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Sample records for intracerebroventricularly injected insulin

  1. Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model.

    PubMed

    Lin, Fangju; Jia, Jianping; Qin, Wei

    2014-11-12

    The β-amyloid (Aβ) oligomer rather than fibrillar Aβ has become the important focus of recent studies on the pathogenesis of Alzheimer's disease (AD). Insulin signaling plays important roles in cognitive disease, such as AD. However, in-vivo evidence for the link between central insulin signaling and the Aβ oligomer are lacking, and the mechanisms underlying the effect of central insulin signaling on AD are still elusive. Our team has established the Presenilin-1 Val97Leu mutant transgenic (PS1V97L) AD mouse model with the intraneuronal Aβ oligomer as the potential initiator for other pathologies, but without extracellular amyloid plaque formation. Using this model, we investigated the roles of disturbed central insulin signaling induced by intracerebroventricular injection of streptozotocin (STZ) in the progression of AD. We observed that PS1V97L mice after intracerebroventricular injection of STZ showed increased Aβ oligomer accumulation and aggravated spatial learning and memory deficit in the absence of diabetes symptoms. Furthermore, STZ administration inhibited the activation of the insulin receptor and enhanced the activation of c-Jun NH2-terminal kinase, which was accompanied by increased production of carboxy-terminal fragments from the amyloid precursor protein, in the brain of PS1V97L mice. Overall, our study provided in-vivo evidence for a role of central insulin signaling in AD progression.

  2. Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats.

    PubMed

    Jessen, Lene; Clegg, Deborah J; Bouman, Stephan D

    2010-01-01

    Insulin detemir is a novel human insulin analog that does not show the usual propensity for weight gain in diabetic patients. We speculated that this beneficial effect could be due to insulin detemir exerting stronger anorectic effects within the brain than other insulins. To study the central effects of regular human insulin and insulin detemir on food intake, the present study was undertaken. We used acute intracerebroventricular insulin injections to compare food intake and body weight in rats fed ad libitum. Contrary to previously published data, we found that neither regular human insulin (8 or 32 mU) nor insulin detemir (1,290 pmol) reduced food intake in this model. Melanotan-II was also injected intracerebroventricularly as a positive control, and significantly reduced food intake and body weight, suggesting that our intracerebroventricular model is able to show anorectic effects. A series of experiments was therefore conducted in which different set-ups were tested to investigate which factors would be required to produce the reported anorectic effect of intracerebroventricular insulin. Although we varied rat strain, stereotactic coordinates, formulations of insulin and vehicle, dose, volume, and time of injection, the anorectic effect of intracerebroventricular insulin could not be replicated. Therefore, we suggest that acute intracerebroventricularly injected insulin does not robustly inhibit food intake in rats. Based on our results, the acute intracerebroventricular injection procedure may not be a preferred method for studying the central anorectic effects of insulin in rats. Instead, administrations over time or locally in hypothalamic nuclei might be recommended.

  3. Insulin/IGF signaling-related gene expression in the brain of a sporadic Alzheimer's disease monkey model induced by intracerebroventricular injection of streptozotocin.

    PubMed

    Lee, Youngjeon; Kim, Young-Hyun; Park, Sang-Je; Huh, Jae-Won; Kim, Sang-Hyun; Kim, Sun-Uk; Kim, Ji-Su; Jeong, Kang-Jin; Lee, Kyoung-Min; Hong, Yonggeun; Lee, Sang-Rae; Chang, Kyu-Tae

    2014-01-01

    We reported previously that the intracerebroventricular streptozotocin (icv-STZ)-treated cynomolgus monkey showed regionally specific glucose hypometabolism in FDG-PET imaging, similar to that observed in the early stages of sporadic Alzheimer's disease (sAD). However, further pathological analyses of this model at the molecular level are needed to validate it as a feasible model for sAD. Two cynomolgus monkeys were injected with 2 mg/kg STZ into the cerebellomedullary cistern at day 1, 7 and 14. Two control monkeys were given normal saline. At 5 months after injection, the expression levels of genes encoding 9 upstream molecules in insulin/insulin-like growth factor (IGF) signaling and markers for 4 cell-type populations in the frontal cortex, hippocampus, posterior cingulate, precuneus, and occipital cortex of control and icv-STZ treated cynomolgus monkeys were examined. Real-time quantitative PCR analyses demonstrated that the overall mRNA expression of insulin/IGF signaling-related genes was mainly impaired in the anterior part of the cerebrum, frontal cortex, and hippocampus, similar to the early stage of sAD. The changes were accompanied by the loss of oligodendrocytes and neurons. The posterior part of the cerebrum did not show degenerative alterations. The present study provides important fundamental information on the icv-STZ monkey model for sAD. These results may help guide future studies using this model for the investigation of pathological mechanisms and the development of drugs for sAD.

  4. Inconsistencies in the Hypophagic Action of Intracerebroventricular Insulin in Mice

    PubMed Central

    Allister, Eugenia Mc; Pacheco-Lopez, Gustavo; Woods, Stephen C.; Langhans, Wolfgang

    2015-01-01

    Insulin inhibits eating after its intracerebroventricular (ICV) administration in multiple species and under a variety of conditions. Nevertheless, the results across reports are inconsistent in that ICV insulin does not always reduce food intake. The reasons for this variability are largely unknown. Using mice as a model, we performed several crossover trials with insulin vs. vehicle when infused into the third cerebral ventricle (i3vt) to test the hypothesis that recent experience with the i3vt procedure contributes to the variability in the effect of ICV insulin on food intake. Using a cross-over design with two days between injections, we found that insulin (0.4 µU/mouse) significantly reduced food intake relative to vehicle in mice that received vehicle on the first and insulin on the second trial, whereas this effect was absent in mice that received insulin on the first and vehicle on the second trial. Higher doses (i3vt 4.0 and 40.0 µU/mouse) had no effect on food intake in this paradigm. When injections were spaced 7 days apart, insulin reduced food intake with no crossover effect. Mice that did not reduce food intake in response to higher doses of i3vt insulin did so in response to i3vt infusion of the melanocortin receptor agonist melanotan-II (MT-II), indicating that the function of the hypothalamic melanocortin system, which mediates the effect of insulin on eating, was not impaired by whatever interfered with the insulin effect, and that this interference occurred upstream of the melanocortin receptors. Overall, our findings suggest that associative effects based on previous experience with the experimental situation can compromise the eating inhibition elicited by i3vt administered insulin. PMID:26344647

  5. Inconsistencies in the hypophagic action of intracerebroventricular insulin in mice.

    PubMed

    Mc Allister, Eugenia; Pacheco-Lopez, Gustavo; Woods, Stephen C; Langhans, Wolfgang

    2015-11-01

    Insulin inhibits eating after its intracerebroventricular (ICV) administration in multiple species and under a variety of conditions. Nevertheless, the results across reports are inconsistent in that ICV insulin does not always reduce food intake. The reasons for this variability are largely unknown. Using mice as a model, we performed several crossover trials with insulin vs. vehicle when infused into the third cerebral ventricle (i3vt) to test the hypothesis that recent experience with the i3vt procedure contributes to the variability in the effect of ICV insulin on food intake. Using a cross-over design with two days between injections, we found that insulin (0.4 μU/mouse) significantly reduced food intake relative to vehicle in mice that received vehicle on the first and insulin on the second trial, whereas this effect was absent in mice that received insulin on the first and vehicle on the second trial. Higher doses (i3vt 4.0 and 40.0 μU/mouse) had no effect on food intake in this paradigm. When injections were spaced 7 days apart, insulin reduced food intake with no crossover effect. Mice that did not reduce food intake in response to higher doses of i3vt insulin did so in response to i3vt infusion of the melanocortin receptor agonist melanotan-II (MT-II), indicating that the function of the hypothalamic melanocortin system, which mediates the effect of insulin on eating, was not impaired by whatever interfered with the insulin effect, and that this interference occurred upstream of the melanocortin receptors. Overall, our findings suggest that associative effects based on previous experience with the experimental situation can compromise the eating inhibition elicited by i3vt administered insulin.

  6. Exercise increases insulin signaling in the hippocampus: physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice.

    PubMed

    Muller, Alexandre P; Gnoatto, Jussânia; Moreira, Julia D; Zimmer, Eduardo R; Haas, Clarissa B; Lulhier, Francisco; Perry, Marcos L S; Souza, Diogo O; Torres-Aleman, Ignácio; Portela, Luis V

    2011-10-01

    Increasing evidence indicates that physical exercise induces adaptations at the cellular, molecular, and systemic levels that positively affect the brain. Insulin plays important functional roles within the brain that are mediated by insulin-receptor (IR) signaling. In the hippocampus, insulin improves synaptic plasticity, memory formation, and learning via direct modulation of GABAergic and glutamatergic receptors. Separately, physical exercise and central insulin administration exert relevant roles in cognitive function. We here use CF1 mice to investigate (i) the effects of voluntary exercise on hippocampal insulin signaling and memory performance and (ii) whether central insulin administration alters the effects of exercise on hippocampal insulin signaling and memory performance. Adult mice performed 30 days of voluntary exercise on running wheel and afterward both, sedentary and exercised groups, received intracerebroventricular (icv) injection of saline or insulin (0.5-5 mU). Memory performance was assessed using the inhibitory avoidance and water maze tasks. Hippocampal tissue was measured for [U-(14)C] glucose oxidation and the immunocontent of insulin receptor/signaling (IR, pTyr, pAktser473). Additionally, the phosphorylation of the glutamate NMDA receptor NR2B subunit and the capacity of glutamate uptake were measured, and immunohistochemistry was used to determine glial reactivity. Exercise significantly increased insulin peripheral sensitivity, spatial learning, and hippocampal IR/pTyrIR/pAktser473 immunocontent. Glucose oxidation, glutamate uptake, and astrocyte number also increased relative to the sedentary group. In both memory tasks, 5 mU icv insulin produced amnesia but only in exercised animals. This amnesia was associated a rapid (15 min) and persistent (24 h) increase in hippocampal pNR2B immunocontent that paralleled the increase in glial reactivity. In conclusion, physical exercise thus increased hippocampal insulin signaling and improved

  7. Intracerebroventricular injection of ghrelin decreases wheel running activity in rats.

    PubMed

    Miyatake, Yumiko; Shiuchi, Tetsuya; Mawatari, Kazuaki; Toda, Satomi; Taniguchi, Yasuko; Futami, Akari; Sato, Fukiko; Kuroda, Masashi; Sebe, Mayu; Tsutsumi, Rie; Harada, Nagakatsu; Minokoshi, Yasuhiko; Kitamura, Tadahiro; Gotoh, Koro; Ueno, Masaki; Nakaya, Yutaka; Sakaue, Hiroshi

    2017-01-01

    There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.

  8. Intracerebroventricular Injection of Rats. A Sensitive Assay Method for Endogenous Pyrogen Circulating in Rats (41015)

    DTIC Science & Technology

    1981-01-01

    8217* " _.-. PRO( DI 0IN (Ii I lil S()( II I ok IrXI. RittI N I 111 IOI O(A ANt) %i-i DR INU 166, 6-Il 19 1) Intracerebroventricular Injection of...8217ohn iases. F’oPy Detrick, Frederick. Maryland 21701 OI! Abstract, Intracerebroventricular tics) injection of endogenous pyrogen (EPI into rats causes...phagocytic conserved. Intracerebroventricular (icy) cells (3). administration of small volumes of crude Its biological activity is currently de- rabbit

  9. Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism.

    PubMed

    Grieb, Paweł

    2016-04-01

    Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer's disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer's brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of

  10. Effects of intracerebroventricular injection of rosiglitazone on appetite-associated parameters in chicks.

    PubMed

    Matias, Justin A; Gilbert, Elizabeth R; Denbow, D Michael; Cline, Mark A

    2015-12-23

    Rosiglitazone, a thiazolidinedione, is a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist that increases insulin sensitivity. A documented side effect of this diabetes drug is increased appetite, although the mechanism mediating this response is unknown. To better understand effects on food intake regulation, we evaluated the appetite-associated effects of rosiglitazone in an alternative vertebrate and agriculturally-relevant model, the domesticated chick. Four day-old chicks received intracerebroventricular (ICV) injections of 0, 5, 10 or 20nmol rosiglitazone and food and water intake were measured. Chicks that received 5 and 10nmol rosiglitazone increased food intake during the 2h observation period, with no effect on water intake. In the next experiment, chicks were ICV-injected with 10nmol rosiglitazone and hypothalamus was collected at 1h post-injection for total RNA isolation. Real-time PCR was performed to measure mRNA abundance of appetite- and glucose regulation-associated factors. Neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA decreased while NPY receptor 1 (NPYr1) mRNA increased in rosiglitazone-injected chicks compared to the controls. Results show that central effects of rosiglitazone on appetite are conserved between birds and mammals, and that increases in food intake might be mediated through NPY and POMC neurons in the hypothalamus.

  11. Insulin Lispro Injection

    MedlinePlus

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

  12. Giving an insulin injection

    MedlinePlus

    ... want. Put the needle into and through the rubber top of the insulin bottle. Push the plunger ... longer-acting insulin. Put the needle into the rubber top of that insulin bottle. Push the plunger ...

  13. Effects of intracerebroventricular injection of histamine and its related compounds on rectal temperature in mice.

    PubMed

    Chen, Z; Sugimoto, Y; Kamei, C

    1995-12-01

    Effects of intracerebroventricular injection of histamine and its related compounds on rectal temperature were studied in mice. Histamine (0.1-1.0 mu g) and histidine (500-1,000 mg/kg) caused a dose-related hypothermia. H1 agonist, 2-methylhistamine and 2-thiazolylethylamine also displayed a dose-dependent hypothermia. In addition, H2 agonists, 4-methylhistamine and dimaprit elicited a decrease in body temperature. Preinjection of not only H1-antagonists (diphenhydramine and chlorpheniramine) but also H2 antagonists (cimetidine and ranitidine) abolished histamine-induced hypothermia. Either intracerebroventricular or intraperitoneal injection of thioperamide, a histamine H3 antagonist, showed hypothermia. The hypothermic effect produced by intracerebroventricular injection of thioperamide was significantly blocked by (R)-alpha-methylhistamine, a selective H3 agonist. In addition, the effect induced by thioperamide was inhibited by H1 and H2 antagonists, indicating that the H3 receptor also participates in histamine-induced hypothermia.

  14. Effect of chronic intracerebroventricular insulin administration in rats on the peripheral glucose metabolism and synaptic plasticity of CA1 hippocampal neurons.

    PubMed

    Kamal, Amer; Ramakers, Geert M J; Gispen, Willem Hendrik; Biessels, Geert Jan

    2012-01-30

    In this study we examined the effects of sustained intracerebroventricular insulin infusion on hippocampal synaptic plasticity in rats. Insulin was infused intracerebroventricularly in male Wistar rats (n=12) for 3 months using osmotic minipumps. A control group (n=12) received a sham operation. Insulin infusion led to an initial reduction in food intake and body weight gain, but these differences attenuated over 12 weeks. Insulin infusion did not affect fasting or non-fasting blood glucose levels. Field synaptic potentials recording from the hippocampus demonstrated a defect in the expression of long-term potentiation. Sharp electrode current-clamp recording showed that CA1 pyramidal cells fire action potentials in response to prolonged depolarizing current injection and those action potentials showed progressive broadening. The action potential broadening in the insulin-perfused animals were significantly longer than the control. The amplitude of slow after hyperpolarization (sAHP) was measured after manually "clamping" the cells at -65 mV and injecting currents to evoke a train of four APs. The sAHP amplitude was significantly longer than in the control animals. We conclude that local insulin infusion into the brain of rats had significant effects on synaptic plasticity in the absence of marked effects on systemic glucose levels. These results indicate that long-term elevation of insulin levels can have adverse effects directly on the brain.

  15. Effect of acute lipopolysaccharide-induced inflammation in intracerebroventricular-streptozotocin injected rats.

    PubMed

    Murtishaw, Andrew S; Heaney, Chelcie F; Bolton, Monica M; Sabbagh, Jonathan J; Langhardt, Michael A; Kinney, Jefferson W

    2016-02-01

    Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 μL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABA(B1), and β-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.

  16. Neuroinflammation induced by intracerebroventricular injection of microbial neuraminidase.

    PubMed

    Granados-Durán, Pablo; López-Ávalos, María D; Grondona, Jesús M; Gómez-Roldán, María Del Carmen; Cifuentes, Manuel; Pérez-Martín, Margarita; Alvarez, Martina; Rodríguez de Fonseca, Fernando; Fernández-Llebrez, Pedro

    2015-01-01

    In the present paper, we describe the facts that took place in the rat brain after a single injection of the enzyme neuraminidase from Clostridium perfringens into the right lateral ventricle. After injection, it diffused through the cerebrospinal fluid of the ipsilateral ventricle and the third ventricle, and about 400 μm into the periventricular brain parenchyma. The expression of ICAM1 in the endothelial cells of the periventricular vessels, IBA1 in microglia, and GFAP in astrocytes notably increased in the regions reached by the injected neuraminidase. The subependymal microglia and the ventricular macrophages begun to express IL1β and some appeared to cross the ependymal layer. After about 4 h of the injection, leukocytes migrated from large venules of the affected choroid plexus, the meninges and the local subependyma, and infiltrated the brain. The invading cells arrived orderly: first neutrophils, then macrophage-monocytes, and last CD8α-positive T-lymphocytes and B-lymphocytes. Leukocytes in the ventricles and the perivascular zones penetrated the brain parenchyma passing through the ependyma and the glia limitans. Thus, it is likely that a great part of the damage produced by microorganism invading the brain may be due to their neuraminidase content.

  17. Neuroinflammation Induced by Intracerebroventricular Injection of Microbial Neuraminidase

    PubMed Central

    Granados-Durán, Pablo; López-Ávalos, María D.; Grondona, Jesús M.; Gómez-Roldán, María del Carmen; Cifuentes, Manuel; Pérez-Martín, Margarita; Alvarez, Martina; Rodríguez de Fonseca, Fernando; Fernández-Llebrez, Pedro

    2015-01-01

    In the present paper, we describe the facts that took place in the rat brain after a single injection of the enzyme neuraminidase from Clostridium perfringens into the right lateral ventricle. After injection, it diffused through the cerebrospinal fluid of the ipsilateral ventricle and the third ventricle, and about 400 μm into the periventricular brain parenchyma. The expression of ICAM1 in the endothelial cells of the periventricular vessels, IBA1 in microglia, and GFAP in astrocytes notably increased in the regions reached by the injected neuraminidase. The subependymal microglia and the ventricular macrophages begun to express IL1β and some appeared to cross the ependymal layer. After about 4 h of the injection, leukocytes migrated from large venules of the affected choroid plexus, the meninges and the local subependyma, and infiltrated the brain. The invading cells arrived orderly: first neutrophils, then macrophage-monocytes, and last CD8α-positive T-lymphocytes and B-lymphocytes. Leukocytes in the ventricles and the perivascular zones penetrated the brain parenchyma passing through the ependyma and the glia limitans. Thus, it is likely that a great part of the damage produced by microorganism invading the brain may be due to their neuraminidase content. PMID:25853134

  18. The intracerebroventricular injection of rimonabant inhibits systemic lipopolysaccharide-induced lung inflammation.

    PubMed

    Johnson, Arnold; Neumann, Paul H; Peng, Jianya; James, Janey; Russo, Vincenzo; MacDonald, Hunter; Gertzberg, Nancy; Feleder, Carlos

    2015-09-15

    We investigated the role of intracerebroventricular (ICV) injection of rimonabant (500ng), a CB1 antagonist, on lipopolysaccharide ((LPS) 5mg/kg)-induced pulmonary inflammation in rats in an isolated perfused lung model. There were decreases in pulmonary capillary pressure (Ppc) and increases in the ((Wet-Dry)/Dry lung weight)/(Ppc) ratio in the ICV-vehicle/LPS group at 4h. There were decreases in TLR4 pathway markers, such as interleukin receptor-associated kinase-1, IκBα, Raf1 and phospho-SFK (Tyr416) at 30min and at 4h increases in IL-6, vascular cell adhesion molecule-1 and myeloperoxidase in lung homogenate. Intracerebroventricular rimonabant attenuated these LPS-induced responses, indicating that ICV rimonabant modulates LPS-initiated pulmonary inflammation.

  19. Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: an animal model.

    PubMed

    Hahn, Margaret K; Chintoh, Araba; Remington, Gary; Teo, Celine; Mann, Steve; Arenovich, Tamara; Fletcher, Paul; Lam, Loretta; Nobrega, Jose; Guenette, Melanie; Cohn, Tony; Giacca, Adria

    2014-03-01

    The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 μg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.

  20. Adiposity and plane of nutrition influence reproductive neuroendocrine and appetite responses to intracerebroventricular insulin and neuropeptide-Y in sheep.

    PubMed

    Miller, D W; Bennett, E J; Harrison, J L; Findlay, P A; Adam, C L

    2011-01-01

    Long-term nutritional background is thought to influence hypothalamic appetite and reproductive neuroendocrine responses to short-term nutritional feedback. In order to investigate this phenomenon, the effects of intracerebroventricular administration of insulin or neuropeptide-Y (NPY) on LH secretion and voluntary food intake (VFI) were examined in sheep that were initially thin and kept on an increasing nutritional plane (INP), or initially fat and kept on a decreasing nutritional plane (DNP), for 10 weeks. Intracerebroventricular insulin stimulated LH secretion and suppressed VFI in INP sheep when initially thin, but not when they became fat, and had no effect on LH in DNP sheep when initially fat, and stimulated LH secretion when they became thin. Intracerebroventricular NPY had no effect on LH or VFI in INP sheep when initially thin, decreased LH secretion and increased VFI when they became fat, and decreased LH secretion in DNP sheep when initially fat but had no effect when they became thin. Therefore, sensitivity to insulin increases with low or decreasing nutritional status and decreases with high or increasing nutritional status, whereas sensitivity to NPY increases with high or increasing nutritional status and decreases with low or decreasing nutritional status. In conclusion, reproductive neuroendocrine and appetite responses to acute changes in nutritional feedback signals depend on the individual's longer-term nutritional background.

  1. Effects of intracerebroventricular injection of histamine on memory deficits induced by hippocampal lesions in rats.

    PubMed

    Kamei, C; Chen, Z; Nakamura, S; Sugimoto, Y

    1997-05-01

    The influence of bilateral hippocampal lesions on active avoidance response was studied in rats, as well as the effect of intracerebroventricular (i.c.v.) injection of histamine on memory deficits caused by hippocampectomy. Retardation of learning acquisition was produced by lesioning of the bilateral dorsal hippocampus in active avoidance response. Memory retention was also impaired by hippocampectomy. Although locomotor activity and rearing behavior measured by open-field test increased after hippocampal lesions, there was no relation between impairment of learning and increase in exploratory behavior. I.c.v. injection of histamine and i.p. injection of histidine resulted in an improvement of memory deficits (not only learning acquisition but also memory retrieval) induced by hippocampal lesions in rats. Histamine contents of the hippocampus and hypothalamus decreased after hippocampectomy, and a decrease in histamine contents of both areas was restored by histamine (i.c.v.) and histidine (i.p.) injection. In addition, a close relationship was found between decrease in response latency of avoidance response and an increase in histamine content of the hippocampus and hypothalamus after histamine injection.

  2. Intracerebroventricular injection of glucagon-like peptide-1 changes lipid metabolism in chicks.

    PubMed

    Tachibana, Tetsuya; Oikawa, Daichi; Adachi, Nami; Boswell, Tim; Furuse, Mitsuhiro

    2007-08-01

    Glucagon-like peptide-1 (GLP-1), derived from proglucagon, is thought to act as a negative regulator of energy homeostasis in mammals, since intracerebroventricular (ICV) injection of GLP-1 inhibits feeding behavior and enhances energy expenditure. The anorexigenic effect of GLP-1 is also observed in chicks, but whether brain GLP-1 enhances energy expenditure has not been investigated. The aim of the present study was to clarify the effect of ICV injection of GLP-1 on energy expenditure as well as metabolic changes in chicks. The injection of GLP-1 did not affect energy expenditure calculated from oxygen consumption and carbon dioxide production. On the other hand, the injection of GLP-1 significantly decreased respiratory quotient, suggesting that brain GLP-1 shifted the use of energy sources from carbohydrates to lipids. In support of this, ICV injection of GLP-1 increased plasma non-esterified fatty acid concentration while plasma glucose concentration was decreased. In conclusion, GLP-1 appears to act in the brain as a metabolic modulator rather than as a regulator of total energy expenditure in chicks.

  3. Characterization of Cerebral Damage in a Monkey Model of Alzheimer's Disease Induced by Intracerebroventricular Injection of Streptozotocin.

    PubMed

    Yeo, Hyeon-Gu; Lee, Youngjeon; Jeon, Chang-Yeop; Jeong, Kang-Jin; Jin, Yeung Bae; Kang, Philyong; Kim, Sun-Uk; Kim, Ji-Su; Huh, Jae-Won; Kim, Young-Hyun; Sim, Bo-Woong; Song, Bong-Seok; Park, Young-Ho; Hong, Yonggeun; Lee, Sang-Rae; Chang, Kyu-Tae

    2015-01-01

    In line with recent findings showing Alzheimer's disease (AD) as an insulin-resistant brain state, a non-transgenic animal model with intracerebroventricular streptozotocin (icv-STZ) administration has been proposed as a representative experimental model of AD. Although icv-STZ rodent models of AD have been increasingly researched, studies in non-human primate models are very limited. In this study, we aimed to characterize the cerebral damage caused by icv-STZ in non-human primates; to achieve this, three cynomolgus monkeys (Macaca fascicularis) were administered four dosages of STZ (2 mg/kg) dissolved in artificial cerebrospinal fluid and another three controls were injected with only artificial cerebrospinal fluid at the cerebellomedullary cistern. In vivo neuroimaging was performed with clinical 3.0 T MRI, followed by quantitative analysis with FSL for evaluation of structural changes of the brain. Immunohistochemistry was performed to evaluate cerebral histopathology. We showed that icv-STZ caused severe ventricular enlargement and parenchymal atrophy, accompanying amyloid-β deposition, hippocampal cell loss, tauopathy, ependymal cell loss, astrogliosis, and microglial activation, which are observed in human aged or AD brain. The findings suggest that the icv-STZ monkey model would be a valuable resource to study the mechanisms and consequences of a variety of cerebral pathologies including major pathological hallmarks of AD. Furthermore, the study of icv-STZ monkeys could contribute to the development of treatments for age- or AD-associated cerebral changes.

