mean (SD) time delay of the raw signals with respect to blood glucose was 9.5 (3.7) min, median was 9 min (interquartile range 4 min). Analysis of time delays observed in the same patients separated by 8 months suggests a patient dependent delay. No significant correlation was observed between delay and anamnestic or anthropometric data. The use of a prediction algorithm reduced the delay by 4 minutes on average. Conclusions: Prediction algorithms should be used to provide real-time CGM readings more consistent with simultaneous measurements by SMBG. Patient specificity may play an important role in improving prediction quality. PMID:26243773

  14. Clinical outcomes of suture delay in forehead flap.

    PubMed

    Isik, Daghan; Kiroglu, Faruk; Isik, Yasemin; Goktas, Ugur; Atik, Bekir

    2012-01-01

    The delay phenomenon is a surgical procedure performed to raise a wider skin flap and to improve the survival of skin flaps. Surgery, chemicals, sutures, and lasers can be used for the delay procedure. In this study, delayed forehead flaps created by suturing were used for coverage of nasal skin defects in eleven patients. In 7 patients, the cross-paramedian forehead flap was used to increase the extent of flap lengthening. In the first session, suture delay was performed on both sides of the forehead flap margin. In the second session, the flap was elevated and sutured to its new position, 7 to 10 days after the initial surgery. All flaps were completely viable, and patient satisfaction was optimal in all cases. The positive effect of surgical delay on flap survival has been shown in experimental and clinical studies. However, experimentally, suture delay or chemical delay procedures have been shown to be beneficial in flap survival only. Suture delay seems to be an inexpensive, effective, easily performed, atraumatic, and safe technique, especially among patients with systemic diseases such as diabetes or cardiovascular diseases, smoking patients who may lose the flap, or patients who need very wide and long flaps. PMID:22337378

  15. Effect of anaesthesia on insulin-induced hypoglycemia in rabbits.

    PubMed

    Haynes, F J; Cheema-Dhadli, S; Halperin, R M; Zettle, R; Robinson, L; Halperin, M L

    1988-12-01

    The aim of this study was to determine how anaesthetized rabbits survive much longer than awake rabbits after receiving an insulin overdose. Insulin appeared to act in both groups of rabbits because there was a prompt fall in circulating glucose, free fatty acids, and beta-hydroxybutyrate concentrations. Carbohydrate appeared to be the principal energy source for anaesthetized rabbits because their respiratory quotient approached unity. Although the fall in glycemia was similar in both groups of rabbits, the circulating lactate concentration rose only in the anaesthetized group. This rise in lactate in the initial 60 min after insulin was given could account for most of the fall in glycemia if the source of lactate was the glucose pool. The decline in hepatic glycogen was close to 100 mumol/g liver; this would account for about one-third of the total energy turnover and close to one-half of the measured glucose appearance in these anaesthetized rabbits. As judged from the rate of oxygen consumption, muscle glycogen seemed to supply two-thirds of the fuel to be oxidized in these rabbits. However, only one-third of the lactate released from muscle was first converted to glucose and the remainder was oxidized directly to CO2. Although insulin provided the metabolic setting for a rapid rate of glucose oxidation, this rate appeared to be diminished when the overall rate of oxygen consumption was lower during anaesthesia. PMID:3067835

  16. Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance

    PubMed Central

    Chabot, François; Caron, Alexandre; Laplante, Mathieu; St-Pierre, David H

    2014-01-01

    Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated (AG) and unacylated (UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesity-related disorders. However, due to the complexity of its biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis. PMID:24936254

  17. Mitochondrial efficiency and insulin resistance.

    PubMed

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  18. Nutritional Modulation of Insulin Resistance

    PubMed Central

    Weickert, Martin O.

    2012-01-01

    Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM). Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts. PMID:24278690

  19. Supervising Remote Humanoids Across Intermediate Time Delay

    NASA Technical Reports Server (NTRS)

    Hambuchen, Kimberly; Bluethmann, William; Goza, Michael; Ambrose, Robert; Rabe, Kenneth; Allan, Mark

    2006-01-01

    The President's Vision for Space Exploration, laid out in 2004, relies heavily upon robotic exploration of the lunar surface in early phases of the program. Prior to the arrival of astronauts on the lunar surface, these robots will be required to be controlled across space and time, posing a considerable challenge for traditional telepresence techniques. Because time delays will be measured in seconds, not minutes as is the case for Mars Exploration, uploading the plan for a day seems excessive. An approach for controlling humanoids under intermediate time delay is presented. This approach uses software running within a ground control cockpit to predict an immersed robot supervisor's motions which the remote humanoid autonomously executes. Initial results are presented.