  4. Effects of treadmill exercise on brain insulin signaling and β-amyloid in intracerebroventricular streptozotocin induced-memory impairment in rats

    PubMed Central

    Kang, Eun Bum; Cho, Joon Yong

    2014-01-01

    [Purpose] The purpose of the study is to explore effect of 6 weeks treadmill exercise on brain insulin signaling and β-amyloid(Aβ). [Methods] The rat model of Alzheimer’s disease(AD) used in the present study was induced by the intracerebroventricular(ICV) streptozotocin(STZ). To produce the model of animal with AD, STZ(1.5mg/kg) was injected to a cerebral ventricle of both cerebrums of Sprague-Dawley rat(20 weeks). The experimental animals were divided into ICV-Sham(n=7), ICV-STZ CON(n=7), ICV-STZ EXE(n=7). Treadmill exercise was done for 30 min a day, 5 days a week for 6 weeks. Passive avoidance task was carried out before and after treadmill exercise. [Results] The results of this study show that treadmill exercise activated Protein kinase B(AKT)/ Glycogen synthase kinase 3α (GSK3α), possibly via activation of insulin receptor(IR) and insulin receptor substrate(IRS) and reduced Aβ in the brain of ICV-STZ rats. More interestingly, treadmill exercise improved cognitive function of ICV-STZ rats. Finally, physical exercise or physical activity gave positive influences on brain insulin signaling pathway. [Conclusion] Therefore, treadmill exercise can be applied to improve AD as preventive and therapeutic method. PMID:25566443

  5. Biphasic changes in body temperature produced by intracerebroventricular injections of histamine in the cat.

    PubMed

    Clark, W G; Cumby, H R

    1976-09-01

    1. Intracerebroventricular administration of histamine to cats caused hypothermia followed by a rise in body temperature. 2-Methylhistamine caused a similar biphasic response, while 3-methylhistamine had no effect on body temperature and 4-methylhistamine produced a delayed hyperthermia. Some tolerance to the hypothermic activity developed when a series of closely spaced injections of histamine was given. 2. Doses of histamine and 2-methylhistamine which altered body temperature when given centrally were ineffective when infused or injected I.V. 3. Pyrilamine, an H1-receptor antagonist, prevented the hypothermic response to histamine. 4. Hypothermic responses to histamine at an environmental temperature of 22 degrees C were comparable to responses in a cold room at 4 degrees C in both resting animals and animals acting to depress a lever to escape an external heat load. A change in error signal from the thermostat could account for these results. However, lesser degrees of hypothermia developed when histamine was given to animals in a hot environment. In some, but not all animals, this smaller response could be attributed to inadequate heat loss in spite of maximal activation of heat-loss mechanisms. 5. The hyperthermic response to histamine was antagonized by central, but not peripheral, injection of metiamide, an H2-receptor antagonist. 6. The results indicate that histamine and related agents can act centrally to cause both hypothermia, mediated by H1-receptors, and hyperthermia, mediated by H2-receptors.

  6. Effects of Intracerebroventricularly (ICV) Injected Ghrelin on Cardiac Inducible Nitric Oxide Synthase Activity/Expression in Obese Rats.

    PubMed

    Sudar Milovanovic, E; Jovanovic, A; Misirkic-Marjanovic, M; Vucicevic, Lj; Janjetovic, K; Isenovic, E R

    2015-11-01

    The aim of this study was to examine the effects of ghrelin on regulation of cardiac inducible nitric oxide synthase (iNOS) activity/expression in high fat (HF), obese rats.For this study, male Wistar rats fed with HF diet (30% fat) for 4 weeks were injected every 24 h for 5 days intracerebroventricularly (ICV) with ghrelin (0.3 nmol/5 µl) or with an equal volume of phosphate buffered saline (PBS). Control rats were ICV injected with an equal volume of PBS. Glucose, insulin and nitric oxide (NO) concentrations were measured in serum, while arginase activity and citrulline concentrations were measured in heart lysate. Protein iNOS and regulatory subunit of nuclear factor-κB (NFκB-p65), phosphorylation of enzymes protein kinase B (Akt) at Ser(473), and extracellular signal-regulated kinases 1/2 (ERK1/2) at Tyr(202)/Tyr(204) were determined in heart lysate by Western blot. For gene expression of iNOS qRT-PCR was used.Results show significantly (p<0.01) higher serum NO production in ghrelin treated HF rats compared with HF rats. Ghrelin significantly reduced citrulline concentration (p<0.05) and arginase activity (p<0.01) in HF rats. In ghrelin treated HF rats, gene and protein expression of iNOS and NFκB-p65 levels were significantly (p<0.05) increased compared with HF rats. Increased phosphorylation of Akt (p<0.01) and decreased (p<0.05) ERK1/2 phosphorylation were detected in HF ghrelin treated rats compared with HF rats hearts.Results from this study indicate that exogenous ghrelin induces expression and activity of cardiac iNOS via Akt phosphorylation followed by NFκB activation in HF rats.

  7. Intracerebroventricular and Intravascular Injection of Viral Particles and Fluorescent Microbeads into the Neonatal Brain.

    PubMed

    Kawasaki, Hideya; Kosugi, Isao; Sakao-Suzuki, Makiko; Meguro, Shiori; Tsutsui, Yoshihiro; Iwashita, Toshihide

    2016-07-24

    In the study on the pathogenesis of viral encephalitis, the infection method is critical. The first of the two main infectious routes to the brain is the hematogenous route, which involves infection of the endothelial cells and pericytes of the brain. The second is the intracerebroventricular (ICV) route. Once within the central nervous system (CNS), viruses may spread to the subarachnoid space, meninges, and choroid plexus via the cerebrospinal fluid. In experimental models, the earliest stages of CNS viral distribution are not well characterized, and it is unclear whether only certain cells are initially infected. Here, we have analyzed the distribution of cytomegalovirus (CMV) particles during the acute phase of infection, termed primary viremia, following ICV or intravascular (IV) injection into the neonatal mouse brain. In the ICV injection model, 5 µl of murine CMV (MCMV) or fluorescent microbeads were injected into the lateral ventricle at the midpoint between the ear and eye using a 10-µl syringe with a 27 G needle. In the IV injection model, a 1-ml syringe with a 35 G needle was used. A transilluminator was used to visualize the superficial temporal (facial) vein of the neonatal mouse. We infused 50 µl of MCMV or fluorescent microbeads into the superficial temporal vein. Brains were harvested at different time points post-injection. MCMV genomes were detected using the in situ hybridization method. Fluorescent microbeads or green fluorescent protein expressing recombinant MCMV particles were observed by fluorescent microscopy. These techniques can be applied to many other pathogens to investigate the pathogenesis of encephalitis.

  8. Changes in plasma adrenocorticotropic hormone and cortisol levels induced by intracerebroventricular injection of histamine and its related compounds in dogs.

    PubMed

    Tsujimoto, S; Kamei, C; Yoshida, T; Tasaka, K

    1993-08-01

    Changes in plasma adrenocorticotropic hormone (ACTH) and cortisol levels induced by intracerebroventricular injection of histamine (H(i)) were studied in dogs. Intracerebroventricular administration of Hi at doses of 5 and 10 micrograms/kg caused a significant increase in plasma ACTH, while more rapid and more marked increase in plasma cortisol was noticed after Hi injection at doses of 2-10 micrograms/kg. Similar results were obtained when 2-methylhistamine was injected; remarkable increases in both plasma ACTH and cortisol levels were observed at doses of 25 and 50 micrograms/kg. However, no such effect was elicited by 4-methylhistamine even at a dose of 50 micrograms/kg. The rate of plasma cortisol increase induced by either Hi or 2-methylhistamine was significantly faster than that of plasma ACTH. Simultaneous application of pyrilamine (intracerebroventricularly) with H(i) resulted in the significant inhibition of H(i)-induced hormone secretions, but in similar administration neither ACTH nor cortisol were affected by cimetidine. In hypophysectomized dogs, a significant increase in plasma cortisol level was also observed after H(i) injection at a dose of 5 micrograms/kg. Intravenous infusion of hexamethonium continued before and after H(i) injection failed to inhibit the increase in plasma ACTH and cortisol levels induced by H(i). From these findings, it can be concluded that intracerebroventricular injection of H(i) caused an increase in plasma ACTH and cortisol levels via H1-receptor, and it is suggested that to some extent, the cortisol release elicited by H(i) is certainly produced without participation of ACTH.

  9. Effects of intracerebroventricular injections of 5-HT on systemic vascular resistances of conscious rats.

    PubMed

    Davisson, Robin L; Bates, James N; Johnson, Alan Kim; Lewis, Stephen J

    2014-09-01

    The aims of this study were to determine (i) the effects of intracerebroventricular (i.c.v.) injections of 5-hydroxytryptamine (5-HT, 10μg) on mean arterial blood pressure (MAP), heart rate (HR) and mesenteric (MR), renal (RR) and hindquarter (HQR) vascular resistances of conscious rats, (ii) the central 5-HT receptor subtype which mediates these effects, and (iii) the role of nitric oxide (NO) in the expression of these responses. The i.c.v. injection of 5-HT had minor effects on MAP but produced a decrease in HR (-18±4%), which lasted for 20min. The i.c.v. injection of 5-HT elicited marked increases in MR (+50±7%) and reductions in HQR (-31±3%). These responses occurred promptly and lasted for 25-35min. 5-HT also produced a transient decrease in RR (-26±8% at 10min). All of these responses were prevented by the prior i.c.v. injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (10μg). The intravenous injection of the NO synthesis inhibitor, L-NAME (25μmol/kg), produced a sustained pressor response, bradycardia and increases in MR, RR and HQR. Subsequent i.c.v. injection of 5-HT produced a minor pressor response (+7±2%), bradycardia (-18±3%), an increase in MR (+52±8%) but no decreases in RR or HQR. This study demonstrates that i.c.v. 5-HT differentially affects peripheral vascular resistances by activation of central 5-HT1/5-HT2-receptors. It appears that L-NAME did not interfere with the central actions of 5-HT as it did not prevent the 5-HT-induced bradycardia or mesenteric vasoconstriction. Since the 5-HT-induced falls in RR and HQR were abolished by L-NAME, it is possible that these responses are mediated by an active neurogenic process involving the release of NO within the vasculature.

  10. Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats.

    PubMed

    Chen, Z; Sugimoto, Y; Kamei, C

    1999-11-01

    The effects of alpha-fluoromethylhistidine (alpha-FMH) on spatial cognition were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (ICV) injection of alpha-FMH resulted in spatial memory deficits characterized by an increase in the number of total errors (TE) and a decrease in the number of initial correct responses (ICR). There was a strong correlation between increases in the number of TE and decreases in histamine contents of the cortex and hippocampus regions of the brain, which are known to participate in learning and memory. On the other hand, both histamine (50-100 ng, ICV) and thioperamide (10 microg, ICV) significantly ameliorated the memory deficit induced by alpha-FMH. However, metoprine showed no significant effect on the alpha-FMH-induced memory deficit. Pyrilamine and R-(alpha)-methylhistamine enhanced the memory deficit induced by alpha-FMH, at doses that had no appreciable effect when administered alone. In contrast, no significant influence on alpha-FMH-induced memory deficit was observed with zolantidine.

  11. NMDA receptor is involved in neuroinflammation in intracerebroventricular colchicine-injected rats.

    PubMed

    Sil, Susmita; Ghosh, Tusharkanti; Ghosh, Rupsa

    2016-07-01

    The neurodegeneration in intracerebroventricular (icv) colchicine injected (ICIR) rats is linked with neuroinflammation. Glutamate excitotoxicity through NMDA receptors is involved with the neuroinflammation in some animal models of Alzheimer Disease (AD), but it has not been explored in ICIR rats. The aim of this study was to investigate the role of NMDA receptors (by blocking it's activity with memantine) in colchicine-induced neuroinflammation and neurodegeneration and impacts on peripheral immune parameters in ICIR rats. Levels of inflammatory markers (IL-1β, TNFα, ROS, nitrite) in the hippocampus and serum, histopathology of the hippocampus and select peripheral immune parameters were measured 14 and 21-days after icv colchicine injection in rats. These parameters were also measured in rats that received daily per os administration of memantine (20 mg/kg) in both study durations. Neuroinflammation in the hippocampus of ICIR rats was associated with neurodegeneration (chromatolysis, plaque formation), along with changes in inflammatory markers in the serum and alterations in peripheral immune parameters (phagocytic activity of WBC and splenic PMN, cytotoxic activity/leukocyte adhesion inhibition by splenic MNC). Administration of memantine to ICIR rats resulted in mitigation of colchicine-induced inflammation in the hippocampus, inflammatory markers in the serum and neurodegeneration and also led to recovery of the measured immune endpoints; most of these effects were greater with the longer duration of study. Phagocytic activity of WBC and splenic PMN cells appeared to correlate with levels of the measured central inflammatory markers. It appears from the results that neuroinflammation might be linked with the NMDA receptor activity in ICIR rats and that this receptor is involved in the process of progressive neuroinflammation and neurodegeneration in the hippocampus of ICIR and potentially in immunomodulation in these same hosts.

  12. Effects of intracerebroventricular injection of histamine and related compounds on corticosterone release in rats.

    PubMed

    Tsujimoto, S; Okumura, Y; Kamei, C; Tasaka, K

    1993-07-01

    1. The effects of intracerebroventricular (i.c.v.) injection of histamine and related compounds on plasma adrenocorticotrophic hormone (ACTH) and corticosterone concentrations were studied in conscious rats. 2. Histamine at doses of 5-20 micrograms kg-1 rapidly increased plasma ACTH and corticosterone concentrations almost simultaneously, and subsequent courses were also similar to each other. However, in the case of CRF-41 (i.v.), the plasma ACTH concentration first increased followed by an increase in plasma corticosterone concentration. Even in hypophysectomized rats, a significant increase in plasma corticosterone concentration was induced by histamine at doses of 20 and 50 micrograms kg-1. 3. Histamine at doses of 10 and 20 micrograms kg-1 elicited an increase in the amplitude of adrenal nerve activity, and electrical stimulation to the adrenal nerves resulted in an increase in plasma corticosterone concentration. 4. Both H1-agonist (2-methylhistamine) and H2-agonists (4-methylhistamine and impromidine) also induced similar effects to those of histamine. Pretreatment with pyrilamine caused an inhibition of histamine-induced increase in plasma ACTH and corticosterone concentrations, while both cimetidine and ranitidine failed to inhibit this effect. However, both H2-blockers were effective in inhibiting the 4-methylhistamine-induced elevation of plasma ACTH and corticosterone concentrations. 5. Neither (R)-alpha-methylhistamine nor thioperamide had a significant effect, indicating that the H3-receptor is not involved in the histamine-induced increase in plasma ACTH and corticosterone concentrations. 6. From these findings, it was concluded that (1) electrical signals transmitted from the brain to the adrenal gland through the neurones may be involved in the rapid corticosterone release induced by histamine, and (2) not only H1- but also H2-receptors are implicated in histamine-induced hormone secretions in rats, though the contribution of the H2-receptor is

  13. Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats.

    PubMed

    Pauliina Markkula, S; Lyons, David; Yueh, Chen-Yu; Riches, Christine; Hurst, Paul; Fielding, Barbara; Heisler, Lora K; Evans, Mark L

    2016-12-01

    Specialized metabolic sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counterregulatory responses. Hypothalamic reactive oxygen species (ROS) may act as a metabolic signal-mediating responses to changes in glucose, other substrates and hormones. The role of ROS in the brain's control of glucose homeostasis remains unclear. We hypothesized that hydrogen peroxide (H2O2), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, intracerebroventricular catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus. Electrophysiological recordings revealed a subset of arcuate nucleus neurons expressing proopiomelanocortin that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, intracerebroventricular catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue, which, through tuning the electrical activity of key neuronal populations such as proopiomelanocortin neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.

  14. Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats

    PubMed Central

    Pauliina Markkula, S.; Lyons, David; Yueh, Chen-Yu; Riches, Christine; Hurst, Paul; Fielding, Barbara; Heisler, Lora K.

    2016-01-01

    Specialized metabolic sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counterregulatory responses. Hypothalamic reactive oxygen species (ROS) may act as a metabolic signal-mediating responses to changes in glucose, other substrates and hormones. The role of ROS in the brain's control of glucose homeostasis remains unclear. We hypothesized that hydrogen peroxide (H2O2), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, intracerebroventricular catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus. Electrophysiological recordings revealed a subset of arcuate nucleus neurons expressing proopiomelanocortin that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, intracerebroventricular catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue, which, through tuning the electrical activity of key neuronal populations such as proopiomelanocortin neurons, may have a role in the brain's influence of glucose homeostasis and energy balance. PMID:27740870

  15. Endomorphin synthesis in rat brain from intracerebroventricularly injected [3H]-Tyr-Pro: a possible biosynthetic route for endomorphins.

    PubMed

    Rónai, András Z; Szemenyei, Erzsébet; Kató, Erzsébet; Kocsis, László; Orosz, György; Al-Khrasani, Mahmoud; Tóth, Géza

    2006-03-15

    In spite of concentrated efforts, the biosynthetic route of mu-opioid receptor agonist brain tetrapeptide endomorphins (Tyr-Pro-Trp-Phe-NH2 and Tyr-Pro-Phe-Phe-NH2), discovered in 1997, is still obscure. We report presently that 30 min after intracerebroventricular injection of 20 or 200 microCi [3H]Tyr-Pro (49.9 Ci mmol(-1)) the incorporated radioactivity was found in endomorphin-related tetra- and tripeptides in rat brain extracts. As detected by the combination of HPLC with radiodetection, a peak corresponding to endomorphin-2-OH could be identified in two of four extracts of "20 microCi" series. Radioactive peaks in position of Tyr, Tyr-Pro, Tyr-Pro-Phe or Tyr-Pro-Trp appeared regularly in both series and also in the "tetrapeptide cluster" constituted by endomorphins and their free carboxylic forms. In one of the four extracts in the "200 microCi" series a robust active peak in the position of endomorphin 2 could be detected. Intracerebroventricularly injected 100 nmol, but not 10 or 1000 nmol cold Tyr-Pro (devoid of opioid activity in vitro), caused a naloxone-reversible prolongation of tail-flick latency in rats, peaking between 15 and 30 min. We suggest that Tyr-Pro may serve as a biosynthetic precursor to endomorphin synthesis.

  16. Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits.

    PubMed

    Kim, Hye Yun; Lee, Dongkeun K; Chung, Bo-Ryehn; Kim, Hyunjin V; Kim, YoungSoo

    2016-03-16

    Amyloid-β (Aβ) is a major pathological mediator of both familial and sporadic Alzheimer's disease (AD). In the brains of AD patients, progressive accumulation of Aβ oligomers and plaques is observed. Such Aβ abnormalities are believed to block long-term potentiation, impair synaptic function, and induce cognitive deficits. Clinical and experimental evidences have revealed that the acute increase of Aβ levels in the brain allows development of Alzheimer-like phenotypes. Hence, a detailed protocol describing how to acutely generate an AD mouse model via the intracerebroventricular (ICV) injection of Aβ is necessary in many cases. In this protocol, the steps of the experiment with an Aβ-injected mouse are included, from the preparation of peptides to the testing of behavioral abnormalities. The process of preparing the tools and animal subjects before the injection, of injecting the Aβ into the mouse brain via ICV injection, and of assessing the degree of cognitive impairment are easily explained throughout the protocol, with an emphasis on tips for effective ICV injection of Aβ. By mimicking certain aspects of AD with a designated injection of Aβ, researchers can bypass the aging process and focus on the downstream pathology of Aβ abnormalities.

  17. The effects of crocin and safranal on the yawning induced by intracerebroventricular injection of histamine in rats

    PubMed Central

    Taati, Mina; Tamaddonfard, Esmaeal; Erfanparast, Amir; Ghasemi, Hamid

    2016-01-01

    Objective: Crocin and safranal, as the major constituents of saffron, have many biological activities. This study investigated the effects of crocin and safranal on yawning response induced by intracerebroventricular (i.c.v.) injection of histamine in rats. Materials and Methods: In ketamine/xylazine-anesthetized rats, a guide cannula was implanted in the right ventricle of the brain and yawning induced by i.c.v. injection of histamine. Crocin and safranal were intraperitoneally (i.p.) injected alone and before i.c.v. injection of histamine. Results: Histamine at the doses of 10 and 20 µg/rat produced yawning. Mepyramine (a histamine H1 receptor antagonist) 40 µg/rat significantly (p<0.05) prevented histamine (20 µg/rat)-induced yawning. Crocin (30 mg/kg) and safranal (1 mg/kg) significantly (p<0.05) increased histamine (10 µg/rat)-induced yawning. Crocin and safranal also induced yawning when injected before mepyramine plus histamine administration. Conclusion: The results of the present study showed a yawning-inducing effect for central histamine, which was inhibited by mepyramine. Crocin and safranal increased histamine-induced yawning, and also produced yawning when the histamine action is blocked. PMID:27516985

  18. Suicide by injecting lispro insulin with an intravenous cannula.

    PubMed

    Behera, C; Swain, Rajanikanta; Mridha, Asit Ranjan; Pooniya, Shashank

    2015-09-01

    Suicide by injecting insulin is not uncommon both in diabetic and non-diabetic people. The victim usually uses an insulin syringe or a traditional syringe attached to a needle for the injection of insulin, of either animal or synthetic origin. We report a case of suicide by a non-diabetic physician by injecting lispro insulin through an intravenous cannula. To the best of our knowledge, the use of an intravenous cannula for the injection of insulin for suicide is unusual and is rarely reported in the medico-legal literature.

  19. Intracerebroventricular injection of trazodone produces 5-HT receptor subtype mediated anti-nociception at the supraspinal and spinal levels.

    PubMed

    Zhang, Rihui; Nagata, Tomonari; Hayashi, Takayuki; Miyata, Mariko; Kawakami, Yoriko

    2004-10-01

    Serotonin (5-HT) mediated anti-nociceptive effects induced by an anti-depressant, trazodone, are related to 5-HT(1A) receptor activities at the supraspinal level. 5-HT(3) receptor activation via the descending anti-nociceptive pathways may contribute to the trazodone mediated anti-nociception at the spinal level. Intracerebroventricular (i.c.v.) injection of trazodone dose-dependently impaired nociceptive responses in the formalin test in mice. Six and 15 microg of trazodone inhibited the early (P<0.05 or 0.01) and the late phases of the formalin test (P<0.05 or 0.01), while 3 microg had no effect. We examined the effects of a selective 5-HT(1A) receptor antagonist, WAY-100635, a single injection of which induced hyperalgesia (P<0.05), and blocked the anti-nociceptive effects of trazodone (P<0.01) when the two were simultaneously injected i.c.v. Intrathecal (i.t.) injection of a selective 5-HT(3) receptor antagonist, 3-tropanylindole-3-carboxylate hydrochloride, blocked the anti-nociceptive effects of i.c.v. trazodone (P<0.01), while WAY-100635 (i.t.) did not impair trazodone mediated anti-nociception. Trazodone mediated anti-nocicepton is related to serotonergic activity at both the supraspinal and the spinal level.

  20. A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection.

    PubMed

    Sil, Susmita; Ghosh, Rupsa; Sanyal, Moumita; Guha, Debjani; Ghosh, Tusharkanti

    2016-01-01

    Colchicine induces neurodegeneration, but the extent of neurodegeneration in different areas of the brain in relation to neuroinflammation remains unclear. Such information may be useful to allow for the development of a model to compare colchicine-induced neurodegeneration with other neurodegenerative diseases such as Alzheimer's Disease (AD). The present study was designed to investigate the extent of neurodegeneration along with neuroinflammation in different areas of the brain, e.g. frontal cortex, parietal cortex, occipital cortex, corpus striatum, amygdala and hippocampus, in rats along with memory impairment 21 days after a single intracerebroventricular (icv) injection of colchicine. Memory parameters were measured before and after icv colchicine injection in all test groups of rats (control, sham-operated, colchicine-injected [ICIR] rats). On Day 21 post-injection, rats from all groups were anesthesized and tissues from the various brain areas were collected for assessment of biomarkers of neuroinflammation (i.e. levels of ROS, nitrite and proinflammatory cytokines TNFα and IL-1β) and neurodegeneration (assessed histologically). The single injection of colchicine resulted in impaired memory and neurodegeneration (significant presence of plaques, Nissl granule chromatolysis) in various brain areas (frontal cortex, amygdala, parietal cortex, corpus striatum), with maximum severity in the hippocampus. While IL-1β, TNFα, ROS and nitrite levels were altered in different brain areas in the ICIR rats, these parameters had their greatest change in the hippocampus. This study showed that icv injection of colchicine caused strong neurodegeneration and neuroinflammation in the hippocampus of rats and the increases in neurodegeneration were corroborated with those of neuroinflammation at the site. The present study also showed that the extent of neurodegeneration and neuroinflammation in different brain areas of the colchicine-injected rats were AD-like and

  1. 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, ...

  2. Distribution of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in canines after intracerebroventricular injection.

    PubMed

    Park, Sang Eon; Jung, Na-Yeon; Lee, Na Kyung; Lee, Jeongmin; Hyung, Brian; Myeong, Su Hyeon; Kim, Hyeong Seop; Suh, Yeon-Lim; Lee, Jung-Il; Cho, Kyung Rae; Kim, Do Hyung; Choi, Soo Jin; Chang, Jong Wook; Na, Duk L

    2016-11-01

    In this study, we investigated the distribution of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) administered via intracerebroventricular (ICV) injection in a canine model. Ten beagles (11-13 kg per beagle) each received an injection of 1 × 10(6) cells into the right lateral ventricle and were sacrificed 7 days after administration. Based on immunohistochemical analysis, hUCB-MSCs were observed in the brain parenchyma, especially along the lateral ventricular walls. Detected as far as 3.5 mm from the cortical surface, these cells migrated from the lateral ventricle toward the cortex. We also observed hUCB-MSCs in the hippocampus and the cervical spinal cord. According to real-time polymerase chain reaction results, most of the hUCB-MSCs were found distributed in the brain and the cervical spinal cord but not in the lungs, heart, kidneys, spleen, and liver. ICV administered hUCB-MSCs also enhanced the endogenous neural stem cell population in the subventricular zone. These results highlighted the ICV delivery route as an optimal route to be performed in stem cell-based clinical therapies for neurodegenerative diseases.

  3. Folic Acid and Coenzyme Q10 Ameliorate Cognitive Dysfunction in the Rats with Intracerebroventricular Injection of Streptozotocin

    PubMed Central

    Dehghani Dolatabadi, Hamid Reza; Reisi, Parham; Alaei, Hojjatallah; Azizi Malekabadi, Hamid; Pilehvarian, Ali Asghar

    2012-01-01

    Objective(s) The present study aimed to investigate the effects of a fat soluble antioxidant, coenzyme Q10 (CoQ10) and folic acid on learning and memory in the rats with intracerebroventricular injection of streptozotocin (ICV-STZ), an animal model of sporadic type of Alzheimer's disease. Materials and Methods The lesion groups were injected bilaterally with ICV-STZ (1.5 mg/kg b.wt., in normal saline). In the treated groups, rats received folic acid (4 mg/kg; i.p.) or CoQ10 (10 mg/kg; i.p.), either alone or together, for 21 days. Passive avoidance learning test was used for evaluation of learning and memory. Results The results showed that learning and memory performance was significantly impaired in the rats with ICV-STZ (P< 0.001), however CoQ10 and folic acid, either alone or together, prevented impairments significantly (P< 0.001), as there was not any significant difference between these treated lesion groups and control group. Conclusion The present results suggest that CoQ10 and folic acid have therapeutic and preventive effects on cognitive impairments in Alzheimer’s disease. PMID:23493655

  4. The role of dorsomedial hypotalamus ionotropic glutamate receptors in the hypertensive and tachycardic responses evoked by Tityustoxin intracerebroventricular injection.

    PubMed

    Silva, F C; Guidine, Patrícia Alves Maia; Machado, Natalia Lima; Xavier, Carlos Henrique; de Menezes, R C; Moraes-Santos, Tasso; Moraes, Márcio Flávio; Chianca, Deoclécio Alves

    2015-03-01

    The scorpion envenoming syndrome is an important worldwide public health problem due to its high incidence and potential severity of symptoms. Some studies address the high sensitivity of the central nervous system to this toxin action. It is known that cardiorespiratory manifestations involve the activation of the autonomic nervous system. However, the origin of this modulation remains unclear. Considering the important participation of the dorsomedial hypotalamus (DMH) in the cardiovascular responses during emergencial situations, the aim of this work is to investigate the involvement of the DMH on cardiovascular responses induced by intracerebroventricular (icv) injection of Tityustoxin (TsTX, a α-type toxin extracted from the Tityus serrulatus scorpion venom). Urethane-anaesthetized male Wistar rats (n=30) were treated with PBS, muscimol or ionotropic glutamate receptor antagonists, bilaterally in DMH and later, with an icv injection of TsTX, or treated only with PBS in both regions. TsTX evoked a marked increase in mean arterial pressure and heart rate in all control rats. Interestingly, injection of muscimol, a GABAA receptor agonist, did not change the pressor and tachycardic responses evoked by TsTX. Remarkably, the injection ionotropic glutamate receptors antagonists in DMH abolished the pressor and the tachycardic response evoked by TsTX. Our data suggest that the central circuit recruited by TsTX, whose activation results in an array of physiological and behavioral alterations, depend on the activation of DMH ionotropic glutamate receptors. Moreover, our data provide new insights on the central mechanisms involved in the development of symptoms in the severe scorpion envenomation syndrome.

  5. [Effect of intracerebroventricular injection of histamine on carotid sinus baroreceptor reflex in anesthetized rats and its mechanism].

    PubMed

    Wang, Guo-Qing; Zhou, Xi-Ping; Huang, Wei-Qiu

    2002-12-25

    The changes in carotid sinus baroreceptor reflex (CSR) performance induced by intracerebroventricular injection (i.c.v.) of histamine (HA) were investigated. The effects of pretreatment with HA receptors antagonists into the cerebroventricle or nucleus of solitary tract (NTS) on the responses of CSR to HA were also examined. Intracarotid sinus pressure (ISP)-mean arterial pressure (MAP) relationship curve was constructed by fitting to the logistic function with five parameters in 50 Wistar rats anesthetized with pentobarbital sodium. The left and right carotid sinus regions were isolated from the systemic circulation and the ISP was altered in a stepwise manner. The main results obtained are as follows. (1) i.c.v. injection of HA (100 ng) significantly shifted the ISP-MAP relationship curve upwards and moved the middle part of ISP-Gain relationship curve downwards, and reduced the MAP range and maximum gain (G(max)), but increased the threshold pressure (TP), saturation pressure (SP) and ISP at G(max) (ISP (Gmax)). (2) The pretreatment with H(1) or H(2) receptors antagonist, chlorpheniramine (CHL, 5 microg) or cimetidine (CIM, 15 microg), could obviously diminish the above-mentioned changes in CSR performance induced by HA, but the effect of CIM was less remarkable than that of CHL. (3) The pretreatment with both CHL and CIM (5 microg and 15 microg) at the same time abolished the responses of CSR performance to HA completely. (4) After microinjection of CHL (0.5 microg) or CIM (1.5 microg) into the NTS, the responses of CSR to HA were similar to those after i.c.v. CHL or CIM, but the change in TP was significantly decreased. These findings suggest that the intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity. The response of CSR to HA might be mediated by both central H(1) and H(2) receptors, especially by H(1) receptors. The effects of the central HA on CSR might be related to a histaminergic

  6. Electroencephalographic and behavioral effects of intracerebroventricular or intraperitoneal injections of toxic honey extract in adult Wistar rats and GAERS.

    PubMed

    Kuru, Pinar; Torun, Merve; Halac, Hande Melike; Temiz, Gozde; Iskender, Ece; Karamahmutoglu, Tugba; Idrizoglu, Medine Gulcebi; Onat, Filiz Yilmaz

    2014-12-01

    Toxic honey, containing grayanotoxin, is obtained from nectar and polen of rhododendron. Consumed in excess it produces seizures and convulsions. In order to investigate whether the toxic honey extract can be used as a seizure model, we examined the electroencephalographic (EEG) and motor effects of intracerebroventricular (icv) or intraperitoneal (ip) injection of toxic honey extract in Wistar rats or in genetic absence epilepsy rats from Strasbourg (GAERS). Male Wistar rats or GAERS were stereotaxically implanted with bilateral cortical recording electrodes in all ip groups and cannula in the icv groups. Based on the previous study, an extract was obtained from the non-toxic and toxic honey. After the injection of the non-toxic or toxic honey extract, seizure stages and changes in EEG were evaluated from 9 am to noon. The icv administration of toxic honey extract produced stage 4 seizures and bilateral cortical spikes within 30-60 min and these effects disappeared after 120 min in Wistar rats or GAERS. The mean of bilateral cortical spike acitivity in EEG of Wistar rats was 804.2 ± 261.0 s in the 3-h period. After the icv administration of toxic honey extract to GAERS, the mean duration of spike-and-wave discharges (SWDs) in GAERS significantly decreased during the first 60 min and then returned to baseline level. Ip injection of toxic honey extract caused no seizure and no change in EEG in either GAERS or Wistars. These results suggest that the icv administration of toxic honey extract can be used as a seizure model.

  7. Effect of intracerebroventricular injection of TiO2 nanoparticles on complex behaviour in the rat.

    PubMed

    Kim, E-M; Palmer, P; Howard, V; Elsaesser, A; Taylor, A; Staats, G; O'Hare, E

    2013-12-01

    There are no data available on the behavioural effects of centrally administered nanoparticles in freely moving intact mammals. Consequently, in the current study male Sprague-Dawley rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement. Under this schedule, ascending and descending sequences of fixed-ratio (FR) lever press requirements for food reinforcement were presented over six cycles, with each discrete FR component completed on the alternate lever to the previous component. The final version of the schedule was comprised of an ascending followed by a descending sequence of the ratio values 2, 6, 12, 20, 30, 42 and 56, repeated over six cycles. When the rats were able to complete this version of the ALCR schedule in 40 min, each was implanted with a permanently indwelling ICV cannula aimed at the lateral ventricle of the brain, and allowed to recover for 7 days. On the first day of the experiment, all rats were injected with either titanium dioxide (TiO2, 9 nm, stabilised with gallic acid, 10 microl volume, 2 mg/ml) nanoparticles, or 10 microl saline (control). Two-hours after the ICV injections, the behaviour of all rats was measured using the ALCR schedule, and their behaviour was also measured (no ICV injection) for the next 7 days. Under the ALCR schedule, the number of lever-switching errors and incorrect lever perseverations significantly increased in the TiO2 group (p < 0.05). Other parameters of the ALCR schedule (RRRs and PRPs), which indicate the induction of malaise or general motor retardation, were not altered following ICV TiO2 injection. The findings of the current study indicate that central administration of TiO2 nanoparticles induced behavioural deterioration in freely moving intact animals, that the induced behavioural deterioration was a result of central rather than peripheral outcomes, and that this effect was chronic rather than acute.

  8. Insulin Detemir (rDNA Origin) Injection

    MedlinePlus

    ... insulin and therefore cannot control the amount of sugar in the blood). It is also used to ... normally and, therefore, cannot control the amount of sugar in the blood) who need insulin to control ...

  9. Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury.

    PubMed

    Yan, Xiao-Ge; Cheng, Bao-Hua; Wang, Xin; Ding, Liang-Cai; Liu, Hai-Qing; Chen, Jing; Bai, Bo

    2015-05-01

    Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 μg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis.

  10. Intracerebroventricular Viral Injection of the Neonatal Mouse Brain for Persistent and Widespread Neuronal Transduction

    PubMed Central

    Levites, Yona; Golde, Todd E.; Jankowsky, Joanna L.

    2014-01-01

    With the pace of scientific advancement accelerating rapidly, new methods are needed for experimental neuroscience to quickly and easily manipulate gene expression in the mouse brain. Here we describe a technique first introduced by Passini and Wolfe for direct intracranial delivery of virally-encoded transgenes into the neonatal mouse brain. In its most basic form, the procedure requires only an ice bucket and a microliter syringe. However, the protocol can also be adapted for use with stereotaxic frames to improve consistency for researchers new to the technique. The method relies on the ability of adeno-associated virus (AAV) to move freely from the cerebral ventricles into the brain parenchyma while the ependymal lining is still immature during the first 12-24 hr after birth. Intraventricular injection of AAV at this age results in widespread transduction of neurons throughout the brain. Expression begins within days of injection and persists for the lifetime of the animal. Viral titer can be adjusted to control the density of transduced neurons, while co-expression of a fluorescent protein provides a vital label of transduced cells. With the rising availability of viral core facilities to provide both off-the-shelf, pre-packaged reagents and custom viral preparation, this approach offers a timely method for manipulating gene expression in the mouse brain that is fast, easy, and far less expensive than traditional germline engineering. PMID:25286085

  11. Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury

    PubMed Central

    Yan, Xiao-ge; Cheng, Bao-hua; Wang, Xin; Ding, Liang-cai; Liu, Hai-qing; Chen, Jing; Bai, Bo

    2015-01-01

    Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 μg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis. PMID:26109951

  12. Physical exercise exacerbates memory deficits induced by intracerebroventricular STZ but improves insulin regulation of H₂O₂ production in mice synaptosomes.

    PubMed

    Muller, Alexandre P; Zimmer, Eduardo Rigon; Kalinine, Eduardo; Haas, Clarissa B; Oses, Jean Pierre; Martimbianco de Assis, Adriano; Galina, Antonio; Souza, Diogo O; Portela, Luis Valmor

    2012-01-01

    Insulin brain resistant state is associated with cognitive deficits and Alzheimer's disease by mechanisms that may involve mitochondrial damage and oxidative stress. Conversely, physical exercise improves cognitive function and brain insulin signaling. The intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) in rodents is an established model of insulin-resistant brain state. This study evaluates the effects of physical exercise on memory performance of i.c.v., STZ-treated mice(1 and 3 mg/kg) and whether insulin (50 and 100 ng/ml) modulates mitochondrial H₂O₂ generation in synaptosomes. S100B levels and SOD and CAT activities were assessed as markers of brain damage caused by STZ. Sedentary and exercise vehicle-treated mice demonstrated similar performance in object recognition memory task. In the water maze test, exercise vehicle-treated mice showed improvement performance in the acquisition and retrieval phases. The administration of STZ (1 mg/kg) before thirty days of voluntary physical exercise protocol impaired recognition and spatial memory only in exercised mice, whereas STZ (3 mg/kg) impaired the performance of sedentary and exercise groups. Moreover, STZ (3 mg/kg) increased hippocampal S100B levels in both groups and SOD/CAT ratio in the sedentary animals. Insulin decreased synaptosomal H₂O₂ production in exercised compared to sedentary mice; however, both STZ doses abolished this effect. Normal brain insulin signaling is mechanistically involved in the improvement of cognitive function induced by exercise through the regulation of mitochondrial H₂O₂ production. However, a prior blockade of brain insulin signaling with STZ abolished the benefits of exercise on memory performance and mitochondrial H₂O₂ regulation.

  13. Antibody-specific behavioral effects: intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice.

    PubMed

    Katzav, Aviva; Ben-Ziv, Tal; Blank, Miri; Pick, Chaim G; Shoenfeld, Yehuda; Chapman, Joab

    2014-07-15

    This study compares the effects of human antiphospholipid (aPL) and anti-P-ribosomal (anti-P) IgG and control IgG on the brain. Intracerebroventricular (ICV) injected aPL mice (exAPS) displayed specific hyperactivity compared to anti-P-injected (exSLE) and control mice. In contrast ICV injected anti-P-injected mice specifically displayed depression-like behavior and olfactory impairment compared to the other 2 groups. Both anti-P and aPL injected mice were impaired in the passive avoidance test compared to controls. The distinct cognitive effects of the 2 pathogenic antibodies argue for a specific and differential direct action of these autoantibodies on the brain in clinical disease.

  14. Insulin amyloid at injection sites of patients with diabetes.

    PubMed

    Nilsson, Melanie R

    2016-09-01

    The formation of insulin amyloid can dramatically impact glycemic control in patients with diabetes, making it an important therapeutic consideration. In addition, the cost associated with the excess insulin required by patients with amyloid is estimated to be $3K per patient per year, which adds to the growing financial burden of this disease. Insulin amyloid has been observed with every mode of therapeutic insulin administration (infusion, injection and inhalation), and the number of reported cases has increased significantly since 2002. The new cases represent a much broader demographic, and include many patients who have used exclusively human insulin and human insulin analogs. The reason for the increase in case reports is unknown, but this review explores the possibility that changes in patient care, improved differential diagnosis and/or changes in insulin type and insulin delivery systems may be important factors. The goal of this review is to raise key questions that will inspire proactive measures to prevent, identify and treat insulin amyloid. Furthermore, this comprehensive examination of insulin amyloid can provide insight into important considerations for other injectable drugs that are prone to form amyloid deposits.

  15. Insulin delivery by injection in children and adolescents with diabetes.

    PubMed

    Hanas, Ragnar; de Beaufort, Carine; Hoey, Hilary; Anderson, Barbara

    2011-08-01

    Type 1 diabetes is treated with insulin, which has traditionally been delivered by vial and syringe. However, for many patients, dosing inaccuracy, pain, anxiety, inconvenience, and social acceptability present barriers to this method of administration (1-5). This has contributed to the increased popularity of alternative insulin delivery systems, including pen delivery devices (4, 6). Evidence suggests that discreet devices, such as insulin pens, facilitate adherence to intensive insulin therapy regimens, help improve lifestyle flexibility, and reduce injection pain compared with the conventional syringe-based regimens, as shown in studies in adults and adolescents (7). In addition, compared with the vial and syringe method of insulin administration, pens may provide more accurate dosing - which is particularly important in children - thereby improving short-term blood glucose control and potentially improving long-term outcomes (5, 8). Children, in particular, may benefit from insulin pens that are simple to use as adherence issues may be more evident in this patient group (9). Pens for insulin delivery in children with type 1 diabetes have been used for a long time in Europe, and have recently gained in popularity in many other places around the world (4, 10). Furthermore, the conventional vial and syringe method of insulin delivery is beginning to be considered as obsolete (11). Moreover, there is a continued drive to improve insulin pen technology, to refine and enhance the functionality and usability of these pens. However, despite recent advances in pen design and function, the selection of pens available especially for children is limited.

  16. Influence of circulating epinephrine on absorption of subcutaneously injected insulin

    SciTech Connect

    Fernqvist, E.; Gunnarsson, R.; Linde, B.

    1988-06-01

    Effects of epinephrine (Epi) infusion on the absorption of subcutaneously injected 125I-labeled soluble human insulin (10 U) from the thigh or the abdomen were studied in 16 healthy subjects and from the thigh in 10 insulin-dependent diabetic (IDDM) patients. Epi was infused at 0.3 (high dose) or 0.1 (low dose; healthy subjects) nmol.kg-1.min-1 i.v., resulting in arterial plasma Epi levels of approximately 6 and 2 nM, respectively. Saline was infused on a control day. Insulin absorption was measured as disappearance of radioactivity from the injection site and as appearance of plasma immunoreactive insulin (IRI). Adipose tissue blood flow was measured with the 133Xe clearance technique. First-order disappearance rate constants of 125I from the thigh depot decreased approximately 40-50% during the high dose of Epi compared with control (P less than .001). The corresponding decrease from the abdominal depot was approximately 40% (P less than .001), whereas no significant change was found during the low Epi dose. IRI fell compared with control in all groups at the high Epi dose. The Epi-induced depression of insulin absorption occurred despite unaltered or even slightly increased subcutaneous blood flow. The results indicate that circulating Epi at levels seen during moderate physical stress depresses the absorption of soluble insulin from subcutaneous injection sites to an extent that might be important for glycemic control in IDDM patients. Furthermore, dissociation is found between changes in insulin absorption and subcutaneous blood flow during Epi infusion, suggesting that factors other than blood flow may also influence the absorption of subcutaneously injected insulin.

  17. Potentiation of morphine-induced conditioned place preference with concurrent use of amantadine and fluvoxamine by the intraperitoneal and intracerebroventricular injection in rat.

    PubMed

    Maleki, Saeid Abbasi; Samini, Morteza; Babapour, Vahab; Mehr, Shahram Ejtemaei; Cheraghiyan, Siyamak; Nouri, Mir H Khayat

    2008-07-19

    In this study, the effect of concurrent use of fluvoxamine and amantadine on morphine-induced conditioned place preference (CPP) was investigated by the intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection in rat. The CPP paradigms took place on 6 consecutive days by using an unbiased procedure. Our results showed that i.p. injection of morphine sulfate (2.5-10mg/kg) induced CPP in rat. On day 6, fluvoxamine (5 and 10mg/kg, i.p.), and amantadine (5 and 10mg/kg, i.p.) both increased morphine-induced conditioned place preference. Intracerebroventricular injection of fluvoxamine (10 microg/rat) and amantadine (10 microg/rat) were also increased morphine-induced conditioned preference significantly. Concurrent use of fluvoxamine (5mg/kg, i.p.; 10 microg/rat i.c.v.) and amantadine (10mg/kg, i.p.; 10 microg/rat, i.c.v.) potentiated morphine-induced conditioned preference significantly. Release of dopamine from neurons cause reinforcing behavior. Morphine produces reinforcement (reward) effect by activation of mu receptors which facilitated dopaminergic transmission through dopamine release. Fluvoxamine, a serotonin reuptake inhibitor, increase serotonin concentration in synaptic clefts, which is a potent stimulator of dopamine release. Amantadine also appears to work by increasing dopamine release from neuron. In conclusion, our results show that concurrent use of fluvoxamine and amantadine potentiate morphine-like effect on CPP through increasing dopaminergic transmission and this combination may simulate the rewarding effect of morphine and can be candidate for controlling the drug compulsive seeking in morphine dependent subjects.

  18. Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector.

    PubMed

    Hironaka, Kohei; Yamazaki, Yoshiyuki; Hirai, Yukihiko; Yamamoto, Motoko; Miyake, Noriko; Miyake, Koichi; Okada, Takashi; Morita, Akio; Shimada, Takashi

    2015-08-18

    Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency in human arylsulfatase A (hASA). We recently reported that ependymal cells and the choroid plexus are selectively transduced by intracerebroventricular (ICV) injection of adeno-associated virus serotype 1 (AAV1) vector and serve as a biological reservoir for the secretion of lysosomal enzymes into the cerebrospinal fluid (CSF). In the present study, we examined the feasibility of this AAV-mediated gene therapy to treat MLD model mice. Preliminary experiments showed that the hASA level in the CSF after ICV injection of self-complementary (sc) AAV1 was much higher than in mice injected with single-stranded AAV1 or scAAV9. However, when 18-week-old MLD mice were treated with ICV injection of scAAV1, the concentration of hASA in the CSF gradually decreased and was not detectable at 12 weeks after injection, probably due to the development of anti-hASA antibodies. As a result, the sulfatide levels in brain tissues of treated MLD mice were only slightly reduced compared with those of untreated MLD mice. These results suggest that this approach is potentially promising for treating MLD, but that controlling the immune response appears to be crucial for long-term expression of therapeutic proteins in the CSF.

  19. Insulin antibodies in patients with type 2 diabetic receiving recombinant human insulin injection: A report of 12 cases.

    PubMed

    Hu, Xiaolei; Ma, Xiaowen; Wang, Xin; Zhao, Xiuli; Xu, Xuling; Gong, Hui; Chen, Fengling; Sun, Junjie

    2015-12-01

    We report 12 cases of patients with type 2 diabetic receiving recombinant human insulin injection, who had uncontrolled hyperglycemia or frequent episodes of hypoglycemia, high levels of serum insulin and positive insulin antibodies. The clinical characteristics and insulin antibodies pharmacokinetics parameters were analyzed. After administration of glucocorticoids, changing insulin formulations or discontinuing the insulin and switching to oral antidiabetic agents, the level of insulin antibodies decreased and the plasma glucose restored. Thus, we recommend to identify the presence of high insulin antibodies in patients with type 2 diabetes who experience unexplained high plasma glucose or frequent reoccurrence of hypoglycemia.

  20. Forum for Injection Technique (FIT), India: The Indian recommendations 2.0, for best practice in Insulin Injection Technique, 2015

    PubMed Central

    Tandon, Nikhil; Kalra, Sanjay; Balhara, Yatan Pal Singh; Baruah, Manash P.; Chadha, Manoj; Chandalia, Hemraj B.; Chowdhury, Subhankar; Jothydev, Kesavadev; Kumar, Prasanna K. M.; V., Madhu S.; Mithal, Ambrish; Modi, Sonal; Pitale, Shailesh; Sahay, Rakesh; Shukla, Rishi; Sundaram, Annamalai; Unnikrishnan, Ambika G.; Wangnoo, Subhash K.

    2015-01-01

    As injectable therapies such as human insulin, insulin analogs, and glucagon-like peptide-1 receptor agonists are used to manage diabetes, correct injection technique is vital for the achievement of glycemic control. The forum for injection technique India acknowledged this need for the first time in India and worked to develop evidence-based recommendations on insulin injection technique, to assist healthcare practitioners in their clinical practice. PMID:25932385

  1. Study the Antinociceptive Effect of Intracerebroventricular Injection of Aqueous Extract of Origanum Vulgare Leaves in Rat: Possible Involvement of Opioid System

    PubMed Central

    Pahlavan, Yasaman; Sepehri, Gholamreza; Sheibani, Vahid; Afarinesh khaki, Mohammadreza; Gojazadeh, Morteza; Pahlavan, Bahare; Pahlavan, Fereshteh

    2013-01-01

    Objective(s): The aim of study was to investigate the antinociceptive effect of intracerebroventricular (ICV) microinjection of Origanum vulgare (ORG) extract and possible involvement of opioid receptors. Materials and Methods: Cannula was inserted into left ventricle of male rats. Five days after surgery Tail Flick Latency (TFL) was measured after ICV microinjection of, ORG (1, 3 and 6 µg / rat). Effective dose of ORG was injected ICV in concomitant with morphine (2 mg/kg, IP), naloxone (2 mg / kg, IP) and saline (0.5 µl/rat) and TFL was recorded. Results: The co- administration of ORG extract with morphine showed a significant increase in TFL and naloxone, pretreatment significantly inhibited the antinociceptive activity of ORG and morphine. Conclusion: The aqueous extract of ORG possesses antinociceptive activities in the tail-flick test in a dose dependent manner. ORG - induced antinociception may have been mediated by opioid systems. PMID:24379969

  2. Central injection of GALR1 agonist M617 attenuates diabetic rat skeletal muscle insulin resistance through the Akt/AS160/GLUT4 pathway.

    PubMed

    Fang, Penghua; Yu, Mei; He, Biao; Guo, Lili; Huang, Xiaoli; Kong, Guimei; Shi, Mingyi; Zhu, Yan; Bo, Ping; Zhang, Zhenwen

    2017-03-01

    Insulin resistance of skeletal muscle plays an important role in the pathogenesis of type 2 diabetes. Galanin, a 29/30-amino-acid neuropeptide, plays multiple biological actions, including anti-diabetic effects. Although recent results of our study showed that administration of galanin could mitigate insulin resistance by promoting glucose transporter 4 (GLUT4) expression and translocation in skeletal muscle of rats, there is no literature available regarding to the effect of type 1 of galanin receptors (GALR1) on insulin resistance in skeletal muscle of type 2 diabetic rats. Herein, we intended to survey the central effect of GALR1 agonist M617 on insulin resistance in skeletal muscle and its underlying mechanisms. We found that the intracerebroventricular injection of M617 increased glucose infusion rates in hyperinsulinemic euglycemic clamp tests, but attenuated the plasma insulin and glucose concentrations of diabetic rats. Furthermore, administration of M617 markedly increased GLUT4 mRNA expression and GLUT4 translocation in skeletal muscle of diabetic rats. Last, perfusion of M617 increased phosphorylated Akt and phosphorylated AS160 levels in the skeletal muscle of diabetic rats. In conclusion, central injection of M617 mitigated insulin resistance of skeletal muscle by enhancing GLUT4 translocation from intracellular pools to plasma membranes via the activation of the Akt/AS160/GLUT4 signaling pathway.

  3. Xanthoceraside Ameliorates Mitochondrial Dysfunction Contributing to the Improvement of Learning and Memory Impairment in Mice with Intracerebroventricular Injection of Aβ1-42

    PubMed Central

    Ji, Xue-Fei; Chi, Tian-Yan; Xu, Qian; He, Xiao-Lu; Zhou, Xiao-Yu; Zhang, Rui; Zou, Li-Bo

    2014-01-01

    The effects of xanthoceraside on learning and memory impairment were investigated and the possible mechanism associated with the protection of mitochondria was also preliminarily explored in Alzheimer's disease (AD) mice model induced by intracerebroventricular (i.c.v.) injection of Aβ1-42. The results indicated that xanthoceraside (0.08–0.32 mg/kg) significantly improved learning and memory impairment in Morris water maze test and Y-maze test. Xanthoceraside significantly reversed the aberrant decrease of ATP levels and attenuated the abnormal increase of ROS levels both in the cerebral cortex and hippocampus in mice injected with Aβ1-42. Moreover, xanthoceraside dose dependently reversed the decrease of COX, PDHC, and KGDHC activity in isolated cerebral cortex mitochondria of the mice compared with Aβ1-42 injected model mice. In conclusion, xanthoceraside could improve learning and memory impairment, promote the function of mitochondria, decrease the production of ROS, and inhibit oxidative stress. The improvement effects on mitochondria may be through withstanding the damage of Aβ to mitochondrial respiratory chain and the key enzymes in Kreb's cycle. Therefore, the results from present study and previous study indicate that xanthoceraside could be a competitive candidate for the treatment of AD. PMID:24976855

  4. Effect of intracerebroventricular injection of histamine on blood sugar level and hypothalamo-pituitary adrenal axis of rats.

    PubMed

    Trivedi, C P; Modi, N T; Balothia, R K

    1976-01-01

    Intraventricular injection of histamine and normal saline in rats caused a marked fall in adrenal ascorbic acid indicating a stimulatory effect of both on pituitary adrenal axis. Intraventricularly injected histamine caused significant hypoglycaemia also in rats as compared to control series.