  20. Patient Perspectives on Biosimilar Insulin

    PubMed Central

    Wilkins, Alasdair R.; Venkat, Manu V.; Brown, Adam S.; Dong, Jessica P.; Ran, Nina A.; Hirsch, James S.

    2014-01-01

    Given that a new wave of biosimilar insulins will likely enter the market in coming years, it is important to understand patient perspectives on these biosimilars. A survey (N = 3214) conducted by the market research company dQ&A, which maintains a 10 000-patient panel of people with type 1 or type 2 diabetes in roughly equal measure, investigated these perspectives. The survey asked whether patients would switch to a hypothetical less expensive biosimilar insulin that was approved by their provider. Approximately 66% of respondents reported that they would “definitely” or “likely” use a biosimilar insulin, while 17% reported that they were “unlikely” to use or would “definitely not use” such a product. Type 2 diabetes patients demonstrated slightly more willingness to use biosimilars than type 1 diabetes patients. Common patient concerns included whether biosimilars would be as effective as reference products (~650 respondents), whether side effect profiles would deviate from those of reference products (~220 respondents), and the design of the delivery device (~50 respondents). While cost savings associated with biosimilar insulins could increase patient uptake, especially among patients without health insurance (some recent estimates suggest that biosimilars will come at a substantial discount), patients may still need assurance that a cheaper price tag is not necessarily associated with substandard quality. Overall, the dQ&A survey indicates that the majority of patients are willing to consider biosimilar insulins, but manufacturers will need to work proactively to address and assuage patient concerns regarding efficacy, safety, drug administration, and other factors. PMID:24876533

  1. A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design

    PubMed Central

    2012-01-01

    Background Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. Methods/design The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. Discussion In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996. PMID:22727048

  2. Selective Insulin Resistance in the Kidney

    PubMed Central

    Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

    2016-01-01

    Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

  3. Immobilization depresses insulin signaling in skeletal muscle.

    PubMed

    Hirose, M; Kaneki, M; Sugita, H; Yasuhara, S; Martyn, J A

    2000-12-01

    Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit (IR-beta) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-beta and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-beta and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways. PMID:11093909

  4. Cafestol, a Bioactive Substance in Coffee, Stimulates Insulin Secretion and Increases Glucose Uptake in Muscle Cells: Studies in Vitro.

    PubMed

    Mellbye, Fredrik Brustad; Jeppesen, Per Bendix; Hermansen, Kjeld; Gregersen, Søren

    2015-10-23

    Diet and exercise intervention can delay or prevent development of type-2-diabetes (T2D), and high habitual coffee consumption is associated with reduced risk of developing T2D. This study aimed to test whether selected bioactive substances in coffee acutely and/or chronically increase insulin secretion from β-cells and improve insulin sensitivity in skeletal muscle cells. Insulin secretion from INS-1E rat insulinoma cells was measured after acute (1-h) and long-term (72-h) incubation with bioactive substances from coffee. Additionally, we measured uptake of radioactive glucose in human skeletal muscle cells (SkMC) after incubation with cafestol. Cafestol at 10(-8) and 10(-6) M acutely increased insulin secretion by 12% (p < 0.05) and 16% (p < 0.001), respectively. Long-term exposure to 10(-10) and 10(-8) M cafestol increased insulin secretion by 34% (p < 0.001) and 68% (p < 0.001), respectively. Caffeic acid also increased insulin secretion acutely and chronically. Chlorogenic acid, trigonelline, oxokahweol, and secoisolariciresinol did not significantly alter insulin secretion acutely. Glucose uptake in SkMC was significantly enhanced by 8% (p < 0.001) in the presence of 10(-8) M cafestol. This newly demonstrated dual action of cafestol suggests that cafestol may contribute to the preventive effects on T2D in coffee drinkers and be of therapeutic interest. PMID:26465380

  5. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?

    PubMed

    Gabriely, Ilan; Ma, Xiao Hui; Yang, Xiao Man; Atzmon, Gil; Rajala, Michael W; Berg, Anders H; Scherer, Phillip; Rossetti, Luciano; Barzilai, Nir

    2002-10-01

    Age-dependent changes in insulin action and body fat distribution are risk factors for the development of type 2 diabetes. To examine whether the accumulation of visceral fat (VF) could play a direct role in the pathophysiology of insulin resistance and type 2 diabetes, we monitored insulin action, glucose tolerance, and the expression of adipo-derived peptides after surgical removal of VF in aging (20-month-old) F344/Brown Norway (FBN) and in Zucker Diabetic Fatty (ZDF) rats. As expected, peripheral and hepatic insulin action were markedly impaired in aging FBN rats, and extraction of VF (accounting for approximately 18% of their total body fat) was sufficient to restore peripheral and hepatic insulin action to the levels of young rats. When examined at the mechanistic level, removal of VF in ZDF rats prevented the progressive decrease in insulin action and delayed the