  5. Humalog(®) KwikPen™: an insulin-injecting pen designed for ease of use.

    PubMed

    Schwartz, Sherwyn L; Ignaut, Debra A; Bodie, Jennifer N

    2010-11-01

    Insulin pens offer significant benefits over vial and syringe injections for patients with diabetes who require insulin therapy. Insulin pens are more discreet, easier for patients to hold and inject, and provide better dosing accuracy than vial and syringe injections. The Humalog(®) KwikPen™ (prefilled insulin lispro [Humalog] pen, Eli Lilly and Company, Indianapolis, IN, USA) is a prefilled insulin pen highly rated by patients for ease of use in injections, and has been preferred by patients to both a comparable insulin pen and to vial and syringe injections in comparator studies. Together with an engineering study demonstrating smoother injections and reduced dosing error versus a comparator pen, recent evidence demonstrates the Humalog KwikPen device is an accurate, easy-to-use, patient-preferred insulin pen.

  6. [New therapies for diabetes: beyond injectable insulin and oral antidiabetics].

    PubMed

    Alfonso, John Edwin Feliciano; Ariza, Iván Darío Sierra

    2008-01-01

    New medicines for the therapy of the type 1 and type 2 diabetes have been incorporated in the list of traditional drugs: oral agents and injectable insulin. These treatment alternatives have a new mechanism of action that takes advantage of the antidiabetic properties of certain peptides such as amylin and glucagon like peptide-1 (GLP-1), whose levels are wanting or insufficient in diabetes. This is attained through amylin and GLP-1 analogues, although it can also be achieved by inhibiting the enzyme that degrades the latter. Furthermore, a new system to administer insulin in a noninvasive way through inhalation has become available in the market. This paper summarizes the most important and updated findings on the action mechanism, efficacy, adverse effects and indications of these innovative drugs.

  7. Analysis: desirable attributes of insulin injection pens that drive patient preference and compliance.

    PubMed

    Zahn, Jeffrey D

    2011-09-01

    Insulin pens are used by approximately half of worldwide insulin users. Insulin pens have made insulin injections easier compared to traditional vial and syringe injections. In an article in this issue of Journal of Diabetes Science and Technology, Dr. Asakura discusses several important design parameters, which are considered during refillable insulin-injection pen design. Ease of cartridge replacement, insulin-dose setting dial use, injection, and prominence of audible clicks can all affect overall dose accuracy and user friendliness of insulin pens in patients suffering from diabetes and related comorbidities. These parameters, along with patient introduction from prescribing physicians and level of training provided, drives patient pen selection and injection-regimen compliance to control their blood sugar.

  8. Orexin-1 receptor mediates the increased food and water intake induced by intracerebroventricular injection of the stable somatostatin pan-agonist, ODT8-SST in rats.

    PubMed

    Karasawa, Hiroshi; Yakabi, Seiichi; Wang, Lixin; Taché, Yvette

    2014-07-25

    Intracerebroventricular (icv) injection of the stable somatostatin pan-agonist, ODT8-SST induces a somatostatin 2 receptor (sst2) mediated robust feeding response that involves neuropeptide Y and opioid systems in rats. We investigated whether the orexigenic system driven by orexin also plays a role. Food and water intake after icv injection was measured concomitantly in non-fasted and non-water deprived rats during the light phase. In vehicle treated rats (100% DMSO, icv), ODT8-SST (1μg/rat, icv) significantly increased the 2-h food and water intake compared to icv vehicle plus saline (5.1±1.0g vs. 1.2±0.4g and 11.3±1.9mL vs. 2.5±1.2mL, respectively). The orexin-1 receptor antagonist, SB-334867 (16μg/rat, icv) completely inhibited the 2-h food and water intake induced by icv ODT8-SST. In contrast, the icv pretreatment with the selective somatostatin sst2 antagonist, S-406-028, established to block the orexigenic effect of icv ODT8-SST, did not modify the increased food and water intake induced by icv orexin-A (10.7μg/rat). These data indicate that orexin-1 receptor signaling system is part of the brain neurocircuitry contributing to the orexigenic and dipsogenic responses induced by icv ODT8-SST and that orexin-A stimulates food intake independently from brain sst2 activation.

  9. Nesfatin-130−59 Injected Intracerebroventricularly Differentially Affects Food Intake Microstructure in Rats Under Normal Weight and Diet-Induced Obese Conditions

    PubMed Central

    Prinz, Philip; Teuffel, Pauline; Lembke, Vanessa; Kobelt, Peter; Goebel-Stengel, Miriam; Hofmann, Tobias; Rose, Matthias; Klapp, Burghard F.; Stengel, Andreas

    2015-01-01

    Nesfatin-1 is well-established to induce an anorexigenic effect. Recently, nesfatin-130−59, was identified as active core of full length nesfatin-11−82 in mice, while its role in rats remains unclear. Therefore, we investigated the effects of nesfatin-130−59 injected intracerebroventricularly (icv) on the food intake microstructure in rats. To assess whether the effect was also mediated peripherally we injected nesfatin-130−59 intraperitoneally (ip). Since obesity affects the signaling of various food intake-regulatory peptides we investigated the effects of nesfatin-130−59 under conditions of diet-induced obesity (DIO). Male Sprague–Dawley rats fed ad libitum with standard diet were icv cannulated and injected with vehicle (5 μl ddH2O) or nesfatin-130−59 at 0.37, 1.1, and 3.3 μg (0.1, 0.3, 0.9 nmol/rat) and the food intake microstructure assessed using a food intake monitoring system. Next, naïve rats were injected ip with vehicle (300 μl saline) or nesfatin-130−59 (8.1, 24.3, 72.9 nmol/kg). Lastly, rats were fed a high fat diet for 10 weeks and those developing DIO were icv cannulated. Nesfatin-1 (0.9 nmol/rat) or vehicle (5 μl ddH2O) was injected icv and the food intake microstructure assessed. In rats fed standard diet, nesfatin-130−59 caused a dose-dependent reduction of dark phase food intake reaching significance at 0.9 nmol/rat in the period of 4–8 h post injection (−29%) with the strongest reduction during the fifth hour (−75%), an effect detectable for 24 h (−12%, p < 0.05 vs. vehicle). The anorexigenic effect of nesfatin-130−59 was due to a reduction in meal size (−44%, p < 0.05), while meal frequency was not altered compared to vehicle. In contrast to icv injection, nesfatin-130−59 injected ip in up to 30-fold higher doses did not alter food intake. In DIO rats fed high fat diet, nesfatin-130−59 injected icv reduced food intake in the third hour post injection (−71%), an effect due to a reduced meal frequency (

  10. Nesfatin-130-59 Injected Intracerebroventricularly Differentially Affects Food Intake Microstructure in Rats Under Normal Weight and Diet-Induced Obese Conditions.

    PubMed

    Prinz, Philip; Teuffel, Pauline; Lembke, Vanessa; Kobelt, Peter; Goebel-Stengel, Miriam; Hofmann, Tobias; Rose, Matthias; Klapp, Burghard F; Stengel, Andreas

    2015-01-01

    Nesfatin-1 is well-established to induce an anorexigenic effect. Recently, nesfatin-130-59, was identified as active core of full length nesfatin-11-82 in mice, while its role in rats remains unclear. Therefore, we investigated the effects of nesfatin-130-59 injected intracerebroventricularly (icv) on the food intake microstructure in rats. To assess whether the effect was also mediated peripherally we injected nesfatin-130-59 intraperitoneally (ip). Since obesity affects the signaling of various food intake-regulatory peptides we investigated the effects of nesfatin-130-59 under conditions of diet-induced obesity (DIO). Male Sprague-Dawley rats fed ad libitum with standard diet were icv cannulated and injected with vehicle (5 μl ddH2O) or nesfatin-130-59 at 0.37, 1.1, and 3.3 μg (0.1, 0.3, 0.9 nmol/rat) and the food intake microstructure assessed using a food intake monitoring system. Next, naïve rats were injected ip with vehicle (300 μl saline) or nesfatin-130-59 (8.1, 24.3, 72.9 nmol/kg). Lastly, rats were fed a high fat diet for 10 weeks and those developing DIO were icv cannulated. Nesfatin-1 (0.9 nmol/rat) or vehicle (5 μl ddH2O) was injected icv and the food intake microstructure assessed. In rats fed standard diet, nesfatin-130-59 caused a dose-dependent reduction of dark phase food intake reaching significance at 0.9 nmol/rat in the period of 4-8 h post injection (-29%) with the strongest reduction during the fifth hour (-75%), an effect detectable for 24 h (-12%, p < 0.05 vs. vehicle). The anorexigenic effect of nesfatin-130-59 was due to a reduction in meal size (-44%, p < 0.05), while meal frequency was not altered compared to vehicle. In contrast to icv injection, nesfatin-130-59 injected ip in up to 30-fold higher doses did not alter food intake. In DIO rats fed high fat diet, nesfatin-130-59 injected icv reduced food intake in the third hour post injection (-71%), an effect due to a reduced meal frequency (-27%, p < 0.05), while meal size was

  11. Neuroblast proliferation on the surface of the adult rat striatal wall after focal ependymal loss by intracerebroventricular injection of neuraminidase.

    PubMed

    Del Carmen Gómez-Roldán, María; Pérez-Martín, Margarita; Capilla-González, Vivian; Cifuentes, Manuel; Pérez, Juan; García-Verdugo, Jose Manuel; Fernández-Llebrez, Pedro

    2008-04-01

    The subventricular zone of the striatal wall of adult rodents is an active neurogenic region for life. Cubic multiciliated ependyma separates the subventricular zone from the cerebrospinal fluid (CSF) and is involved in the control of adult neurogenesis. By injecting neuraminidase from Clostridium perfringens into the right lateral ventricle of the rat, we provoked a partial detachment of the ependyma in the striatal wall. The contralateral ventricle was never affected and was used as the experimental control. Neuraminidase caused widening of the intercellular spaces among some ependymal cells and their subsequent detachment and disintegration in the CSF. Partial ependymal denudation was followed by infiltration of the CSF with macrophages and neutrophils from the local choroid plexus, which ependymal cells never detached after neuraminidase administration. Inflammation extended toward the periventricular parenchyma. The ependymal cells that did not detach and remained in the ventricle wall never proliferated. The lost ependyma was never recovered, and ependymal cells never behaved as neural stem cells. Instead, a scar formed by overlapping astrocytic processes sealed those regions devoid of ependyma. Some ependymal cells at the border of the denudated areas lost contact with the ventricle and became located under the glial layer. Concomitantly with scar formation, some subependymal cells protruded toward the ventricle through the ependymal breaks, proliferated, and formed clusters of rounded ventricular cells that expressed the phenotype of neuroblasts. Ventricular clusters of neuroblasts remained in the ventricle up to 90 days after injection. In the subventricular zone, adult neurogenesis persisted.

  12. Study on the distribution sites and the molecular mechanism of analgesia after intracerebroventricular injection of rat/mouse hemokinin-1 in mice.

    PubMed

    Xia, Rui-Long; Fu, Cai-Yun; Zhang, Shi-Fu; Jin, Yuan-Ting; Zhao, Fu-Kun

    2013-05-01

    Hemokinin-1 is a peptide encoded by Pptc, which belongs to the family of mammalian tachykinins. Our previous results showed that rat/mouse hemokinin-1 (r/m HK-1) produced striking analgesia after intracerebroventricular (i.c.v.) injection in mice, and the analgesia could be blocked by the NK1 receptor antagonist and the opioid receptor antagonist, respectively. However, the precise distribution sites and the molecular mechanism involved in the analgesic effect after i.c.v. administration of r/m HK-1 are needed to be further investigated deeply. Using the fluorescence labeling method, our present results directly showed that r/m HK-1 peptides were mainly distributed at the ventricular walls and several juxta-ventricular structures for the first time. Our results showed that the mRNA expressions of NK1 receptor, PPT-A, PPT-C, KOR, PDYN, DOR and PENK were not changed markedly, as well as the protein expression of NK1 receptor was hardly changed. However, both the transcripts and proteins of MOR and POMC were up-regulated significantly, indicating that the analgesic effect induced by i.c.v. administration of r/m HK-1 is related to the activation of NK1 receptor first, then it is related to the release of endogenous proopiomelanocortin, as well as the increased expression level of μ opioid receptor. These results should facilitate further the analysis of the analgesia of r/m HK-1 in the central nerval system in acute pain and may open novel pharmacological interventions.

  13. Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection.

    PubMed

    McLean, Jesse R; Smith, Gaynor A; Rocha, Emily M; Hayes, Melissa A; Beagan, Jonathan A; Hallett, Penelope J; Isacson, Ole

    2014-07-25

    Adeno-associated viral (AAV) gene transfer holds great promise for treating a wide-range of neurodegenerative disorders. The AAV9 serotype crosses the blood-brain barrier and shows enhanced transduction efficiency compared to other serotypes, thus offering advantageous targeting when global transgene expression is required. Neonatal intravenous or intracerebroventricular (i.c.v.) delivery of recombinant AAV9 (rAAV9) have recently proven effective for modeling and treating several rodent models of neurodegenerative disease, however, the technique is associated with variable cellular tropism, making tailored gene transfer a challenge. In the current study, we employ the human synapsin 1 (hSYN1) gene promoter to drive neuron-specific expression of green fluorescent protein (GFP) after neonatal i.c.v. injection of rAAV9 in mice. We observed widespread GFP expression in neurons throughout the brain, spinal cord, and peripheral nerves and ganglia at 6 weeks-of-age. Region-specific quantification of GFP expression showed high neuronal transduction rates in substantia nigra pars reticulata (43.9±5.4%), motor cortex (43.5±3.3%), hippocampus (43.1±2.7%), cerebellum (29.6±2.3%), cervical spinal cord (24.9±3.9%), and ventromedial striatum (16.9±4.3%), among others. We found that 14.6±2.2% of neuromuscular junctions innervating the gastrocnemius muscle displayed GFP immunoreactivity. GFP expression was identified in several neuronal sub-types, including nigral tyrosine hydroxylase (TH)-positive dopaminergic cells, striatal dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32)-positive neurons, and choline acetyltransferase (ChAT)-positive motor neurons. These results build on contemporary gene transfer techniques, demonstrating that the hSYN1 promoter can be used with rAAV9 to drive robust neuron-specific transgene expression throughout the nervous system.

  14. Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.

    PubMed

    Souza, Leandro Cattelan; Jesse, Cristiano R; Antunes, Michelle S; Ruff, Jossana Rodrigues; de Oliveira Espinosa, Dieniffer; Gomes, Nathalie Savedra; Donato, Franciele; Giacomeli, Renata; Boeira, Silvana Peterini

    2016-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aβ1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aβ-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aβ-induced neuroinflammation.

  15. 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

  16. Accuracy and Injection Force of the Gla-300 Injection Device Compared With Other Commercialized Disposable Insulin Pens

    PubMed Central

    Klonoff, David; Nayberg, Irina; Thonius, Marissa; See, Florian; Abdel-Tawab, Mona; Erbstein, Frank; Haak, Thomas

    2015-01-01

    Background: To deliver insulin glargine 300 U/mL (Gla-300), the widely used SoloSTAR® pen has been modified to allow for accurate and precise delivery of required insulin units in one-third of the volume compared with insulin glargine 100 U/mL, while improving usability. Here we compare the accuracy and injection force of 3 disposable insulin pens: Gla-300 SoloSTAR®, FlexPen®, and KwikPen™. Methods: For the accuracy assessment, 60 of each of the 3 tested devices were used for the delivery of 3 different doses (1 U, half-maximal dose, and maximal dose), which were measured gravimetrically. For the injection force assessment, 20 pens of each of the 3 types were tested twice at half-maximal and once at maximal dose, at an injection speed of 6 U/s. Results: All tested pens met the International Organization for Standardization (ISO) requirements for dosing accuracy, with Gla-300 SoloSTAR showing the lowest between-dose variation (greatest reproducibility) at all dose levels. Mean injection force was significantly lower for Gla-300 SoloSTAR than for the other 2 pens at both half maximal and maximal doses (P < .0271). Conclusion: All tested pens were accurate according to ISO criteria, and the Gla-300 SoloSTAR pen displayed the greatest reproducibility and lowest injection force of any of the 3 tested devices. PMID:26311720

  17. Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot

    PubMed Central

    2016-01-01

    In this work we demonstrate that blood glucose can be controlled remotely through light stimulated release of insulin from an injected cutaneous depot. Human insulin was tethered to an insoluble but injectable polymer via a linker, which was based on the light cleavable di-methoxy nitrophenyl ethyl (DMNPE) group. This material was injected into the skin of streptozotocin-treated diabetic rats. We observed insulin being released into the bloodstream after a 2 min trans-cutaneous irradiation of this site by a compact LED light source. Control animals treated with the same material, but in which light was blocked from the site, showed no release of insulin into the bloodstream. We also demonstrate that additional pulses of light from the light source result in additional pulses of insulin being absorbed into circulation. A significant reduction in blood glucose was then observed. Together, these results demonstrate the feasibility of using light to allow for the continuously variable control of insulin release. This in turn has the potential to allow for the tight control of blood glucose without the invasiveness of insulin pumps and cannulas. PMID:27653828

  18. The regulatory system for diabetes mellitus: Modeling rates of glucose infusions and insulin injections

    NASA Astrophysics Data System (ADS)

    Yang, Jin; Tang, Sanyi; Cheke, Robert A.

    2016-08-01

    Novel mathematical models with open and closed-loop control for type 1 or type 2 diabetes mellitus were developed to improve understanding of the glucose-insulin regulatory system. A hybrid impulsive glucose-insulin model with different frequencies of glucose infusions and insulin injections was analyzed, and the existence and uniqueness of the positive periodic solution for type 1 diabetes, which is globally asymptotically stable, was studied analytically. Moreover, permanence of the system for type 2 diabetes was demonstrated which showed that the glucose concentration level is uniformly bounded above and below. To investigate how to prevent hyperinsulinemia and hyperglycemia being caused by this system, we developed a model involving periodic intakes of glucose with insulin injections applied only when the blood glucose level reached a given critical glucose threshold. In addition, our numerical analysis revealed that the period, the frequency and the dose of glucose infusions and insulin injections are crucial for insulin therapies, and the results provide clinical strategies for insulin-administration practices.

  19. Audit of multiple insulin injection regimens in a large outpatient diabetic population.

    PubMed

    Gordon, D; Wilson, M; Paterson, K R; Semple, C G

    1992-08-01

    One hundred out-patients treated by multiple insulin injection regimens underwent clinical audit by retrospective analysis of their case-notes. Patients had been on multiple insulin injection therapy (MIIT) for 1.0-4.5 years (median, 3.6 years) and had had diabetes for 2 months-33 years (median, 8.7 years) at the time of starting pen therapy. Median daily insulin dose per patient did not differ significantly following stabilisation on MIIT or at latest follow-up. The median glycated haemoglobin did not change during each of the 4 years of follow-up. During the year prior to commencing MIIT the patients showed no significant alteration in body weight. Patients' weights rose significantly during each subsequent year. Median weight gains were 0.9 kg (P less than 0.005) during the first year, 1.4 kg (P less than 0.005) during the second year, 0.9 kg (P less than 0.05) during the third year and 1.4 kg (P less than 0.05) during year 4. No such weight gain was recorded in a control group of 30 patients matched for age and duration of diabetes and treated by twice daily insulin injections. Multiple insulin injection regimens used over prolonged periods in a routine clinic setting do not alter metabolic control. However, continuing weight gain appears to occur despite similar daily insulin doses.

  20. Visualization of subcutaneous insulin injections by x-ray computed tomography

    NASA Astrophysics Data System (ADS)

    Thomsen, M.; Poulsen, M.; Bech, M.; Velroyen, A.; Herzen, J.; Beckmann, F.; Feidenhans'l, R.; Pfeiffer, F.

    2012-11-01

    We report how the three-dimensional structure of subcutaneous injections of soluble insulin can be visualized by x-ray computed tomography using an iodine based contrast agent. The injections investigated are performed ex vivo in porcine adipose tissue. Full tomography scans carried out at a laboratory x-ray source with a total acquisition time of about 1 min yield CT-images with an effective pixel size of 109 × 109 μm2. The depots are segmented using a modified Chan-Vese algorithm and we are able to observe differences in the shape of the injection depot and the position of the depot in the skin among equally performed injections. To overcome the beam hardening artefacts, which affect the quantitative prediction of the volume injected, we additionally present results concerning the visualization of two injections using synchrotron radiation. The spatial concentration distribution of iodine is calculated to show the dilution of the insulin drug inside the depot. Characterisation of the shape of the depot and the spatial concentration profile of the injected fluid is important knowledge when improving the clinical formulation of an insulin drug, the performance of injection devices and when predicting the effect of the drug through biomedical simulations.

  1. V-Go Insulin Delivery System Versus Multiple Daily Insulin Injections for Patients With Uncontrolled Type 2 Diabetes Mellitus.

    PubMed

    Winter, Abigail; Lintner, Michaela; Knezevich, Emily

    2015-04-21

    Type 2 diabetes mellitus affects over 29.1 million Americans, diagnosed and undiagnosed. Achieving and maintaining glycemic control for these patients is of extreme importance when working to prevent complications and improve quality of life for patients. The V-Go is a newly developed insulin delivery system. The push of a button inserts a needle into the patient once daily and remains attached for 24 hours. The V-Go is designed to release a set basal rate throughout the day, while allowing patients to provide up to 36 units of on-demand bolus insulin with the manual click of 2 buttons. It is a spring-loaded device filled daily with rapid-acting insulin that runs without the use of batteries or computer software. The main objective of this prospective active comparator study was to observe the A1C lowering effects of multiple daily insulin injections (MDII) versus the use of the V-Go insulin delivery system for patients with uncontrolled type 2 diabetes mellitus over a 3-month period. In addition, the effect on insulin requirement for these patients was assessed with secondary comparisons of weight, blood pressure, prevalence of hypoglycemic events, and quality of life before and after 3 months of intensified insulin therapy with regular monitoring by a clinical pharmacist at an internal medicine clinic. The average A1C lowering experienced by the 3 patients in the V-Go group was 1.5%, while the average A1C change in the 3 patients in the MDII group was an increase of 0.2%. All patients in the V-Go group experienced a decrease in insulin total daily dose (TDD), with an average decrease of 26.3 units. All patients in the MDII group experienced an increase in insulin TDD with an average of 15 units daily to achieve therapeutic goals individualized for each patient. All patients who underwent intensification of insulin therapy experienced an increase in subjective quality of life (QOL) as determined using the Diabetes-39 (D-39) questionnaire, though QOL results lacked

  2. Thermoresponsive biodegradable PEG-PCL-PEG based injectable hydrogel for pulsatile insulin delivery.

    PubMed

    Payyappilly, Sanal; Dhara, Santanu; Chattopadhyay, Santanu

    2014-05-01

    An injectable biodegradable hydrogel was prepared for temperature-responsive pulsatile release of insulin. Triblock copolymer of poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) was prepared by ring opening bulk copolymerization and characterized using FT-IR, (1) HNMR, and gel permeation chromatography. Aqueous solution of PECE formed an injectable hydrogel, which was solution at room temperature and transformed into gel at 37°C. The temperature-responsive sol-gel transition and crystallinity of PECE hydrogel was studied and compared with pluronic, a well-studied nonbiodegradable injectable hydrogel. In vitro release study revealed that insulin release profile of PECE was similar to pluronic, and its viscosity was 1/30(th) of pluronic sol at 10,000 s(-1) shear rate. Release behavior of insulin from PECE hydrogels followed Fickian diffusion of first order. Insulin retained its secondary structure after release as confirmed by circular dichroism spectrum. A threefold increase in Fickian diffusion coefficient was evidenced when temperature was increased from 34 to 40°C because of crystalline melting of PCL part of PECE. Pulsatile release of insulin showed a correlation coefficient of 0.90 with the change of temperature.

  3. Improved diabetic control in adolescents using the Penject syringe for multiple insulin injections.

    PubMed

    McCaughey, E S; Betts, P R; Rowe, D J

    1986-05-01

    Eleven adolescent diabetics, aged 15.1 +/- 1.3 years (mean +/- 1SD) in poor glycaemic control (HbA1 12.0 +/- 1.5% at entry) were commenced on a four times daily insulin injection regimen using the Penject fountain-pen syringe with Initard (50:50 mixture of porcine soluble and isophane) insulin on a sliding scale. Diabetic control improved over a 3-month period, assessed by a reduction in both the mean preprandial blood glucose concentrations (10.9 +/- 3.3 mmol/l to 7.7 +/- 2.3 mmol/l) and mean glycosylated haemoglobin concentrations (12.0 +/- 1.5% to 9.5 +/- 0.9%). Further improvement was again seen in 5 patients who remained on four daily injections for an additional 3 months (mean HbA1: 9.6 +/- 0.9% to 8.4 +/- 1.0%), whereas diabetic control in 6 patients who returned to twice daily injections deteriorated (mean HbA1 rose from 9.5 +/- 1.0% to 10.6 +/- 1.6%). Multiple insulin injections using an injection pen are acceptable to adolescent diabetics and improve their control.

  4. Chronic treatment with taurine after intracerebroventricular streptozotocin injection improves cognitive dysfunction in rats by modulating oxidative stress, cholinergic functions and neuroinflammation.

    PubMed

    Reeta, K H; Singh, Devendra; Gupta, Y K

    2017-03-08

    The present study investigated the neuroprotective effects of taurine, an essential amino acid for growth and development of central nervous system. Intracerebroventricular streptozotocin (ICV-STZ) model of cognitive impairment was used in male Wistar rats (270 ± 20 g). Morris water maze, elevated plus maze and passive avoidance paradigm were used to assess cognitive performance. Taurine (40, 60 and 120 mg/kg) was administered orally for 28 days following STZ administration on day 1. Oxidative stress parameters (malondialdehyde, glutathione, nitric oxide and superoxide dismutase) and cholinesterases (acetylcholinesterase and butyrylcholinesterase) activity were measured at end of the study in the cortex and hippocampus. Levels of TNF-α, IL-1β, expression of rho kinase-II (ROCK-II), glycogen synthase kinase-3β (GSK-3β) and choline acetyltransferase (ChAT) were studied in cortex and hippocampus. STZ caused significant cognitive impairment as compared to normal control. Chronic administration of taurine attenuated STZ-induced cognitive impairment. Increased oxidative stress and increased levels of TNF-α, IL-1β induced by STZ were also significantly attenuated by taurine. Taurine significantly (p < 0.05) decreased the STZ-induced increased expression of ROCK-II in cortex and hippocampus. Further, STZ-induced increased activity of cholinesterases was significantly (p < 0.001) mitigated by taurine. STZ decreased the expression of ChAT in hippocampus which was significantly (p < 0.05) reversed by taurine. However, GSK-3β expression was not altered by either STZ or taurine. The present study indicates that taurine exerts a neuroprotective role against STZ-induced cognitive impairment in rats. This effect is probably mediated by modulating oxidative stress, cholinesterases, inflammatory cytokines and expression of ROCK-II. Thus, this study suggests a potential of chronic taurine administration in cognitive impairment of Alzheimer's type.

  5. Impairment of blood brain barrier is related with the neuroinflammation induced peripheral immune status in intracerebroventricular colchicine injected rats: An experimental study with mannitol.

    PubMed

    Sil, Susmita; Ghosh, Arijit; Ghosh, Tusharkanti

    2016-09-01

    The neurodegeneration in AD patients may be associated with changes of peripheral immune responses. Some peripheral immune responses are altered due to neuroinflammation in colchicine induced AD (cAD) rats. The leaky blood brain barrier (BBB) in cAD-rats may be involved in inducing peripheral inflammation, though there is no report in this regard. Therefore, the present study was designed to investigate the role of BBB in cADrats by altering the BBB in a time dependent manner with injection (i.v.) of mannitol (BBB opener). The inflammatory markers in the brain and serum along with the peripheral immune responses were measured after 30 and 60min of mannitol injection in cAD rats. The results showed higher inflammatory markers in the hippocampus and serum along with alterations in peripheral immune parameters in cAD rats. Although the hippocampal inflammatory markers did not further change after mannitol injection in cAD rats, the serum inflammatory markers and peripheral immune responses were altered and these changes were greater after 60min than that of 30min of mannitol injection. The present study shows that the peripheral immune responses in cAD rats after 30 and 60min of mannitol injection are related to magnitude of impairment of BBB in these conditions. It can be concluded from this study that impairment of BBB in cAD rats is related to the changes of peripheral immune responses observed in that condition.

  6. Insulin Therapy

    MedlinePlus

    ... 3 hours and lasts 12 to 16 hours.Long-acting insulin (such as insulin glargine and insulin detemir) ... hard to time their meals around regular insulin injections. Sometimes they end up eating too soon or ...

  7. IDegLira: Redefining insulin optimisation using a single injection in patients with type 2 diabetes.

    PubMed

    Hughes, Eugene

    2016-06-01

    In type 2 diabetes (T2D), treatment is optimised to minimise hyperglycaemia and the risk of microvascular complications. While there are a number of effective treatments, intensive treatment is associated with negative side effects such as increased hypoglycaemia and weight gain. With complementary modes of action, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and a basal insulin in combination offer an alternative to basal-bolus therapy in T2D. This review describes the rationale behind this treatment combination and presents clinical data available for IDegLira, the first basal insulin (insulin degludec) and GLP-1RA (liraglutide) co-formulation available in one pen for a single injection daily.

  8. Flow injection amperometric detection of insulin at cobalt hydroxide nanoparticles modified carbon ceramic electrode.

    PubMed

    Habibi, Esmaeil; Omidinia, Eskandar; Heidari, Hassan; Fazli, Maryam

    2016-02-15

    Cobalt hydroxide nanoparticles were prepared onto a carbon ceramic electrode (CHN|CCE) using the cyclic voltammetry (CV) technique. The modified electrode was characterized by X-ray diffraction and scanning electron microscopy. The results showed that CHN with a single-layer structure was uniformly electrodeposited on the surface of CCE. The electrocatalytic activity of the modified electrode toward the oxidation of insulin was studied by CV. CHN|CCE was also used in a homemade flow injection analysis system for insulin determination. The limit of detection (signal/noise [S/N] = 3) and sensitivity were found to be 0.11 nM and 11.8 nA/nM, respectively. Moreover, the sensor was used for detection of insulin in human serum samples. This sensor showed attractive properties such as high stability, reproducibility, and high selectivity.

  9. Attempted suicide by massive insulin injection: a case report and review of the literature.

    PubMed

    Thewjitcharoen, Yotsapon; Lekpittaya, Nampetch; Himathongkam, Thep

    2008-12-01

    The authors present a case of an 80-year-old man, non-diabetic, who attempted suicide by injecting himself subcutaneously with 10,000 units of Humulin R and 6000 units of Humulin N. Administration of dextrose intravenously was required for 13 days to maintain the capillary blood glucose within the range of 100-180 mg/dl. Hyponatremia, hypokalemia, hypophosphatemia, and elevated liver enzymes were also seen after massive insulin injection. Glucose requirement index was established to demonstrate the trend of glucose requirement during hospitalization. He recovered completely without any complication after monitoring blood glucose and titrating intravenous glucose carefully for two weeks. Current literature about how to manage insulin overdose was reviewed in the present article.

  10. Acute repeated intracerebroventricular injections of angiotensin II reduce agonist and antagonist radioligand binding in the paraventricular nucleus of the hypothalamus and median preoptic nucleus in the rat brain.

    PubMed

    Speth, Robert C; Vento, Peter J; Carrera, Eduardo J; Gonzalez-Reily, Luz; Linares, Andrea; Santos, Kira; Swindle, Jamala D; Daniels, Derek

    2014-10-02

    Angiotensin II (Ang II) stimulates water and saline intakes when injected into the brain of rats. This arises from activation of the AT1 Ang II receptor subtype. Acute repeated injections, however, decrease the water intake response to Ang II without affecting saline intake. Previous studies provide evidence that Ang II-induced water intake is mediated via the classical G protein coupling pathway, whereas the saline intake caused by Ang II is mediated by an ERK 1/2 MAP kinase signaling pathway. Accordingly, the different behavioral response to repeated injections of Ang II may reflect a selective effect on G protein coupling. To test this hypothesis, we examined the binding of a radiolabeled agonist ((125)I-sarcosine(1) Ang II) and a radiolabeled antagonist ((125)I-sarcosine(1), isoleucine(8) Ang II) in brain homogenates and tissue sections prepared from rats given repeated injections of Ang II or vehicle. Although no treatment-related differences were found in hypothalamic homogenates, a focus on specific brain structures using receptor autoradiography, found that the desensitization treatment reduced binding of both radioligands in the paraventricular nucleus of the hypothalamus (PVN) and median preoptic nucleus (MnPO), but not in the subfornical organ (SFO). Because G protein coupling is reported to have a selective effect on agonist binding without affecting antagonist binding, these findings do not support a G protein uncoupling treatment effect. This suggests that receptor number is more critical to the water intake response than the saline intake response, or that pathways downstream from the G protein mediate desensitization of the water intake response.

  11. One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance

    PubMed Central

    Gao, Mei Hua; Giamouridis, Dimosthenis; Lai, N. Chin; Walenta, Evelyn; Paschoal, Vivian Almeida; Kim, Young Chul; Miyanohara, Atsushi; Guo, Tracy; Liao, Min; Liu, Li; Ciaraldi, Theodore P.; Bhargava, Aditi; Oh, Da Young; Hammond, H. Kirk

    2016-01-01

    Using mice rendered insulin resistant with high fat diets (HFD), we examined blood glucose levels and insulin resistance after i.v. delivery of an adeno-associated virus type 8 encoding murine urocortin 2 (AAV8.UCn2). A single i.v. injection of AAV8.UCn2-normalized blood glucose and glucose disposal within weeks, an effect that lasted for months. Hyperinsulinemic-euglycemic clamps showed reduced plasma insulin, increased glucose disposal rates, and increased insulin sensitivity following UCn2 gene transfer. Mice with corticotropin-releasing hormone type 2-receptor deletion that were rendered insulin resistant by HFD showed no improvement in glucose disposal after UCn2 gene transfer, indicating that the effect requires UCn2’s cognate receptor. We also demonstrated increased glucose disposal after UCn2 gene transfer in db/db mice, a second model of insulin resistance. UCn2 gene transfer reduced fatty infiltration of the liver in both models of insulin resistance. UCn2 increases Glut4 translocation to the plasma membrane in skeletal myotubes in a manner quantitatively similar to insulin, indicating a mechanism through which UCn2 operates to increase insulin sensitivity. UCn2 gene transfer, in a dose-dependent manner, is insulin sensitizing and effective for months after a single injection. These findings suggest a potential long-term therapy for clinical type-2 diabetes. PMID:27699250

  12. Insulin Injection

    MedlinePlus

    ... quinine; quinidine; salicylate pain relievers such as aspirin; sulfa antibiotics; and thyroid medications. Your doctor may need ... may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online ( ...

  13. Continuous insulin therapy versus multiple insulin injections in the management of type 1 diabetes: a longitutinal study

    PubMed Central

    Ribeiro, Maria Estela Bellini; Liberatore, Raphael Del Roio; Custodio, Rodrigo; Martinelli, Carlos Eduardo

    2016-01-01

    Abstract Objective: To compare multiple doses of insulin and continuous insulin infusion therapy as treatment for type 1 diabetes mellitus. Methods: 40 patients with type 1 diabetes mellitus (21 female) with ages between 10 and 20 years (mean=14.2) and mean duration of diabetes of 7 years used multiple doses of insulin for at least 6 months and after that, continuous insulin infusion therapy for at least 6 months. Each one of the patients has used multiple doses of insulin and continuous insulin infusion therapy. For analysis of HbA1c, mean glycated hemoglobin levels (mHbA1c) were obtained during each treatment period (multiple doses of insulin and continuous insulin infusion therapy period). Results: Although mHbA1c levels were lower during continuous insulin infusion therapy the difference was not statistically significant. During multiple doses of insulin, 14.2% had mHbA1c values below 7.5% vs. 35.71% while on continuous insulin infusion therapy; demonstrating better glycemic control with the use of continuous insulin infusion therapy. During multiple doses of insulin, 15–40 patients have severe hypoglycemic events versus 5–40 continuous insulin infusion therapy. No episodes of ketoacidosis events were recorded. Conclusions: This is the first study with this design comparing multiple doses of insulin and continuous insulin infusion therapy in Brazil showing no significant difference in HbA1c; hypoglycemic events were less frequent during continuous insulin infusion therapy than during multiple doses of insulin and the percentage of patients who achieved a HbA1c less than 7.5% was greater during continuous insulin infusion therapy than multiple doses of insulin therapy. PMID:26826879

  14. Decreased forelimb ability in mice intracerebroventricularly injected with low dose 6-hydroxidopamine: A model on the dissociation of bradykinesia from hypokinesia.

    PubMed

    Ribeiro, Renata Pietsch; Santos, Danúbia Bonfanti; Colle, Dirleise; Naime, Aline Aita; Gonçalves, Cinara Ludvig; Ghizoni, Heloisa; Hort, Mariana Appel; Godoi, Marcelo; Dias, Paulo Fernando; Braga, Antonio Luiz; Farina, Marcelo

    2016-05-15

    Bradykinesia and hypokinesia represent well-known motor symptoms of Parkinson's disease (PD). While bradykinesia (slow execution of movements) is present in less affected PD patients and aggravates as the disease severity increases, hypokinesia (reduction of movement) seems to emerge prominently only in the more affected patients. Here we developed a model based on the central infusion of low dose (40μg) 6-hydroxydopamine (6-OHDA) in mice in an attempt to discriminate bradykinesia (accessed through forelimb inability) from hypokinesia (accessed through locomotor and exploratory activities). The potential beneficial effects of succinobucol against 6-OHDA-induced forelimb inability were also evaluated. One week after the beginning of treatment with succinobucol (i.p. injections, 10mg/kg/day), mice received a single i.c.v. infusion of 6-OHDA (40μg/site). One week after 6-OHDA infusion, general locomotor/exploratory activities (open field test), muscle strength (grid test), forelimb skill (single pellet task), as well as striatal biochemical parameters related to oxidative stress and cellular homeostasis (glutathione peroxidase, glutathione reductase and NADH dehydrogenases activities, lipid peroxidation and TH levels), were evaluated. 6-OHDA infusions did not change locomotor/exploratory activities and muscle strength, as well as the evaluated striatal biochemical parameters. However, 6-OHDA infusions caused significant reductions (50%) in the single pellet reaching task performance, which detects forelimb skill inability and can be used to experimentally identify bradykinesia. Succinobucol partially protected against 6-OHDA-induced forelimb inability. The decreased forelimb ability with no changes in locomotor/exploratory behavior indicates that our 6-OHDA-based protocol represents a useful tool to mechanistically study the dissociation of bradykinesia and hypokinesia in PD.

  15. Glycaemic control with modified intensive insulin injections (MII) using insulin pens and premixed insulin in children with type-1 diabetes: a randomized controlled trial.

    PubMed

    Soliman, Ashraf T; Omar, Magdi; Rizk, Mostafa M; El Awwa, Ahmad; AlGhobashy, Fatma M

    2006-08-01

    The objective of this study was to compare glycemic control and insulin dosage in children with type 1 diabetes treated by a modified intensified insulin therapy MII using insulin pens (and premixed and regular insulin) with those on conventional insulin therapy. This was a longitudinal, randomized controlled trial for 6 months or more. From a cohort of 125 children with previously diagnosed type-1 diabetes (more than a year after diagnosis) two groups were randomly selected Group AI (n=20) and Group B (n=20). Group AI children and 10 children with recently diagnosed type 1 diabetes (Group AII) were allocated to MII using regular insulin and premixed insulin (30/70 and 40/60 and 50/50). Group B patients continued their conventional insulin therapy for the whole period of the trial. The main outcome measures were glycemic control measured by mean blood glucose concentration and percentage of glycated haemoglobin and total daily insulin dose. Mean blood glucose concentrations before the three main meals, and at midnight, (148, 147, 179 and 127 mg/dl, respectively) were lower in children receiving intensified MII compared with those receiving conventional insulin therapy (192, 174, 194 and 179 mg/dl, respectively) (standardized mean difference 34+/-15 mg/dl), equivalent to a difference of 1.9+/-0.8 mmol/l. This improved control during MII was achieved with no change in the average daily insulin dose in group-AI. In group-AII insulin dose decreased significantly during their first 6 moths of treatment (honeymooning). Glycemic control is better during MII using insulin pens and premixed and regular insulin compared with conventional insulin therapy, without any significant change in insulin dose needed to achieve this level of control. The difference in glycemic control between the two methods is significant and could reduce the risk of micro-vascular complications.

  16. Intracerebroventricular administration of 26RFa produces an analgesic effect in the rat formalin test.

    PubMed

    Yamamoto, Tatsuo; Miyazaki, Rika; Yamada, Toshihiko

    2009-09-01

    GPR103 is one of the orphan G protein-coupled receptors. Recently, an endogenous ligand for GPR103, 26RFa, was identified. Many 26RFa binding sites have been observed in various nuclei of the brain involved in the processing of pain such as the parafascicular thalamic nucleus, the locus coeruleus, the dorsal raphe nucleus, and the parabrachial nucleus. In the present study, the effects of intracerebroventricular injection of 26RFa were tested in the rat. Intracerebroventricular injection of 26RFa significantly decreased the number of both phase 1 and phase 2 agitation behaviors induced by paw formalin injection. This analgesic effect of 26RFa on the phase 1 response, but not phase 2 response, was antagonized by BIBP3226, a mixed antagonist of neuropeptide Y Y1 and neuropeptide FF receptors. Intracerebroventricular injection of 26RFa has no effect in the 52.5 degrees C hot plate test. Intracerebroventricular injection of 26RFa had no effect on the expression of Fos-like immunoreactivity induced by paw formalin injection in the superficial layers of the spinal dorsal horn. These data suggest that (1) 26RFa modulates nociceptive transmission at the supraspinal site during a formalin test, (2) the mechanism 26RFa uses to produce an analgesic effect on the phase 1 response is different from that on the phase 2 response, and (3) intracerebroventricularly injected 26RFa dose not directly inhibit the nociceptive input to the spinal cord.

  17. Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE).

    PubMed

    2017-03-30

    Objective To compare the effectiveness of insulin pumps with multiple daily injections for adults with type 1 diabetes, with both groups receiving equivalent training in flexible insulin treatment.Design Pragmatic, multicentre, open label, parallel group, cluster randomised controlled trial (Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial).Setting Eight secondary care centres in England and Scotland.Participants Adults with type 1 diabetes who were willing to undertake intensive insulin treatment, with no preference for pumps or multiple daily injections. Participants were allocated a place on established group training courses that taught flexible intensive insulin treatment ("dose adjustment for normal eating," DAFNE). The course groups (the clusters) were then randomly allocated in pairs to either pump or multiple daily injections.Interventions Participants attended training in flexible insulin treatment (using insulin analogues) structured around the use of pump or injections, followed for two years.Main outcome measures The primary outcomes were a change in glycated haemoglobin (HbA1c) values (%) at two years in participants with baseline HbA1c value of ≥7.5% (58 mmol/mol), and the proportion of participants achieving an HbA1c value of <7.5%. Secondary outcomes included body weight, insulin dose, and episodes of moderate and severe hypoglycaemia. Ancillary outcomes included quality of life and treatment satisfaction.Results 317 participants (46 courses) were randomised (156 pump and 161 injections). 267 attended courses and 260 were included in the intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of ≥7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was -0.85% with pump treatment and -0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the

  18. Improved insulin absorption by means of standardized injection site modulation results in a safer and more efficient prandial insulin treatment. A review of the existing clinical data.

    PubMed

    Pfützner, Andreas; Raz, Itamar; Bitton, Gabriel; Klonoff, David; Nagar, Ron; Hermanns, Norbert; Haak, Thomas

    2015-01-01

    Temperature changes on the surface of the skin lead to modifications of subcutaneous microcirculation. This phenomenon is employed in a standardized way by the InsuPad device to stabilize skin conditions before injections, which is associated with enhanced prandial insulin absorption. Three programmed warming cycles to 40°C within 50 minutes are resulting in faster insulin appearance in the plasma. Early standardized meal tolerance studies indicated a substantial improvement in postprandial glucose control when the same short-acting insulin analog dose was applied using InsuPad, and a dose reduction by 20% resulted in comparable glucose excursions. Similar results were obtained when patients applied the device under real-world conditions for 1 month. The InsuPad device was also tested in a prospective, controlled, parallel 3-month real-world study with 145 well-controlled but insulin-resistant patients with type 1 or type 2 diabetes. Patients were treated to target in both treatment arms (6.2 ± 0.5% in each group), with or without the device. However, patients with InsuPad needed 28% less prandial insulin, needed 12.5% less total insulin, and had 46% less confirmed hypoglycemic events (blood glucose < 63 mg/dL) as compared to the control group. Except for very few inflammatory or allergic skin reactions, there were no device-specific adverse events reported from these studies. In conclusion, use of InsuPad when applying prandial insulin doses may result in a safer and more efficient treatment of type 1 or type 2 diabetes.

  19. Improved Insulin Absorption by Means of Standardized Injection Site Modulation Results in a Safer and More Efficient Prandial Insulin TreatmentA Review of the Existing Clinical Data

    PubMed Central

    Raz, Itamar; Bitton, Gabriel; Klonoff, David; Nagar, Ron; Hermanns, Norbert; Haak, Thomas

    2014-01-01

    Temperature changes on the surface of the skin lead to modifications of subcutaneous microcirculation. This phenomenon is employed in a standardized way by the InsuPad device to stabilize skin conditions before injections, which is associated with enhanced prandial insulin absorption. Three programmed warming cycles to 40°C within 50 minutes are resulting in faster insulin appearance in the plasma. Early standardized meal tolerance studies indicated a substantial improvement in postprandial glucose control when the same short-acting insulin analog dose was applied using InsuPad, and a dose reduction by 20% resulted in comparable glucose excursions. Similar results were obtained when patients applied the device under real-world conditions for 1 month. The InsuPad device was also tested in a prospective, controlled, parallel 3-month real-world study with 145 well-controlled but insulin-resistant patients with type 1 or type 2 diabetes. Patients were treated to target in both treatment arms (6.2 ± 0.5% in each group), with or without the device. However, patients with InsuPad needed 28% less prandial insulin, needed 12.5% less total insulin, and had 46% less confirmed hypoglycemic events (blood glucose < 63 mg/dL) as compared to the control group. Except for very few inflammatory or allergic skin reactions, there were no device-specific adverse events reported from these studies. In conclusion, use of InsuPad when applying prandial insulin doses may result in a safer and more efficient treatment of type 1 or type 2 diabetes. PMID:25352633

  20. Feeding, drinking, and temperature responses of chickens to intracerebroventricular histamine.

    PubMed

    Meade, S; Denbow, D M

    2001-05-01

    The present study examines the effects of intracerebroventricular injections of histamine (HA) and two HA antagonists, the H(1) receptor antagonist chloropheneramine maleate (CM) and the H(2) receptor antagonist cimetidine (CIM), on food and water consumption and body temperature in chickens. Single-Comb White Leghorns (SCWL) and broiler cockerels were utilized for these experiments. The first pair of experiments consisted of intracerebroventricular injections of HA and its effects on food and water consumption. HA was infused at dosages of 0, 25, 50, and 100 microg/10 microl of artificial cerebrospinal fluid (aCSF). HA significantly decreased food and water intake in a dose-dependent manner. The second pair of experiments examined the effects of HA on water intake while birds had no access to feed. Water intake was not significantly affected by intracerebroventricular injections of HA. The next pair of experiments examined the effects of HA on body temperature. In SCWL, body temperature was not affected by HA until 165 min postinjection when HA decreased temperature in a quadratic dose-response with maximum hypothermia being achieved at a dose of 25 microg. In contrast, HA increased body temperature in broilers beginning at 75 min postinjection. In the final series of experiments, the anorexia induced by HA was attenuated in SCWL and broilers with pretreatment of either CM or CIM. These results suggest that HA has an anorexigenic effect in SCWL and broiler cockerels, and this effect is mediated by both H(1) and H(2) receptors. Water intake is not directly affected by the intracerebroventricular injection of HA. Whereas HA increased body temperature in broilers, the response in SCWL is equivocal.

  1. Insulin

    MedlinePlus

    ... container that can be closed like a laundry detergent bottle. Check the expiration date on the insulin ... in a hard container like an empty laundry detergent bottle or a metal coffee can. Make sure ...

  2. Comparisons of insulin related parameters in commercial-type chicks: Evidence for insulin resistance in broiler chicks.

    PubMed

    Shiraishi, Jun-Ichi; Yanagita, Kouichi; Fukumori, Rika; Sugino, Toshihisa; Fujita, Masanori; Kawakami, Shin-Ichi; McMurtry, John P; Bungo, Takashi

    2011-05-03

    The aim of this study is to elucidate whether insulin acts differentially within the central nervous system (CNS) of two types of commercial chicks to control ingestive behavior. Male layer and broiler chicks (4-day-old) were intracerebroventricularly (ICV) injected with saline or insulin under satiated and starved conditions. Feed intake was measured at 30, 60 and 120 min after treatment. Secondly, blood and hypothalamus were collected from both chick types under ad libitum feeding and fasting for 24 h. Plasma insulin concentration was measured by time-resolved fluoro-immunoassay. Hypothalamic insulin receptor mRNA expression levels were measured by quantitative RT-PCR. The ICV injection of insulin significantly inhibited feed consumption in layer chicks when compared with saline (P<0.05), but not broiler chicks (P>0.1). Plasma insulin concentration of both chick types significantly decreased following 24 h of fasting, while insulin concentrations in the broiler chicks were significantly higher compared to the layers fed under ad libitum conditions. Hypothalamic insulin receptor mRNA expression levels were significantly lower (P<0.05) in broiler chicks than in layer ones under ad libitum feeding. Feed deprivation significantly decreased insulin receptor mRNA levels in layer chicks (P<0.01), but not in broiler chicks (P>0.1). Moreover, plasma insulin concentrations correlated negatively with hypothalamic insulin receptor protein expression in the two types of chicks fed ad libitum (P<0.05). These results suggest that insulin resistance exists in the CNS of broiler chicks, possibly due to persistent hyperinsulinemia, which results in a down-regulation of CNS insulin receptor expression compared to that in layer chicks.

  3. 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.

  4. Intracerebroventricular opioids for intractable pain

    PubMed Central

    Raffa, Robert B; Pergolizzi, Joseph V

    2012-01-01

    When pain is refractory to systemic opioid and non-opioid analgesic therapy and palliative chemoradiation or ablative or stimulant neurosurgical procedures are not possible, palliative treatment becomes limited, particularly if the patient wishes to be at home at the end of life. Intracerebroventricular (ICV) infusion of morphine in the home setting might be presented as an option. The present article reviews the basic and clinical evidence of the efficacy and safety of ICV administration of opioids. Information was gathered from various bibliographic sources, including PubMed and others, and summarized and evaluated to assess the efficacy and safety of ICV opioids for pain relief. Results from ICV infusion of morphine into terminally ill patients refractory to other pain treatments have been reported since the early 1980s. Good efficacy has been achieved for the vast majority of patients, without serious development of analgesic tolerance. There have also been a low incidence of adverse effects, such as constipation and respiratory depression, and a significant retention of alertness associated with this route of administration. Intracerebroventricular infusion of opioid analgesics thus appears to be a safe and effective therapy for the palliative treatment of refractory pain. PMID:22295988

  5. Effects of intracerebroventricularly and intraperitoneally administered growth hormone on body weight and food intake in fa/fa Zucker rats.

    PubMed

    Schulz, Carla; Wieczorek, Ingo; Reschke, Kirsten; Lehnert, Hendrik

    2002-01-01

    Growth hormone (GH) possesses multiple metabolic effects, in particular with regard to glucose and lipid homeostasis. Studies on the effects of GH on body weight and food and water intake are scarce and have yielded controversial results. We investigated the effects of different modes of GH administration on the parameters of body weight and food intake as well as on insulin and leptin concentrations in fa/fa Zucker rats. In control experiments, aqua pro injection was given. GH was administered over a time period of 11 days at a daily dose of 250 microg intraperitoneally (i.p.) and 25 microg intracerebroventricularly (i.c.v.). While both food intake and body weight were found to be unaltered in the four groups after this observation period, there was an enhanced food intake and consecutively an increase in body weight over the day period when compared to the night period in the groups of rats that received GH i.c.v. or i.p. This tendency was also shown for water intake. Insulin and leptin concentrations were similar in all groups. Thus, injection of GH appears to modify food intake-related behavior, since the periods of enhanced food and water intake were shifted from night- to daytime. Thus, while in general the metabolic parameters remained unchanged, the activity pattern was clearly modified.

  6. Improvement in morning hyperglycaemia with basal human ultratard and prandial human actrapid insulin--a comparison of multiple injection regimens.

    PubMed

    Davies, R R; McEwen, J; Moreland, T A; Durnin, C; Newton, R W

    1988-10-01

    Three 'pen'-administered multiple injection regimens have been compared with twice daily insulin injection regimens by means of 24-h profiles of plasma glucose and free insulin concentrations. Ten Type 1 diabetic patients received their usual twice daily insulin regimen and were then randomized to receive the same total daily insulin dose in four divided doses using (1) 50:50 premixed soluble and isophane, (2) 30:70 premixed soluble and isophane, and (3) preprandial soluble and evening crystalline-zinc insulins. Profiles were performed after 1 week on each regimen. Plasma glucose concentrations were similar during the twice daily regimen and the two premixed regimens, rising during the early hours of the morning to a peak between 0900 and 0930 h of 13.8 +/- 2.8 (+/- SD) mmol l-1 on the twice daily regimen, 13.6 +/- 5.3 mmol l-1 on the premixed 50:50 regimen, and 13.5 +/- 4.2 mmol-1 on the premixed 30:70 regimen. With the basal and prandial regimen, overnight plasma glucose concentrations were higher than with the other regimens between 2400 and 0300 h (p less than 0.05). Concentrations then fell until breakfast, and rose after this meal to a peak of 9.5 +/- 4.3 mmol l-1 (p less than 0.01). Mean plasma glucose concentrations were significantly lower than on the other three regimens between 0830 and 1100 h (p less than 0.05). Less variability was observed in 24-h mean plasma glucose concentrations during the basal and prandial regimen than during the other three regimens.

  7. Intracerebroventricular administration of morphine confers remote cardioprotection--role of opioid receptors and calmodulin.

    PubMed

    Zhang, Ye; Irwin, Michael G; Lu, Yao; Mei, Bin; Zuo, You-Mei; Chen, Zhi-Wu; Wong, Tak-Ming

    2011-04-10

    The current study aimed to delineate the mechanism of remote preconditioning by intracerebroventricular morphine (RMPC) against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were given an intracerebroventricular morphine injection before myocardial ischemia and reperfusion injury. Ischemia-reperfusion injury was achieved by 30min of left coronary artery occlusion followed by 120min of reperfusion. The effects of remote preconditioning by intracerebroventricular morphine preconditioning were also determined upon selective blockade of the δ, κ or μ-opioid receptors, or calmodulin (CaM). The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Remote preconditioning by intracerebroventricular morphine reduced infarct size in the ischemic/reperfused myocardium, and the effect was abolished by the selective blockade of any one of the three δ, κ and μ opioid receptors or CaM. Furthermore, remote preconditioning by intracerebroventricular morphine increased the expression of CaM in the hippocampus and the plasma level of calcitonin gene-related peptide (CGRP). The results of the present study provide evidence that the cardioprotection of remote preconditioning by intracerebroventricular morphine involves not only all three types of opioid receptors in the central nervous system, but also CaM, which releases CGRP, one of the mediators of remote preconditioning.

  8. Rotation of the anatomic regions used for insulin injections and day-to-day variability of plasma glucose in type I diabetic subjects.

    PubMed

    Bantle, J P; Weber, M S; Rao, S M; Chattopadhyay, M K; Robertson, R P

    1990-04-04

    Treatment of type I diabetes mellitus is hindered by the often large fluctuations in blood glucose concentration experienced by affected individuals. To determine to what extent day-to-day variation in blood glucose levels can be reduced if insulin is injected in the same anatomic region rather than in different regions using a rotational scheme, as is commonly recommended, 12 type I diabetic subjects were studied. Insulin injections were given in the abdomen for 3 days and rotated among arms, abdomen, and thighs for 3 days using a crossover design with random assignment of treatment order. Blood samples for measurement of plasma glucose levels were obtained at nine scheduled times on each day. Insulin dose, diet, and physical activity were held constant for each subject. During the abdominal injection period, the mean SD of plasma glucose levels and the mean variance of plasma glucose levels were both less at all nine time points than during the rotating injection period. Overall values for the SD of plasma glucose levels were 2.7 +/- 0.2 mmol/L for the abdominal injection period and 3.7 +/- 0.3 mmol/L for the rotating injection period. Overall values for the variance of plasma glucose levels were 9.2 +/- 1.4 mmol2/L2 for the abdominal injection period and 17.4 +/- 2.2 mmol2/L2 for the rotating injection period. We conclude that the common clinical practice of rotating the anatomic regions used for insulin injections increases day-to-day variation in blood glucose concentration. Use of a single anatomic region, eg, the abdomen, for all insulin injections may reduce this variation and allow greater precision in the adjustment of insulin doses.

  9. A problem-solving approach to effective insulin injection for patients at either end of the body mass index.

    PubMed

    Juip, Micki; Fitzner, Karen

    2012-06-01

    People with diabetes require skills and knowledge to adhere to medication regimens and self-manage this complex disease. Effective self-management is contingent upon effective problem solving and decision making. Gaps existed regarding useful approaches to problem solving by individuals with very low and very high body mass index (BMI) who self-administer insulin injections. This article addresses those gaps by presenting findings from a patient survey, a symposium on the topic of problem solving, and recent interviews with diabetes educators to facilitate problem-solving approaches for people with diabetes with high and low BMI who inject insulin and/or other medications. In practice, problem solving involves problem identification, definition, and specification; goal and barrier identification are a prelude to generating a set of potential strategies for problem resolution and applying these strategies to implement a solution. Teaching techniques, such as site rotation and ensuring that people with diabetes use the appropriate equipment, increase confidence with medication adherence. Medication taking is more effective when people with diabetes are equipped with the knowledge, skills, and problem-solving behaviors to effectively self-manage their injections.

  10. Continuous subcutaneous insulin infusion versus multiple daily injections in individuals with type 1 diabetes: a systematic review and meta-analysis.

    PubMed

    Benkhadra, Khalid; Alahdab, Fares; Tamhane, Shrikant U; McCoy, Rozalina G; Prokop, Larry J; Murad, Mohammad Hassan

    2017-01-01

    The relative efficacy of continuous subcutaneous insulin infusion and multiple daily injections in individuals with type 1 diabetes is unclear. We sought to synthesize the existing evidence about the effect of continuous subcutaneous insulin infusion on glycosylated hemoglobin, hypoglycemic events, and time spent in hypoglycemia compared to multiple daily injections. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus from January 2008 through November 2015 for randomized controlled trials that enrolled children or adults with type 1 diabetes. Trials identified in a previous systematic review and published prior to 2008 were also included. We included 25 randomized controlled trials at moderate risk of bias. Meta-analysis showed a significant reduction in glycosylated hemoglobin in patients treated with continuous subcutaneous insulin infusion compared to multiple daily injections (mean difference 0.37; 95 % confidence interval, 0.24-0.51). This effect was demonstrated in both children and adults. There was no significant difference in minor or severe hypoglycemic events. Continuous subcutaneous insulin infusion was associated with lower incidence of nocturnal hypoglycemia. There was no significant difference in the time spent in hypoglycemia. In children and adults with type 1 diabetes and compared to multiple daily injections, continuous subcutaneous insulin infusion is associated with a modest reduction in glycosylated hemoglobin. There was no difference in severe or minor hypoglycemia, but likely a lower incidence of nocturnal hypoglycemia with continuous subcutaneous insulin infusion.

  11. Effectiveness of multiple daily injections or continuous subcutaneous insulin infusion for children with type 1 diabetes mellitus in clinical practice.

    PubMed

    Gong, Chun-Xiu; Wei, Li-Ya; Wu, Di; Cao, Bing-Yan; Meng, Xi; Wang, Lin-Lin

    2014-01-01

    Aims. To determine whether multiple daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII) contributes to better glucose control in children with different type 1 diabetes duration. Methods. Subjects were grouped according to early (≤1 year after disease onset; 1A) or late (1-3 years after onset; 2A) MDIs/CSII treatment initiation. Corresponding control groups (1B, 2B) received insulin injections twice daily. Results. HbA1c levels were consistently lower in group 1A than in group 1B (6 months (T2): 7.37% versus 8.21%; 12 months (T3): 7.61% versus 8.41%; 24/36 months (T4/T5): 7.61% versus 8.72%; all P < 0.05), but were lower in group 2A than in group 2B only at T2 (8.36% versus 9.19%; P = 0.04). Levels were lower in group 1A than in group 2A when disease duration was matched (7.61% versus 8.49%; P < 0.05). Logistic regression revealed no correlation between HbA1c level and MDIs/CSII therapy. HbA1c levels were only negatively related to insulin dosage. Conclusions. Blood glucose control was better in patients receiving MDIs/CSII than in those receiving conventional treatment. Early MDIs/CSII initiation resulted in prolonged maintenance of low HbA1c levels compared with late initiation. MDIs/CSII therapy should be combined with comprehensive management.

  12. Trans and interesterified fat and palm oil during the pregnancy and lactation period inhibit the central anorexigenic action of insulin in adult male rat offspring.

    PubMed

    Bispo, Kenia Pereira; de Oliveira Rodrigues, Letícia; da Silva Soares de Souza, Érica; Mucci, Daniela; Tavares do Carmo, Maria das Graças; de Albuquerque, Kelse Tibau; de Carvalho Sardinha, Fatima Lucia

    2015-01-01

    Palm oil and interesterified fat have been used to replace partially hydrogenated fats, rich in trans isomers, in processed foods. This study investigated whether the maternal consumption of normolipidic diets containing these lipids affects the insulin receptor and Akt/protein kinase B (PKB) contents in the hypothalamus and the hypophagic effect of centrally administered insulin in 3-month-old male offspring. At 90 days, the intracerebroventricular injection of insulin decreased 24-h feeding in control rats but not in the palm, interesterified or trans groups. The palm group exhibited increases in the insulin receptor content of 64 and 69 % compared to the control and trans groups, respectively. However, the quantifications of PKB did not differ significantly across groups. We conclude that the intake of trans fatty acid substitutes during the early perinatal period affects food intake regulation in response to centrally administered insulin in the young adult offspring; however, the underlying mechanisms remain unclear.

  13. Acute stress or systemic insulin injection increases flunitrazepam sensitive-GABAA receptor density in synaptosomes of chick forebrain: Modulation by systemic epinephrine.

    PubMed

    Cid, Mariana Paula; Arce, Augusto; Salvatierra, Nancy Alicia

    2008-03-01

    Interactions between acute stress and systemic insulin and epinephrine on GABAA receptor density in the forebrain were studied. Here, 10 day-old chicks were intraperitoneally injected with insulin, epinephrine or vehicle and then immediately stressed by partial water immersion for 15 min and killed by decapitation. Non-stressed controls were similarly injected, then returned to their rearing boxes for 15 min and then killed. Forebrains were dissected and GABAA receptor density was measured ex vivo in synaptosomes by 3[H]-flunitrazepam binding assay. In non-stressed chicks, insulin at 1.25, 2.50 and 5.00 IU/kg of body weight (non-hypoglycemic doses) increased Bmax by 33, 53 and 44% compared to saline, respectively. A similar increase of 41% was observed in receptor density after stress. However, the insulin effect was not additive to the stress-induced increase suggesting that both effects occur through similar mechanisms. In contrast, epinephrine, at 0.25 and 0.5 mg/kg did not induce any changes in Bmax in non-stressed chicks. Nevertheless, after stress these doses increased the receptor density by about 13 and 27%, respectively. Similarly, the same epinephrine doses co-administered with insulin (2.50 IU/kg), increased the receptor density by about 20% compared to insulin alone. These results suggest that systemic epinephrine, perhaps by evoking central norepinephrine release, modulates the increase in forebrain GABAA receptor binding induced by both insulin and stress.

  14. Knowledge and Self-Reported Practice of Insulin Injection Device Disposal among Diabetes Patients in Gondar Town, Ethiopia: A Cross-Sectional Study

    PubMed Central

    Taye Haile, Kaleab; Melese Birru, Eshetie

    2016-01-01

    Background. Incorrect sharp disposal practices may expose the public to needle-stick injuries. The present study aimed at assessing the knowledge and practice of diabetic patients towards insulin injection device disposal in Gondar town, Ethiopia. Methods. A cross-sectional study was employed on insulin requiring diabetes patients who visited the diabetes clinic at Gondar University Referral Hospital (GURH) from February 1 to March 28, 2016. Frequencies, percentages, and ANOVA (analysis of variance) and Student's t-test were used to analyze variables. Results. About half of the participants (49.5%) had poor knowledge towards safe insulin injection waste disposal. More than two-thirds (80.7%) of respondents had poor practice and 64.3% of respondents did not put insulin needle and lancets into the household garbage. 31% of respondents threw sharps on street when they travel outside. Respondents living in urban areas had a higher mean of knowledge and practice score than those who live in rural area. Conclusions. This study revealed that knowledge and practice of diabetic patients were low towards safe insulin injection waste disposal in study area. Healthcare providers should also be aware of safe disposing system and counsel patients on appropriate disposal of used syringes. PMID:27738637

  15. Hypothalamic differences in expression of genes involved in monoamine synthesis and signaling pathways after insulin injection in chickens from lines selected for high and low body weight.

    PubMed

    Zhang, Wei; Kim, Sungwon; Settlage, Robert; McMahon, Wyatt; Sumners, Lindsay H; Siegel, Paul B; Dorshorst, Benjamin J; Cline, Mark A; Gilbert, Elizabeth R

    2015-04-01

    Long-term selection for juvenile body weight from a common founder population resulted in two divergent chicken lines (low-weight selected line (LWS), high-weight selected line (HWS)) that display distinct food intake and blood glucose responses to exogenous neuropeptides and insulin. The objective of this study was to elucidate putative targets affecting food intake and energy homeostasis by sequencing hypothalamic RNA from LWS and HWS chickens after insulin injection. Ninety-day-old female LWS and HWS chickens were injected with either vehicle or insulin and hypothalamus collected at 1 h postinjection. Through RNA sequencing, a total of 361 differentially expressed genes (DEGs) were identified. There was greater expression of genes, mainly tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase (DDC), and vesicular monoamine transporter (VMAT), involved in serotonin and dopamine biosynthesis and signaling in LWS than in HWS vehicle-injected chickens. In contrast, after insulin injection, these genes were more highly expressed in HWS than in LWS. We identified 90 single nucleotide polymorphisms (SNPs) existing only in the HWS and 121 SNPs specific to LWS and 5119 SNPs close to fixation (with absolute frequency difference ≥0.9). Four were located in genes encoding enzymes associated with serotonergic and dopaminergic pathways, such as DDC, TH, and solute carrier family 18, member 2 (VMAT). These data implicate differences in biogenic amines such as serotonin and dopamine in hypothalamic physiology between the chicken lines, and these differences might be associated with polymorphisms during long-term selection. Changes in serotonergic and dopaminergic signaling pathways in response to insulin injection suggest a role in whole-body energy homeostasis.

  16. Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients

    PubMed Central

    Mader, Julia K.; Birngruber, Thomas; Korsatko, Stefan; Deller, Sigrid; Köhler, Gerd; Boysen, Susanne; Augustin, Thomas; Mautner, Selma I.; Sinner, Frank; Pieber, Thomas R.

    2013-01-01

    OBJECTIVE We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo. RESEARCH DESIGN AND METHODS Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide–negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration. RESULTS The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08). CONCLUSIONS A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system. PMID:23193211

  17. Insulin allergy.

    PubMed

    Ghazavi, Mohammad K; Johnston, Graham A

    2011-01-01

    Insulin reactions occur rarely but are of tremendous clinical importance. The first was reported in 1922 as a callus reaction at the injection site of insufficiently purified bovine insulin. Porcine insulin was subsequently found to be less allergenic than bovine insulin. Increasingly pure insulins have decreased the risk of adverse reactions, and the production of recombinant insulin with the same amino sequence as human insulin saw a large decrease in adverse reactions. Currently, the prevalence of allergic reactions to insulin products appears to be approximately 2%, and less than one-third of these events have been considered related to the insulin itself. Other reactions occur due to the preservatives added to insulin, including zinc, protamine, and meta-cresol. Allergic reactions can be type I or immunoglobulin E-mediated, type III or Arthus, and type IV or delayed-type hypersensitivity reactions. Type I reactions are the most common and can, rarely, cause anaphylaxis. In contrast, type IV reactions can occur after a delay of several days. Investigations include skin prick testing, patch testing, intradermal testing, and occasionally, skin biopsy.

  18. Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat.

    PubMed

    de Almeida, M A; Izquierdo, I

    1988-01-01

    The immediate posttraining intracerebroventricular injection of histamine (1 or 10 ng/rat) facilitated memory both of a stepdown inhibitory avoidance task, and of the habituation of rearing responses to an open field. As previously shown for the avoidance task, the combination of cimetidine (1,000 ng/rat) plus prometazine (1,000 ng/rat), but not each drug on its own, blocked the effect of histamine in the habituation task. The effect of histamine was not shared by the intracerebroventricular administration of the mast cell histamine releaser, 48/80 (0.1 to 100 micrograms/rat). The present findings indicate that the memory facilitatory action of histamine might be general across tasks, and that 48/80-releasable, presumably mast cell, endogenous histamine is probably not involved in memory regulation.

  19. Multiple daily injection of insulin regimen for a 10-month-old infant with type 1 diabetes mellitus and diabetic ketoacidosis

    PubMed Central

    Park, Ji Hyun; Shin, So Young; Shim, Ye Jee; Choi, Jin Hyeok

    2016-01-01

    The incidence of type 1 diabetes is increasing worldwide, and the greatest increase has been observed in very young children under 4 years of age. A case of infantile diabetic ketoacidosis in a 10-month-old male infant was encountered by these authors. The infant's fasting glucose level was 490 mg/dL, his PH was 7.13, his pCO2 was 15 mmHg, and his bicarbonate level was 5.0 mmol/L. The glycosylated hemoglobin level had increased to 9.4%. Ketonuria and glucosuria were detected in the urinalysis. The fasting C-peptide and insulin levels had decreased. The infant was positive for anti-insulin and antiglutamic acid decarboxylase antibodies. Immediately after the infant's admission, fluid therapy and intravenous insulin infusion therapy were started. On the second day of the infant's hospitalization and after fluid therapy, he recovered from his lethargic condition, and his general condition improved. Feeding was started on the third day, and he was fed a formula 5 to 7 times a day and ate rice, vegetables, and lean meat. Due to the frequent feeding, the frequency of rapid-acting insulin injection was increased from 3 times before feeding to 5 times, adjusted according to the feeding frequency. The total dose of insulin that was injected was 0.8–1.1 IU/kg/day, and the infant was discharged on the 12th day of his hospitalization. The case is presented herein with a brief review of the relevant literature. PMID:27462587

  20. Low-cost production of proinsulin in tobacco and lettuce chloroplasts for injectable or oral delivery of functional insulin and C-peptide

    PubMed Central

    Boyhan, Diane; Daniell, Henry

    2012-01-01

    Summary Current treatment for type I diabetes includes delivery of insulin via injection or pump, which is highly invasive and expensive. The production of chloroplast-derived proinsulin should reduce cost and facilitate oral delivery. Therefore, tobacco and lettuce chloroplasts were transformed with the cholera toxin B subunit fused with human proinsulin (A, B, C peptides) containing three furin cleavage sites (CTB-PFx3). Transplastomic lines were confirmed for site-specific integration of transgene and homoplasmy. Old tobacco leaves accumulated proinsulin up to 47% of total leaf protein (TLP). Old lettuce leaves accumulated proinsulin up to 53% TLP. Accumulation was so stable that up to ~40% proinsulin in TLP was observed even in senescent and dried lettuce leaves, facilitating their processing and storage in the field. Based on the yield of only monomers and dimers of proinsulin (3 mg/g leaf, a significant underestimation), with a 50% loss of protein during the purification process, one acre of tobacco could yield up to 20 million daily doses of insulin per year. Proinsulin from tobacco leaves was purified up to 98% using metal affinity chromatography without any His-tag. Furin protease cleaved insulin peptides in vitro. Oral delivery of unprocessed proinsulin bioencapsulated in plant cells or injectable delivery into mice showed reduction in blood glucose levels similar to processed commercial insulin. C-peptide should aid in long-term treatment of diabetic complications including stimulation of nerve and renal functions. Hyper-expression of functional proinsulin and exceptional stability in dehydrated leaves offer a low-cost platform for oral and injectable delivery of cleavable proinsulin. PMID:21143365

  1. Similar insulin secretory response to a gastric inhibitory polypeptide bolus injection at euglycemia in first-degree relatives of patients with type 2 diabetes and control subjects.

    PubMed

    Meier, Juris J; Nauck, Michael A; Siepmann, Nina; Greulich, Michael; Holst, Jens J; Deacon, Carolyn F; Schmidt, Wolfgang E; Gallwitz, Baptist

    2003-12-01

    Insulin secretion following the intravenous infusion of gastric inhibitory polypeptide (GIP) is diminished in patients with type 2 diabetes and at least a subgroup of their first-degree relatives at hyperglycemic clamp conditions. Therefore, we studied the effects of an intravenous bolus administration of GIP at normoglycemic conditions in the fasting state. Ten healthy control subjects were studied with an intravenous bolus administration of placebo, and of 7, 20, and 60 pmol GIP/kg body weight (BW), respectively. Forty-five first-degree relatives of patients with type 2 diabetes and 33 matched control subjects were studied with (1) a 75-g oral glucose tolerance test (OGTT) and (2) an intravenous bolus injection of 20 pmol GIP/kg BW with blood samples drawn over 30 minutes for determination of plasma glucose, insulin, C-peptide, and GIP. Statistical analysis applied repeated-measures analysis of variance (ANOVA) and Duncan's post hoc tests. Insulin secretion was stimulated after the administration of 20 and of 60 pmol GIP/kg BW in the dose-response experiments (P <.0001). GIP administration (20 pmol/kg BW) led to a significant rise of insulin and C-peptide concentrations in the first-degree relatives and control subjects (P <.0001), but there was difference between groups (P =.64 and P =.87, respectively). Also expressed as increments over baseline, no differences were apparent (Delta(insulin), 7.6 +/- 1.2 and 7.6 +/- 1.6 mU/L, P =.99; Delta(C-peptide), 0.35 +/- 0.06 and 0.38 +/- 0.08 ng/mL, P =.75). Integrated insulin and C-peptide responses after GIP administration significantly correlated with the respective insulin and C-peptide responses after glucose ingestion (insulin, r = 0.78, P <.0001; C-peptide, r = 0.35, P =.0015). We conclude that a reduced insulinotropic effect of GIP in first-degree relatives of patients with type 2 diabetes cannot be observed at euglycemia. Therefore, a reduced GIP-induced insulin secretion in patients with type 2 diabetes and

  2. Quantity of glucose transporter and appetite-associated factor mRNA in various tissues after insulin injection in chickens selected for low or high body weight.

    PubMed

    Zhang, Wei; Sumners, Lindsay H; Siegel, Paul B; Cline, Mark A; Gilbert, Elizabeth R

    2013-11-15

    Chickens from lines selected for low (LWS) or high (HWS) body weight differ by 10-fold in body weight at 56 days old with differences in food intake, glucose regulation, and body composition. To evaluate if there are differences in appetite-regulatory factor and glucose transporter (GLUT) mRNA that are accentuated by hypoglycemia, blood glucose was measured, and hypothalamus, liver, pectoralis major, and abdominal fat collected at 90 days of age from female HWS and LWS chickens, and reciprocal crosses, HL and LH, at 60 min after intraperitoneal injection of insulin. Neuropeptide Y (NPY) and receptor (NPYR) subtypes 1 and 5 mRNA were greater in LWS compared with HWS hypothalamus (P < 0.05), but greater in HWS than LWS in fat (P < 0.05). Expression of NPYR2 was greater in LWS than HWS in pectoralis major (P < 0.05). There was greater expression in HWS than LWS for GLUT1 in hypothalamus and liver (P < 0.05), GLUT2 in fat and liver (P < 0.05), and GLUT9 in liver (P < 0.05). Insulin was associated with reduced blood glucose in all populations (P < 0.05) and reduced mRNA of insulin receptor (IR) and GLUT 2 and 3 in liver (P < 0.05). There was heterosis for mRNA, most notably NPYR1 (-78%) and NPYR5 (-81%) in fat and GLUT2 (-70%) in liver. Results suggest that NPY and GLUTs are associated with differences in energy homeostasis in LWS and HWS. Reduced GLUT and IR mRNA after insulin injection suggest a compensatory mechanism to prevent further hypoglycemia.

  3. Safety of Intracerebroventricular Copper Histidine in Adult Rats

    PubMed Central

    Lem, Kristen E.; Brinster, Lauren R.; Tjurmina, Olga; Lizak, Martin; Lal, Simina; Centeno, Jose A.; Liu, Po-Ching; Godwin, Sarah C.; Kaler, Stephen G.

    2007-01-01

    Classical Menkes disease is an X-linked recessive neurodegenerative disorder caused by mutations in a P-type ATPase (ATP7A) that normally delivers copper to the developing central nervous system. Infants with large deletions, or other mutations in ATP7A that incapacitate copper transport to the brain, show poor clinical outcomes and subnormal brain copper despite early subcutaneous copper histidine (CuHis) injections. These findings suggest a need for direct central nervous system approaches in such patients. To begin to evaluate an aggressive but potentially useful new strategy for metabolic improvement of this disorder, we studied the acute and chronic effects of CuHis administered by intracerebroventricular (ICV) injection in healthy adult rats. Magnetic resonance imaging (MRI) after ICV CuHis showed diffuse T1-signal enhancement, indicating wide brain distribution of copper after ICV administration, and implying the utility of this paramagnetic metal as a MRI contrast agent. The maximum tolerated dose (MTD) of CuHis, defined as the highest dose that did not induce overt toxicity, growth retardation, or reduce lifespan, was 0.5 mcg. Animals receiving multiple infusions of this MTD showed increased brain copper concentrations, but no significant differences in activity, behavior, and somatic growth, or brain histology compared to saline-injected controls. Based on estimates of the brain copper deficit in Menkes disease patients, CuHis doses 10-fold lower than the MTD found in this study may restore proper brain copper concentration. Our results suggest that ICV CuHis administration have potential as a novel treatment approach in Menkes disease infants with severe mutations. Future trials of direct CNS copper administration in mouse models of Menkes disease will be informative. PMID:17336116

  4. Injectable supramolecular hydrogel from insulin-loaded triblock PCL-PEG-PCL copolymer and γ-cyclodextrin with sustained-release property.

    PubMed

    Khodaverdi, Elham; Heidari, Zinat; Tabassi, Sayyed A Sajadi; Tafaghodi, Mohsen; Alibolandi, Mona; Tekie, Farnaz Sadat Mirzazadeh; Khameneh, Bahman; Hadizadeh, Farzin

    2015-02-01

    Supramolecular hydrogels formed by cyclodextrins and polymers have been widely investigated as a biocompatible, biodegradable and controllable drug delivery system. In this study, a supramolecular hydrogel based on biodegradable poly(caprolactone)-poly(ethylene glycol)-poly(caprolactone) (PCL-PEG-PCL) triblock copolymers and γ-cyclodextrin (γ-CD) was prepared through inclusion complexation as an injectable, sustained-release vehicle for insulin. The triblock copolymer PCL-PEG-PCL was synthesised by the ring-opening polymerisation method, using microwave irradiation. The polymerisation reaction and the copolymer structures were evaluated by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). The supramolecular hydrogel was prepared in aqueous solution by blending an aqueous γ-CD solution with an aqueous solution of PCL-PEG-PCL triblock copolymer at room temperature. In vitro insulin release through the hydrogel system was studied. The relative surface hydrophobicity of standard and released insulin from the SMGel was estimated using 8-anilino-1-naphthalene sulfonic acid (ANS). Results of (1)HNMR and gel permeation chromatography revealed that microwave irradiation is a simple and reliable method for synthesis of PCL-PEG-PCL copolymer. Gelation occurred within a minute. The supramolecular hydrogel obtained by mixing 10.54% (w/v) γ-CD and 2.5% (w/v) copolymer had an excellent syringeability. Insulin was released up to 80% over a period of 20 days. Insulin kept its initial folding after formulating and releasing from SMGel. A supramolecular hydrogel based on complexation of triblock PCL-PEG-PCL copolymer with γ-cyclodextrin is a suitable system for providing sustained release of therapeutic proteins, with desirable flow behaviour.

  5. Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats.

    PubMed

    Yang, Wenqing; Ma, Jing; Liu, Zheng; Lu, Yongliang; Hu, Bin; Yu, Huarong

    2014-05-01

    Recent evidence indicates that severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease pathology. It has been reported that naringenin (NAR), derived from citrus aurantium, exhibits antioxidant potential and protects the brain against neurodegeneration. The current study was designed to further investigate the protective effect of the NAR on neurodegeneration in a rat model of AD induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ), and to determine whether this neuroprotective effect was associated with brain insulin signaling. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with NAR (25, 50 mg, 100 mg/kg, respectively) for 3 weeks. The ICV-STZ injected rats did not have elevated blood glucose levels. 21 days following ICV-STZ injection, rats treated with NAR had better learning and memory performance in the Morris water maze test compared with rats treated with saline. We demonstrated that NAR increased the mRNA expression of INS and INSR in cerebral cortex and hippocampus. In addition, NAR reversed ICV-STZ induced Tau hyper-phosphorylation in both hippocampus and cerebral cortex through downregulation of glycogen synthase kinase-3β (GSK-3β) activity, a key kinase in the insulin signaling. Brain levels of Abeta, which were elevated in ICV-STZ rats, were significantly reduced in NAR-treated rats via upregulation of insulin degrading enzyme. These effects were mediated by increased insulin and insulin receptors expression in the brain, suggesting that insulin sensitizer agents might have therapeutic efficacy in early AD.

  6. Comparative study on treatment satisfaction and health perception in children and adolescents with type 1 diabetes mellitus on multiple daily injection of insulin, insulin pump and sensor-augmented pump therapy

    PubMed Central

    Hussain, Tara; Akle, Mariette; Nagelkerke, Nico; Deeb, Asma

    2017-01-01

    Objectives: Diabetes management imposes considerable demands on patients. Treatment method used has an impact on treatment satisfaction. We aim to examine the relationship between treatment satisfaction and health perception with the method used for treatment of type 1 diabetes mellitus in children and adolescents. Subjects and method: We have interviewed patients with type 1 diabetes mellitus using questionnaires to assess treatment satisfaction and health perception. Patients were divided into three groups based on treatment used: multiple daily injection, insulin pump and sensor-augmented pump therapy. Comparison of scores was done between the groups. Results: A total of 72 patients were enrolled (36 males). Mean age (standard deviation) was 11.4 (4.4) years and duration of diabetes of 4.9 (3.5) years. Mean (standard deviation) HbA1c was 8.1 (1.2). Median (range) duration of sensor use was 17.7 (3–30) days/month. Mean scale for treatment satisfaction and health perception questions was 25.3, 29.7 and 31.7 and 60, 79.7 and 81 for the multiple daily injection, pump and sensor-augmented pump, respectively (p = 0.00). Significant difference was seen between the multiple daily injection and both other groups. Sensor-augmented pump group scored higher than the pump group. However, the difference was not statistically significant. Duration of sensor use showed no correlation with treatment satisfaction. Conclusion: The method used for diabetes treatment has an impact on patients’ satisfaction and health perception in children and adolescents with type 1 diabetes mellitus. Insulin pump users have a higher treatment satisfaction and better health perception than those on multiple daily injection. Augmenting pump therapy with sensor use adds value to treatment satisfaction without correlation with the duration of the sensors use. PMID:28321303

  7. Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats.

    PubMed

    Haas, Clarissa B; Kalinine, Eduardo; Zimmer, Eduardo R; Hansel, Gisele; Brochier, Andressa W; Oses, Jean P; Portela, Luis V; Muller, Alexandre P

    2016-11-01

    Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze. Insulin increased memory performance in young rats, but not in aged rats. Thus, we searched for cellular and molecular mechanisms that might account for this distinct memory response. In contrast with our expectation, insulin treatment increased the proliferative activity in aged rats, but not in young rats, implying that neurogenesis-related effects do not explain the lack of insulin effects on memory in aged rats. Furthermore, the expression levels of the IR and downstream signaling proteins such as GSK3-β, mTOR, and presynaptic protein synaptophysin were increased in aged rats in response to insulin. Interestingly, insulin treatment increased the expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptors in the hippocampus of young rats, but not of aged rats. Our data therefore indicate that aged rats can have normal IR downstream protein expression but failed to mount a BDNF response after challenge in a spatial memory test. In contrast, young rats showed insulin-mediated TrkB/BDNF response, which paralleled with improved memory performance.

  8. Effects of intracerebroventricular capsaicin on thermoregulatory behavior in the rat.

    PubMed

    Dib, B

    1982-01-01

    To clarify the action of capsaicin on the thermoregulatory system of rat, behavioral and autonomic responses were studied following intracerebroventricular (ICV) injection. Rats were chronically implanted with a lateral cerebral ventricular guide cannula. After the recovery period they were placed in a climatic chamber at ambient temperature (Ta) of 20, 30 or 35 degrees C. In the first series of experiments, they had access to a lever which activated a fan that drew cool outside air into the chamber. After ICV capsaicin (23 micrograms), the rats increased bar-pressing behavior for fresh air at Ta ranging from 20 degrees C to 35 degrees C. In the second series of experiment, the rats had no access to fanning. ICV capsaicin produced a fall in rectal and hypothalamic temperature (Thy) and an increased in cutaneous temperature. These changes depended on Ta. At a Ta of 30 degrees C Thy fell slightly (mean of 0.2 +/- 0.16 degrees C). At a Ta of 20 degrees C Thy fell to a mean of 1 degree C +/- 0.17 degrees C. The conclusion drawn is ICV capsaicin activated behavioral as well as autonomic thermoregulatory heat-loss responses. The effect of capsaicin resembles the effect of local heating of the hypothalamus. However, since hypothalamic temperature decreased the drug may have lowered the thermal set point, or excited directly hypothalamic warm-sensitive neurons.

  9. Central Administration of Galanin Receptor 1 Agonist Boosted Insulin Sensitivity in Adipose Cells of Diabetic Rats

    PubMed Central

    Zhang, Zhenwen; Fang, Penghua; He, Biao; Guo, Lili; Runesson, Johan; Langel, Ülo; Shi, Mingyi; Zhu, Yan; Bo, Ping

    2016-01-01

    Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB)/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats. PMID:27127795

  10. Analysis of Comparison of Patient Preference for Two Insulin Injection Pen Devices in Relation to Patient Dexterity Skills

    PubMed Central

    Antinori-Lent, Kellie J.

    2012-01-01

    Insulin therapy is the cornerstone of medical treatment for many patients with diabetes. Self-administration of this life-saving medication is no longer limited to the traditional vial and syringe. Instead, more and more patients worldwide are using prefilled insulin pen devices. Ease of use, convenience, confidence in dosing accuracy, and improved quality of life are just a few of their advantages. As with any medical technology, safe and proper use is vital. Many studies have examined pen device preference and usability. Until now, no study has included patients with both visual and dexterity impairments. To ensure safe and simple self-administration of insulin for all patients, it is time for the special needs of patients with diabetes to be considered not only during product development, but during postmarketing studies as well. PMID:22920819

  11. Changes in plasma melanocyte-stimulating hormone, ACTH, prolactin, GH, LH, FSH, and thyroid-stimulating hormone in response to injection of sulpiride, thyrotropin-releasing hormone, or vehicle in insulin-sensitive and -insensitive mares.

    PubMed

    Valencia, N Arana; Thompson, D L; Mitcham, P B

    2013-05-01

    Six insulin-sensitive and 6 insulin-insensitive mares were used in a replicated 3 by 3 Latin square design to determine the pituitary hormonal responses (compared with vehicle) to sulpiride and thyrotropin-releasing hormone (TRH), 2 compounds commonly used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. Mares were classified as insulin sensitive or insensitive by their previous glucose responses to direct injection of human recombinant insulin. Treatment days were February 25, 2012, and March 10 and 24, 2012. Treatments were sulpiride (racemic mixture, 0.01 mg/kg BW), TRH (0.002 mg/kg BW), and vehicle (saline, 0.01 mL/kg BW) administered intravenously. Blood samples were collected via jugular catheters at -10, 0, 5, 10, 20, 30, 45, 60, 90, and 120 min relative to treatment injection. Plasma ACTH concentrations were variable and were not affected by treatment or insulin sensitivity category. Plasma melanocyte-stimulating hormone (MSH) concentrations responded (P < 0.01) to both sulpiride and TRH injection and were greater (P < 0.05) in insulin-insensitive mares than in sensitive mares. Plasma prolactin concentrations responded (P < 0.01) to both sulpiride and TRH injection, and the response was greater (P < 0.05) for sulpiride; no effect of insulin sensitivity was observed. Plasma thyroid-stimulating hormone (TSH) concentrations responded (P < 0.01) to TRH injection only and were higher (P < 0.05) in insulin-sensitive mares in almost all time periods. Plasma LH and FSH concentrations varied with time (P < 0.05), particularly in the first week of the experiment, but were not affected by treatment or insulin sensitivity category. Plasma GH concentrations were affected (P < 0.05) only by day of treatment. The greater MSH responses to sulpiride and TRH in insulin-insensitive mares were similar to, but not as exaggerated as, those observed by others for PPID horses. In addition, the reduced TSH concentrations in insulin-insensitive mares are

  12. Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer’s rat model

    PubMed Central

    Guo, Zhangyu; Chen, Yanxing; Mao, Yan-Fang; Zheng, Tingting; Jiang, Yasi; Yan, Yaping; Yin, Xinzhen; Zhang, Baorong

    2017-01-01

    Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer’s disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin. PMID:28382978

  13. 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

  14. Effects of bacterial lipopolysaccharide injection on white blood cell counts, hematological variables, and serum glucose, insulin, and cortisol concentrations in ewes fed low- or high-protein diets.

    PubMed

    Yates, D T; Löest, C A; Ross, T T; Hallford, D M; Carter, B H; Limesand, S W

    2011-12-01

    Bacterial lipopolysaccharide endotoxins (LPS) elicit inflammatory responses reflective of acute bacterial infection. We determined if feeding ewes high-CP (15.5%) or low-CP (8.5%) diets for 10 d altered inflammatory responses to an intravenous bolus of 0 (control), 0.75 (L75), or 1.50 (L150) μg of LPS/kg of BW in a 2 × 3 factorial arrangement of treatments (n = 5/treatment). Rectal temperatures, heart and respiratory rates, blood leukocyte concentrations, and serum cortisol, insulin, and glucose concentrations were measured for 24 h after an LPS bolus (bolus = 0 h). In general, rectal temperatures were greater (P ≤ 0.05) in control ewes fed high CP, but LPS increased (P ≤ 0.05) rectal temperatures in a dose-dependent manner at most times between 2 and 24 h after the bolus. Peak rectal temperatures in L75 and L150 occurred 4 h after the bolus. A monophasic, dose-independent increase (P ≤ 0.023) in serum cortisol occurred from 0.5 to 24 h after the bolus, with peak cortisol at 4 h. Serum insulin was increased (P ≤ 0.016) by LPS in a dose-dependent manner from 4 to 24 h after the bolus. Insulin did not differ between control ewes fed high- and low-CP diets but was greater (P < 0.001) in L75 ewes fed low CP compared with high CP and in L150 ewes fed high CP compared with low CP. Increased insulin was not preceded by increased serum glucose. Total white blood cell concentrations were not affected (P ≥ 0.135) by LPS, but the neutrophil and monocyte fractions of white blood cells were increased (P ≤ 0.047) by LPS at 12 and 24 h and at 24 h after the bolus, respectively, and the lymphocyte fraction was increased (P = 0.037) at 2 h and decreased (P ≤ 0.006) at 12 and 24 h after the bolus. Red blood cell and hemoglobin concentrations and hematocrit (%) were increased (P ≤ 0.022) by LPS at 2 and 4 h after the bolus. Rectal temperatures and serum glucose were greater (P ≤ 0.033) in ewes fed a high-CP diet before LPS injection, but these effects were lost at

  15. Edaravone attenuates intracerebroventricular streptozotocin-induced cognitive impairment in rats.

    PubMed

    Reeta, K H; Singh, Devendra; Gupta, Yogendra K

    2017-02-15

    Alzheimer's disease is a major cause of dementia worldwide. Edaravone, a potent free radical scavenger, is reported to be neuroprotective. The present study was designed to investigate the effect of chronic edaravone administration on intracerebroventricular-streptozotocin (ICV-STZ) induced cognitive impairment in male Wistar rats. Cognitive impairment was developed by single ICV-STZ (3 mg/kg) injection bilaterally on day 1. Edaravone (1, 3 and 10 mg/kg, orally, once daily) was administered for 28 days. Morris water maze and passive avoidance tests were used to assess cognitive functions at baseline and on days 14 and 28. ICV-STZ caused cognitive impairment as evidenced by increased escape latency and decreased time spent in target quadrant in the Morris water maze test and reduced retention latency in the passive avoidance test. STZ caused increase in oxidative stress, cholinesterases, inflammatory cytokines and protein expression of ROCK-II and decrease in protein expression of ChAT. Edaravone ameliorated the STZ-induced cognitive impairment. STZ-induced increase in oxidative stress and increased levels of pro-inflammatory cytokines (TNF-α, IL-1β) were mitigated by edaravone. Edaravone also prevented STZ-induced increased protein expression of ROCK-II. Moreover, edaravone significantly prevented STZ-induced increased activity of cholinesterases in the cortex and hippocampus. The decreased expression of ChAT caused by STZ was brought towards normal by edaravone in the hippocampus. The results thus show that edaravone is protective against STZ-induced cognitive impairment, oxidative stress, cholinergic dysfunction and altered protein expressions. This study thus suggests the potential of edaravone as an adjuvant in the treatment of Alzheimer's disease.

  16. Usability, Participant Acceptance, and Safety of a Prefilled Insulin Injection Device in a 3-Month Observational Survey in Everyday Clinical Practice in Australia

    PubMed Central

    Carter, John; Beilin, Jonathan; Morton, Adam; De Luise, Mario

    2009-01-01

    Background SoloSTAR® (SOL; sanofi-aventis, Paris, France) is a prefilled insulin pen device for the injection of insulin glargine and insulin glulisine. This is the first Australian survey to determine its usability, participant acceptance, and safety in clinical practice. Methods A 3-month, nonrandomized, noncomparative, observational survey in Australia was conducted in individuals with diabetes. Participants were given SOL pens containing glargine, the instruction leaflet, and a toll-free helpline number. Training was offered to all participants. Safety data, including product technical complaints (PTCs), were gathered from ongoing feedback given by the participant or health care professional (HCP) and by independent interviews conducted 6–10 weeks after study start. Results Some 2674 people consented to take part across 93 sites (150 HCPs), and 2029 participated in interviews. Of these, 52.6% had type 1 diabetes, 16.3% had manual dexterity problems, and 15.5% had poor eyesight not corrected by glasses. At the time of interview, 96.8% of participants were still using SOL. None of the eight PTCs reported were due to technical defects; most were related to handling errors. Some 62 participants reported 77 adverse events; none were related to a PTC. The vast majority of participants (95.4%) were “very satisfied” or “satisfied” with using SOL, and 89.7% of the participants had no questions or concerns using SOL on a daily basis. Similar positive findings were reported by participants with manual or dexterity impairments. Conclusions In this survey of everyday clinical practice, SOL had a good safety profile and was very well accepted by participants. PMID:20144398

  17. Effect of intracerebroventricular and intravenous administration of nitric oxide donors on blood pressure and heart rate in anaesthetized rats.

    PubMed Central

    Nurminen, M. L.; Vapaatalo, H.

    1996-01-01

    1. The effects of nitric oxide (NO) releasing substances, sodium nitroprusside, 3-morpholino sydnonimine (SIN-1) and a novel oxatriazole derivative, GEA 3162, on blood pressure and heart rate were studied after peripheral or central administration in anaesthetized normotensive Wistar rats. 2. Given as cumulative intravenous injections, both nitroprusside and GEA 3162 (24-188 nmol kg-1) induced short-lasting and dose-dependent decreases in mean arterial pressure, while SIN-1 decreased blood pressure only slightly even after larger doses (94-3000 nmol kg-1). Heart rate increased concomitantly with the hypotensive effect of the NO-releasing substances. 3. Cumulative intracerebroventricular administration of GEA 3162 (24-188 nmol kg-1) induced a dose-dependent hypotension with slight but insignificant increases in heart rate. In contrast, intracerebroventricular nitroprusside induced little change in blood pressure, while a large dose of SIN-1 (3000 nmol kg-1, i.c.v.) slightly increased mean arterial pressure. However, intracerebroventricular nitroprusside and SIN-1 increased heart rate at doses that did not significantly affect blood pressure. 4. To determine whether the cardiovascular effects of GEA 3162 were attributable to an elevation of cyclic GMP levels, pretreatments with methylene blue, a putative guanylate cyclase inhibitor, were performed. This substance failed to attenuate the cardiovascular effects of peripherally or centrally administered GEA 3162, suggesting that the effects were independent of guanylate cyclase. 5. In conclusion, the centrally administered NO-donor, GEA 3162, induced a dose-dependent. hypotensive response without significant changes in heart rate. Furthermore, intracerebroventricular injections of nitroprusside and SIN-1 increased heart rate without affecting blood pressure. These results suggest that NO released by these drugs may affect central mechanisms involved in cardiovascular regulation independently of cyclic GMP. PMID:8968551

  18. Insulin use in NIDDM.

    PubMed

    Genuth, S

    1990-12-01

    The effects of insulin treatment on the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM) are reviewed herein. Short-term studies indicate variable and partial reduction in excessive hepatic glucose output, decrease in insulin resistance, and enhancement of beta-cell function. These beneficial actions may be due to a decrease in secondary glucose toxicity rather than a direct attack on the primary abnormality. Insulin should be used as initial treatment of new-onset NIDDM in the presence of ketosis, significant diabetes-induced weight loss (despite residual obesity), and severe hyperglycemic symptoms. In diet-failure patients, prospective randomized studies comparing insulin to sulfonylurea treatment show approximately equal glycemic outcomes or a slight advantage to insulin. A key goal of insulin therapy is to normalize the fasting plasma glucose level. In contrast to the conventional use of morning injections of intermediate- and long-acting insulin, preliminary studies suggest potential advantages of administering the same insulins only at bedtime. Obese patients may require several hundred units of insulin daily and still not achieve satisfactory control. In some, addition of a sulfonylurea to insulin may reduce hyperglycemia, the insulin dose, or both. However, long-term benefits from such combination therapy remain to be demonstrated conclusively. Established adverse effects of insulin treatment in NIDDM are hypoglycemia, particularly in the elderly, and weight gain. Self-monitoring of blood glucose can identify patients in whom excessive weight gain is caused by subtle hypoglycemia. Whether insulin causes weight gain by direct effects on appetite or energy utilization remains controversial. A potential adverse effect of insulin has been suggested by epidemiological studies showing associations between hyperinsulinemia or insulin resistance and increased risk for coronary artery disease, stroke, and hypertension. Although potential mechanisms

  19. Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors

    PubMed Central

    2013-01-01

    Background Activation of the tryptophan degrading enzyme indoleamine-2,3-dioxygenase 1 (IDO1) is associated with the development of behavioral signs of depression. Systemic immune challenge induces IDO1 in both the periphery and the brain, leading to increased circulating and brain concentrations of kynurenines. However, whether IDO1 activity within the brain is necessary for the manifestation of depression-like behavior of mice following a central immune challenge remains to be elucidated. Methods We investigated the role of brain IDO1 in mediating depression-like behavior of mice in response to intracerebroventricular injection of saline or lipopolysaccharide (LPS, 10 ng). Results LPS increased the duration of immobility in the tail suspension test and decreased preference for a sucrose solution. These effects were associated with an activation of central but not peripheral IDO1, as LPS increased brain kynurenine but had no effect on plasma concentrations of kynurenine. Interestingly, genetic deletion or pharmacological inhibition of IDO1, using 1-methyl-tryptophan, abrogated the reduction in sucrose preference induced by intracerebroventricular LPS. 1-Methyl-tryptophan also blocked the LPS-induced increase in duration of immobility during the tail suspension test. Conclusions These data indicate that activation of brain IDO1 is sufficient to induce depression-like behaviors of mice in response to central LPS. PMID:23866724

  20. Evaluation of behavioral parameters and mortality in a model of temporal lobe epilepsy induced by intracerebroventricular pilocarpine administration.

    PubMed

    Medina-Ceja, Laura; Pardo-Peña, Kenia; Ventura-Mejía, Consuelo

    2014-06-06

    The pilocarpine model of temporal lobe epilepsy (TLE) is a useful tool that is used to investigate the mechanisms underlying the generation and maintenance of seizures. Although this model has been modified significantly to reduce mortality and to promote the appearance of spontaneous recurrent seizures, to date, no detailed evaluation has been performed of the behavioral parameters and mortality in TLE induced by intracerebroventricular pilocarpine administration; therefore, this was the goal of the present study. A single dose of pilocarpine hydrochloride (2.4 mg in a total volume of 2 µl) was injected into the right lateral brain ventricle of rats; the convulsive behavior was rated using the Racine scale and the mortality was analyzed in these animals. We found that 30-90 min after animals received intracerebroventricular pilocarpine injections, 73% developed status epilepticus (SE) with an activity score of 4/5 on the Racine scale. Moreover, these seizures were associated with the propagation of epileptiform activity to different hippocampal regions. Of the animals that developed SE, spontaneous recurrent seizures were observed in 32.5% at different times after SE induction. A 35% mortality rate was observed, which included animals that died during pilocarpine injection and after SE induction. On the basis of these findings, and given the observed latency between the insult (SE induction by pilocarpine injection) and the manifestation of spontaneous recurrent seizures, we propose that this model is a useful tool for basic biomedical research of SE and TLE.

  1. [Treatment by external insulin pump].

    PubMed

    Clavel, Sylvaine

    2010-12-01

    Since the recent recommendations by the French speaking association for research on diabetes and metabolic illnesses (Alfediam), treatment by insulin pump has found itself in competition with basal-bolus, a procedure using similar injections of insulin which has become a benchmark treatment. The latest Alfediam guidelines focus on defining ways of treating diabetics with an external insulin pump.

  2. Xanthoceraside attenuates learning and memory deficits via improving insulin signaling in STZ-induced AD rats.

    PubMed

    Liu, Peng; Zou, Libo; Jiao, Qing; Chi, Tianyan; Ji, Xuefei; Qi, Yue; Xu, Qian; Wang, Lihua

    2013-05-24

    Xanthoceraside, a triterpenoid saponin extracted from the fruit husks of Xanthoceras sorbifolia Bunge, has been shown to reverse the cognitive deficits observed in several Alzheimer's disease (AD) animal models. Increasing evidence suggests the involvement of the insulin signaling pathway in neurodegenerative disorders such as AD. Thus, we used an AD animal model of cognitive impairment induced by the intracerebroventricular (ICV) injection of streptozotocin (STZ) to test the effects of xanthoceraside on behavioral impairments and insulin signaling mechanisms. In our present study, memory impairment was assessed using the Morris water maze test. The expression of IR, IGF-1R and Raf-1/ERK/CREB was tested by western blotting. The STZ group showed memory deficits in the Morris water maze test and significant decreases in IR and IGF-1R protein levels in the hippocampus. Xanthoceraside treatment significantly rescued memory deficits, as well as IR and IGF-1R protein expression levels. STZ inhibited the Ras/ERK signaling cascade and decreased the phosphorylation of CREB; these effects were also attenuated by xanthoceraside treatment. These results suggest the potential use of xanthoceraside for the treatment of neurodegenerative disorders in which brain insulin signaling may be involved.

  3. Insulin and Insulin Resistance

    PubMed Central

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  4. Safe and Efficacious Use of Automated Bolus Advisors in Individuals Treated With Multiple Daily Insulin Injection (MDI) Therapy: Lessons Learned From the Automated Bolus Advisor Control and Usability Study (ABACUS).

    PubMed

    Parkin, Christopher G; Barnard, Katharine; Hinnen, Deborah A

    2015-03-20

    Numerous studies have shown that use of integrated automated bolus advisors (BAs) provides significant benefits to individuals using insulin pump devices, including improved glycemic control and greater treatment satisfaction. Within the past few years, BA devices have been developed specifically for individuals treated with multiple daily insulin injection (MDI) therapy; however, many clinicians who treat these individuals may be unfamiliar with insulin pump therapy and, thus, BA use. Findings from the Automated Bolus Advisor Control and Usability Study (ABACUS) revealed that BA use can be efficacious and clinically meaningful in MDI therapy, and that most patients are willing and able to use this technology appropriately when adequate clinical support is provided. The purpose of this article is to review key learnings from ABACUS and provide practical advice for initiating BA use and monitoring therapy.

  5. Increase of histidine decarboxylase activity in mice hypothalamus after intracerebroventricular administration of lipopolysaccharide.

    PubMed

    Niimi, M; Mochizuki, T; Cacabelos, R; Yamatodani, A

    1993-10-01

    The effect of intracerebroventricular (icv) administration of lipopolysaccharide on histidine decarboxylase activity and histamine content in the hypothalamus were investigated in male mice of ddY strain in vivo. Two-fold increase in histidine decarboxylase activity (HDC) was observed 4 h after administration of 50 mcg lipopolysaccharide, and HDC activity returned to the basal level within 12 h after injection. Furthermore, histamine contents showed a slight decrease at 1 and 2 h and a mild increase at 12 h after administration. However, changes in histamine content were not statistically significant. These results suggest that the increase of HDC activity in the hypothalamus by lipopolysaccharide may be involved in the central neuroimmune responses.

  6. 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

  7. Intracerebroventricular Streptozotocin as a Model of Alzheimer's Disease: Neurochemical and Behavioral Characterization in Mice.

    PubMed

    Ravelli, Katherine Garcia; Rosário, Barbara Dos Anjos; Camarini, Rosana; Hernandes, Marina Sorrentino; Britto, Luiz Roberto

    2017-04-01

    Streptozotocin has been widely used to mimic some aspects of Alzheimer's disease (AD). However, especially in mice, several characteristics involved in the streptozotocin (STZ)-induced AD pathology are not well known. The main purpose of this study was to evaluate temporally the expression of AD-related proteins, such as amyloid-β (Aβ), choline acetyltransferase (ChAT), synapsin, axonal neurofilaments, and phosphorylated Tau in the hippocampus following intracerebroventricular (icv) administration of STZ in adult mice. We also analyzed the impact of STZ on short- and long-term memory by novel object recognition test. Male mice were injected with STZ or citrate buffer, and AD-related proteins were evaluated by immunoblotting assays in the hippocampus at 7, 14, or 21 days after injection. No differences between the groups were found at 7 days. The majority of AD markers evaluated were found altered at 14 days, i.e., the STZ group showed increased amyloid-β protein and neurofilament expression, increased phosphorylation of Tau protein, and decreased synapsin expression levels compared to controls. Except for synapsin, all of these neurochemical changes were transient and did not last up to 21 days of STZ injection. Moreover, both short-term and long-term memory deficits were demonstrated after STZ treatment at 14 and 21 days after STZ treatment.

  8. Intracerebroventricular Pain Treatment with Analgesic Mixtures including Ziconotide for Intractable Pain.

    PubMed

    Staquet, Héléne; Dupoiron, Denis; Nader, Edmond; Menei, Philippe

    2016-07-01

    Intracerebroventricular (ICV) administration of opioids for control of intractable cancer pain has been used since 1982. We present here our experience of intracerebroventricular administration of pain treatments including ziconotide associated with morphine and ropivacaine for patients resistant to a conventional approach, with nociceptive, neuropathic, or mixed pain. These clinical cases were conducted with patients suffering from refractory pain, more than 6/10 on a numerical pain rating scale (NPRS) while on high-dose medical treatment and/or intolerance with significant side effects from oral medication. The baseline study visit included a physical examination and an assessment of pain intensity on a NPRS. Under general anesthesia, a neuronavigation device was used to place the catheter on the floor of the third ventricle, supported by an endoscope. Then, drugs were injected in the cerebroventricular system, through a pump (external or subcutaneous). The primary objective was to measure pain evaluation with ICV treatment after a complete withdrawal of other medications.Four patients were enrolled: 3 with intractable cancer pain and one with central neuropathic pain. The median NPRS at baseline was 9.5 [8.5; 19]. The mean NPRS after one month was 3.5 [3; 4.5]. Ziconotide was initiated at 0.48 µg/d and up to a median of 1.2 µg/d [1.0; 1.56]. The median dose of morphine and ropivacaine used initially was respectively 0.36 mg/d [0.24; 0.66] up to 0.6 mg/d [0.45; 4.63] and 1.2 mg/d [0; 2.4] up to 2.23 mg/d [1.2; 3.35]. Minor side effects were initially observed but transiently. One psychiatric agitation required discontinuation of ziconotide infusion. For intractable pain, using ziconotide by intracerebroventricular infusion seems safe and efficient, specifically for chronic neoplastic pain of cervicocephalic, thoracic, or diffuse origin and also for pain arising from a central neuropathic mechanism.

  9. Inhaled human insulin.

    PubMed

    Strack, Thomas R

    2006-04-01

    The benefit of subcutaneous insulin therapy in patients with diabetes is frequently limited due to difficulty in convincing patients of the importance of multiple daily insulin injections to cope effectively with meal-associated glycemic changes. Thus, the aim of achieving tight glycemic control, which is critical for reducing the risk of long-term diabetes-related complications, frequently remains elusive. The successful development of an inhalable insulin as a noninvasive alternative promises to change the management of diabetes. The first product to become available to patients is inhaled human insulin, a dry-powder formulation packaged into discrete blisters containing 1 or 3 mg of dry-powder human insulin and administered via a unique pulmonary inhaler device. It has recently been approved in both the United States and the European Union for the control of hyperglycemia in adult patients with type 1 or type 2 diabetes. The pharmacokinetic profile of inhaled human insulin closely mimics the natural pattern of insulin secretion, and resembles that of rapid-acting subcutaneous analogs. Similarly to rapid-acting subcutaneous analogs, inhaled human insulin has a more rapid onset of glucose-lowering activity compared to subcutaneous regular insulin, allowing it to be administered shortly before meals. It has a duration of glucose-lowering activity comparable to subcutaneous regular insulin and longer than rapid-acting insulin analogs. Inhaled human insulin effectively controls postprandial glucose concentrations in patients with type 1 or type 2 diabetes without increasing the risk of hypoglycemia, and even improves fasting glucose levels compared to subcutaneous insulin. Inhaled human insulin has an overall favorable safety profile. There are small reductions in lung function (1-1.5% of total lung forced expiratory volume in the first second [FEV1] capacity) after onset of treatment that are reversible in most patients if treatment is discontinued. Inhaled human

  10. Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats.

    PubMed

    Sil, Susmita; Ghosh, Tusharkanti; Ghosh, Rupsa; Gupta, Pritha

    2017-02-15

    Intracerebroventricular (i.c.v.) injection of colchicine induces neurodegeneration, memory impairments and changes of some systemic immune responses in rats. Though the role of cox 2 in these colchicine induced changes have been evaluated, the influence of nitric oxide synthase (NOS) remains to be studied. The present study was designed to assess the role of NOS on the i.c.v. colchicine induced neurodegeneration, memory impairments and changes of some systemic immune responses by inhibiting its activity with aminoguanidine. In the present study the impairments of working and reference memories, neurodegeneration (chromatolysis and plaque formation) and changes of neuroinflammatory markers in the hippocampus (increased TNF α, IL 1β, ROS and nitrite) along with changes of serum inflammatory markers (TNF α, IL 1β, ROS and nitrite) and alteration of systemic immune responses (higher phagocytic activity of blood WBC and splenic PMN, higher cytotoxicity and lower leukocyte adhesion inhibition index of splenic MNC) were measured in the intracerebroventricular colchicine injected rats (ICIR). Administration of aminoguanidine (p.o. 30/50mg/kg body weight) to ICIR resulted in recovery of neuroinflammation and partial prevention of neurodegeneration which could be corroborated with the partial recovery of memory impairments in this model. The recovery of serum inflammatory markers and the systemic immune responses in ICIR was also observed after administration of aminoguanidine. Therefore, the present study shows that aminoguanidine can protect the colchicine induced neurodegeneration, memory impairments, and changes of systemic immune systemic responses in ICIR by inhibiting the iNOS.

  11. Peripheral and central effects of intracerebroventricular microinjection of Hottentotta gentili (Pallary, 1924) (Scorpiones, Buthidae) venom.

    PubMed

    El Hidan, Moulay Abdelmonaim; Touloun, Oulaid; El Hiba, Omar; Laadraoui, Jawad; Ferehan, Hind; Boumezzough, Ali

    2016-03-01

    Central effects of scorpion venom toxins have been neglected, due both to the common belief that scorpion venoms act by targeting peripheral organs and also to the misunderstanding that these peptides do not cross the brain-blood barrier (BBB). Determining whether scorpion neurotoxicity is restricted to peripheral actions or whether a central mechanism may be partly responsible for systemic manifestations could be crucial in clinical therapy trends. The present study therefore aims to assess histopathological damages in some organs (heart, kidney, liver, and lungs) and the related biochemical impairments, together with a neurobehavioral investigation following an intracerebroventricular (i.c.v) micro-injection of Hottentotta gentili (Scorpiones, Buthidae) venom (0.47 μg/kg). I.c.v. injection of venom produced focal fragmentation of myocardial fibers, while lungs showed rupture of the alveolar structure. Concurrently, there was a significant rise in the serum enzymes levels of ASAT, ALAT, CPK and LDH. Meanwhile, we observed behavioral alterations such as a hypoactivity, and in addition the venom seems to have a marked anxiogenic-like effect. The present investigation has brought new experimental evidence of a peripheral impact of central administration of H. gentili venom, such impact was manifested by physiological and behavioral disturbances, the last of these appearing to reflect profound neuro-modulatory action of H. gentili venom.

  12. Insulin Basics

    MedlinePlus

    ... long insulin continues to lower blood glucose. Insulin Strength All insulins come dissolved or suspended in liquids. The standard and most commonly used strength in the United States today is U-100, ...

  13. Effects of intracerebroventricular administered fluoxetine on cardio-ventilatory functions in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Kermorgant, Marc; Lancien, Frédéric; Mimassi, Nagi; Tyler, Charles R; Le Mével, Jean-Claude

    2014-09-01

    Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor present in the aquatic environment which is known to bioconcentrate in the brains of exposed fish. FLX acts as a disruptor of various neuroendocrine functions in the brain, but nothing is known about the possible consequence of FLX exposure on the cardio-ventilatory system in fish. Here we undertook to investigate the central actions of FLX on ventilatory and cardiovascular function in unanesthetized rainbow trout (Oncorhynchus mykiss). Intracerebroventricular (ICV) injection of FLX (dosed between 5 and 25 μg) resulted in a significantly elevated total ventilation (VTOT), with a maximum hyperventilation of +176% (at a dose of 25μg) compared with vehicle injected controls. This increase was due to an increase in ventilatory amplitude (VAMP: +126%) with minor effects on ventilatory frequency. The highest dose of FLX (25 μg) produced a significant increase in mean dorsal aortic blood pressure (PDA: +20%) without effects on heart rate (ƒH). In comparison, intra-arterial injections of FLX (500-2,500 μg) had no effect on ventilation but the highest doses increased both PDA and ƒH. The ICV and IA cardio-ventilatory effects of FLX were very similar to those previously observed following injections of 5-HT, indicating that FLX probably acts via stimulating endogenous 5-HT activity through inhibition of 5-HT transporter(s). Our results demonstrate for the first time in fish that FLX administered within the brain exerts potent stimulatory effects on ventilation and blood pressure increase. The doses of FLX given to fish in our study are higher than the brain concentrations of FLX in fish that result from acute exposure to FLX through the water. Nonetheless, our results indicate possible disrupting action of long term exposure to FLX discharged into the environment on central target sites sensitive to 5-HT involved in cardio-ventilatory control.

  14. CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5

    PubMed Central

    Chou, Szu-Yi; Ajoy, Reni; Changou, Chun Austin; Hsieh, Ya-Ting; Wang, Yang-Kao; Hoffer, Barry

    2016-01-01

    Many neurodegenerative diseases are accompanied by metabolic disorders. CCL5/RANTES, and its receptor CCR5 are known to contribute to neuronal function as well as to metabolic disorders such as type 2 diabetes mellitus, obesity, atherosclerosis and metabolic changes after HIV infection. Herein, we found that the lack of CCR5 or CCL5 in mice impaired regulation of energy metabolism in hypothalamus. Immunostaining and co-immunoprecipitation revealed the specific expression of CCR5, associated with insulin receptors, in the hypothalamic arcuate nucleus (ARC). Both ex vivo stimulation and in vitro tissue culture studies demonstrated that the activation of insulin, and PI3K-Akt pathways were impaired in CCR5 and CCL5 deficient hypothalamus. The inhibitory phosphorylation of insulin response substrate-1 at Ser302 (IRS-1S302) but not IRS-2, by insulin was markedly increased in CCR5 and CCL5 deficient animals. Elevating CCR5/CCL5 activity induced GLUT4 membrane translocation and reduced phospho-IRS-1S302 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, MetCCL5, abolished the de-phosphorylation of IRS-1S302 and insulin signal activation. In addition, intracerebroventricular delivery of MetCCL5 interrupted hypothalamic insulin signaling and elicited peripheral insulin responsiveness and glucose intolerance. Taken together, our data suggest that CCR5 regulates insulin signaling in hypothalamus which contributes to systemic insulin sensitivity and glucose metabolism. PMID:27898058

  15. CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5.

    PubMed

    Chou, Szu-Yi; Ajoy, Reni; Changou, Chun Austin; Hsieh, Ya-Ting; Wang, Yang-Kao; Hoffer, Barry

    2016-11-29

    Many neurodegenerative diseases are accompanied by metabolic disorders. CCL5/RANTES, and its receptor CCR5 are known to contribute to neuronal function as well as to metabolic disorders such as type 2 diabetes mellitus, obesity, atherosclerosis and metabolic changes after HIV infection. Herein, we found that the lack of CCR5 or CCL5 in mice impaired regulation of energy metabolism in hypothalamus. Immunostaining and co-immunoprecipitation revealed the specific expression of CCR5, associated with insulin receptors, in the hypothalamic arcuate nucleus (ARC). Both ex vivo stimulation and in vitro tissue culture studies demonstrated that the activation of insulin, and PI3K-Akt pathways were impaired in CCR5 and CCL5 deficient hypothalamus. The inhibitory phosphorylation of insulin response substrate-1 at Ser302 (IRS-1(S302)) but not IRS-2, by insulin was markedly increased in CCR5 and CCL5 deficient animals. Elevating CCR5/CCL5 activity induced GLUT4 membrane translocation and reduced phospho-IRS-1(S302) through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, (Met)CCL5, abolished the de-phosphorylation of IRS-1(S302) and insulin signal activation. In addition, intracerebroventricular delivery of (Met)CCL5 interrupted hypothalamic insulin signaling and elicited peripheral insulin responsiveness and glucose intolerance. Taken together, our data suggest that CCR5 regulates insulin signaling in hypothalamus which contributes to systemic insulin sensitivity and glucose metabolism.

  16. Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats.

    PubMed

    Zarrindast, Mohammad-Reza; Rostami, Parvin; Zarei, Morteza; Roohbakhsh, Ali

    2005-11-01

    Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.

  17. Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats.

    PubMed

    Majkutewicz, Irena; Kurowska, Ewelina; Podlacha, Magdalena; Myślińska, Dorota; Grembecka, Beata; Ruciński, Jan; Plucińska, Karolina; Jerzemowska, Grażyna; Wrona, Danuta

    2016-07-15

    Intracerebroventricular (ICV) injection of streptozotocin (STZ) is a widely-accepted animal model of sporadic Alzheimer's disease (sAD). The present study evaluated the ability of dimethyl fumarate (DMF), an agent with antioxidant and anti-inflammatory properties, to prevent spatial memory impairments and hippocampal neurodegeneration mediated by ICV injection of STZ in 4-month-old rats. Rodent chow containing DMF (0.4%) or standard rodent chow was made available on day 0. Rat body weight and food intake were measured daily for whole the experiment (21days). STZ or vehicle (SHAM) ICV injections were performed on days 2 and 4. Spatial reference and working memory were evaluated using the Morris water maze on days 14-21. Cells containing Fluoro-Jade B (neurodegeneration marker), IL-6, IL-10 were quantified in the hippocampus and choline acetyltransferase (ChAT) in the basal forebrain. The disruption of spatial memory and a high density of hippocampal CA1-3 cells labeled with Fluoro-Jade B or containing IL-6 or IL-10 were observed in the STZ group but not in the STZ+DMF group, as compared to the SHAM or SHAM+DMF groups. STZ vs. STZ+DMF differences were found: worse reference memory acquisition, fewer ChAT-positive neurons in the medial septum (Ch1), more Fluoro-Jade-positive CA1 hippocampal cells in STZ rats. DMF therapy in a rodent model of sAD prevented the disruption of spatial reference and working memory, loss of Ch1 cholinergic cells and hippocampal neurodegeneration as well as the induction of IL-6 and IL-10 in CA1. These beneficial cognitive and molecular effects validate the anti-inflammatory and neuroprotective properties of DMF in the hippocampus.

  18. 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

  19. A randomized controlled trial of liraglutide versus insulin detemir plus sitagliptin: Effective switch from intensive insulin therapy to the once-daily injection in patients with well-controlled type 2 diabetes.

    PubMed

    Inoue, Yuichiro; Nakamura, Akinobu; Kondo, Yoshinobu; Hamano, Kumiko; Satoh, Shinobu; Terauchi, Yasuo

    2015-07-01

    This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA1c ] ≤ 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA1c change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA1c from baseline were 0.1% ± 0.9% versus 0.3% ± 0.8% in the liraglutide versus detemir groups, respectively (P = .46). The "overall" satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 ± 7.4 to 29.9 ± 5.3 (P < .001) and from 26.4 ± 6.1 to 28.3 ± 6.4 (P = .12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA1c between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control.

  20. Intracerebroventricular infusions of TNF-alpha preferentially recruit blood lymphocytes and induce a perivascular leukocyte infiltrate.

    PubMed

    Seabrook, T J; Hay, J B

    2001-02-01

    Tumour necrosis factor (TNF)-alpha is important in several central nervous system (CNS) inflammatory diseases, however, its role in the recruitment of leukocytes into the cerebral spinal fluid (CSF) and CNS is incompletely understood. Therefore, we examined the effect of intracerebroventricular (icv) and parenchymal infusions of TNF-alpha on the type of leukocyte, the pool and subset of lymphocytes recruited into CSF and brain parenchyma. Parenchymal injections of 500 ng of recombinant human TNF-alpha did not induce inflammation, whereas an icv infusion of TNF-alpha caused CSF leuckocytosis and a perivascular infiltrate. Twenty-four hours after the icv infusion neutrophils predominated, with CD4+ T cells being the major lymphocyte subset in CSF. By 48 h lymphocytes were the dominant cell type with CD8+ cells surpassing CD4+ cells in both the CSF and the perivascular infiltrate. The labeled recirculating lymphocyte pool prevailed in normal CSF, but after the infusion of TNF-alpha, the blood pool of lymphocytes was preferentially recruited. These results have implications for the immune surveillance of the CNS.

  1. Cervical lymph cannulation to investigate the efflux and effects of intracerebroventricular cytokine infusions.

    PubMed

    Seabrook, T J; Dickstein, J B; Hay, J B

    2001-02-01

    It is well documented that there is communication between the cerebral spinal fluid (CSF) and cervical lymphatics. Recently, it has been demonstrated that tumor necrosis factor alpha (TNF-alpha) introduced into the CSF appears in the cervical lymph. However, the functional significance of this is less clear. Here we describe a protocol to quantitate the efflux of TNF-alpha from the CSF into cervical lymph. In addition, we describe a methodology to examine the effects of an intracerebroventricular (i.c.v.) infusion of TNF-alpha on lymph volume, cellularity and cell phenotype. While TNF-alpha was recovered in the cervical lymph following infusion of 125-I labeled TNF-alpha, the dosage of TNF-alpha used in this study had no effect on cervical lymph flow, cellularity or cell subsets. This protocol can be used to study the efflux of i.c.v. injected macromolecules and their effects on lymphocytes in cervical lymph and the regional lymph nodes.

  2. Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex.

    PubMed

    Sui, Li; Song, Xiao-Jin; Ren, Jie; Ju, Li-Hua; Wang, Yan

    2013-08-01

    Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 μl of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which did not be affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

  3. Insulin signaling and insulin resistance.

    PubMed

    Beale, Elmus G

    2013-01-01

    Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (eg, hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke, and kidney failure). It is thus important to understand those factors that affect insulin sensitivity. This review stems from the surprising discovery that interference with angiotensin signaling improves insulin sensitivity, and it provides a general overview of insulin action and factors that control insulin sensitivity.

  4. Insulin therapy in children and adolescents.

    PubMed

    Tamborlane, William V; Sikes, Kristin A

    2012-03-01

    Insulin therapy is the mainstay of treatment in children and adolescents with type 1 diabetes (T1D) and is a key component in the treatment of type 2 diabetes (T2D) in this population as well. A major aim of current insulin replacement therapy is to simulate the normal pattern of insulin secretion as closely as possible. This aim can best be achieved with basal-bolus therapy using multiple daily injections (MDI) or continuous insulin infusion (CSII) pump therapy. Only a few years ago, options for insulin formulations were limited. There are now more than 10 varieties of biosynthetic human and analogue insulin.

  5. Food and water intake suppression by intracerebroventricular administration of substance P in food- and water-deprived rats.

    PubMed

    Dib, B

    1999-05-29

    The purpose of this present experiment was to determine the effect of substance P (SP) on the feeding and drinking behavior. This was investigated in male rats totally food and water deprived for a period of 24 h. The intracerebroventricular (i.c.v.) administration of SP (20 microg 10 microl-1 rat-1) suppressed food and water intakes during the 8 h following administration. At 24 h after i.c.v. injection of SP, the rats were not recovered 10.5% of their feeding and 24.9% of their drinking behavior. However, contrary to what happened with SP, i.c.v. injection of the vehicle of SP did not suppress feeding and drinking behavior, as was observed also in the rats (second control) cannulated i.c.v. but which did not receive any injection. At 48 h after SP injection, no alteration of food and water intakes was observed. These results indicated that SP may function as an endogenous anorexigenic peptide.

  6. Intracerebroventricular administration of corticotropin-releasing factor antagonist attenuates arousal response accompanied by yawning behavior in rats.

    PubMed

    Kita, Ichiro; Kubota, Natsuko; Yanagita, Shinya; Motoki, Chiharu

    2008-03-15

    We have reported that an arousal response accompanied by yawning behavior can be evoked by electrical and chemical stimulation of the hypothalamic paraventricular nucleus (PVN) in rats, although the mechanism responsible for the arousal response accompanied by yawning evoked by PVN stimulation is still unknown. In the present study, we examined the involvement of corticotropin-releasing factor (CRF) in the arousal response during yawning induced by electrical stimulation of the PVN in anesthetized, spontaneous breathing rats using intracerebroventricular (icv) injection of alpha-helical CRF, a CRF antagonist (4.2 microg, lateral ventricle). The electrocorticogram (ECoG) was recorded to evaluate arousal responses during yawning. Fast Fourier transform was used to obtain the power spectrum in delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-20 Hz) bands. We also recorded the intercostal electromyogram as an index of inspiratory activity and blood pressure (BP) as an index of autonomic function to evaluate yawning response. PVN stimulation induced significant increases in relative powers of theta, alpha, and beta bands, but not delta band, concurrent with yawning events regardless of icv injection, though the relative powers after icv injection of alpha-helical CRF were significantly lower than those after saline injection. These findings suggest that CRF neurons in the PVN are primarily responsible for the arousal response accompanied by yawning behavior.

  7. [Machanism of the stimulatory effect of intracerebroventricular administration of histamine on gastatric acid secretion induced by pentagastrin in rats].

    PubMed

    Zhang, J; Wang, Z L; Lu, G Q

    1997-08-01

    The present experiment was designed to study the mechanism underlying the stimulatory effect of histamine (HA, i.c.v.) on the gastric acid secretion in subdiaphragmatic vagotomized SD rats. Gastric acid was continuously washed out with 37 degrees C saline by a perfusion pump. Drugs were injected into the third ventricle or the vein to examine the effect on gastric acid secretion and the level of plasma corticosterone. The results are as follows: (1) HA (1.0 microgram, i.c.v.) potentiated gastric acid secretion induced by G-5, which could be abolished by preintramuscular injection of diphenhydramine hydrochloride (8.0 micrograms). (2) Corticotropin-releasing factor (CRF) (0.5 microgram, 1.0 microgram, i.c.v.) augmented gastric acid secretion in a dose dependent manner. (3) HA (1.0 microgram, i.c.v.) increased the plasma corticosterone level. (4) Intravenous injection of corticosterone 21-sulfale (15, 30 micrograms) augmented gastric acid secretion in a dose dependent manner. These results suggested that intracerebroventricular injection of HA could stimulate the release of CRF by specificably binding with H1 receptor in some areas of hypothalamus, which, in turn, increased gastric acid secretion induced by G-5 via increasing the level of plasma corticosterone.

  8. Neuroprotective effect of ebselen against intracerebroventricular streptozotocin-induced neuronal apoptosis and oxidative stress in rats.

    PubMed

    Unsal, Cuneyt; Oran, Mustafa; Albayrak, Yakup; Aktas, Cevat; Erboga, Mustafa; Topcu, Birol; Uygur, Ramazan; Tulubas, Feti; Yanartas, Omer; Ates, Ozkan; Ozen, Oguz Aslan

    2016-04-01

    The goal of this study was to examine the neuroprotective effect of ebselen against intracerebroventricular streptozotocin (ICV-STZ)-induced oxidative stress and neuronal apoptosis in rat brain. A total of 30 adult male Sprague-Dawley rats were randomly divided into 3 groups of 10 animals each: control, ICV-STZ, and ICV-STZ treated with ebselen. The ICV-STZ group rats were injected bilaterally with ICV-STZ (3 mg/kg) on days 1 and 3, and ebselen (10 mg/kg/day) was administered for 14 days starting from 1st day of ICV-STZ injection to day 14. Rats were killed at the end of the study and brain tissues were removed for biochemical and histopathological investigation. Our results demonstrated, for the first time, the neuroprotective effect of ebselen on Alzheimer's disease (AD) model in rats. Our present study, in ICV-STZ group, showed significant increase in tissue malondialdehyde levels and significant decrease in enzymatic antioxidants superoxide dismutase and glutathione peroxidase in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that ebselen markedly reduced the ICV-STZ-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The number of apoptotic neurons was increased in frontal cortex tissue after ICV-STZ administration. Treatment of ebselen markedly reduced the number of degenerating apoptotic neurons. The study demonstrates the effectiveness of ebselen, as a powerful antioxidant, in preventing the oxidative damage and morphological changes caused by ICV-STZ in rats. Thus, ebselen may have a therapeutic value for the treatment of AD.

  9. Protamine-containing insulin but not analog insulin and duration of insulin use are risk factors for the production of insulin autoantibodies in insulin-treated patients with diabetes mellitus.

    PubMed

    Nishimura, Hidenao; Iizuka, Katsumi; Takeda, Jun

    2014-01-01

    Insulin autoantibodies can be produced by insulin injections but rarely cause severe side effects such as glucose instability and insulin allergy. We study the characteristics of insulin autoantibody-positive diabetic patients with a medical history of insulin therapy using single and multiple (adjusted for age, sex, type of diabetes) logistic regression analyses. Associations between insulin autoantibodies and age, sex, type of diabetes, HbA1c, and serum creatinine were not significant, but the association between insulin autoantibodies and duration of insulin use was significant. Unadjusted and adjusted odds ratios were 1.08 (1.02-1.14) and 1.07 (1.01-1.14), respectively. Unadjusted and adjusted odds ratios for protamine-containing insulin were 3.08 (1.49-6.34) and 4.27 (1.90-9.58), respectively. The adjusted odds ratios for premixed biphasic insulin and intermediate-acting insulin were 2.21 (1.03-4.73) and 2.35 (1.01-5.49), respectively. Associations between insulin autoantibodies and any insulin analog were not significant. These results suggest that protamine-containing insulin and duration of insulin use are risk factors for the production of insulin autoantibodies. If patients with poorly controlled diabetes have a history of protamine-containing insulin therapy over a long time, the appearance of insulin autoantibodies should be monitored.

  10. A Comparison of the Anorexic Effects of Chicken, Porcine, Human and Bovine Insulin on the Central Nervous System of Chicks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of the present study was to determine if some naturally-occurring substitutions of amino acid residues of insulin could act differentially within the central nervous system (CNS) of neonatal chicks to control ingestive behavior. Intracerebroventricular (ICV) administration of chicken insuli...

  11. Insulin Test

    MedlinePlus

    ... ovarian syndrome (PCOS) , prediabetes or heart disease , or metabolic syndrome . A health practitioner also may order insulin and ... such as appears in type 2 diabetes and metabolic syndrome Decreased insulin levels are seen with: Diabetes Hypopituitarism ...

  12. Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12‐month data from the OpT2mise randomized trial

    PubMed Central

    Reznik, Y.; Conget, I.; Castañeda, J. A.; Runzis, S.; Lee, S. W.; Cohen, O.

    2016-01-01

    Aims To compare insulin pump therapy and multiple daily injections (MDI) in patients with type 2 diabetes receiving basal and prandial insulin analogues. Methods After a 2‐month dose‐optimization period, 331 patients with glycated haemoglobin (HbA1c) levels ≥8.0% and ≤12% were randomized to pump therapy or continued MDI for 6 months [randomization phase (RP)]. The MDI group was subsequently switched to pump therapy during a 6‐month continuation phase (CP). The primary endpoint was the between‐group difference in change in mean HbA1c from baseline to the end of the RP. Results The mean HbA1c at baseline was 9% in both groups. At the end of the RP, the reduction in HbA1c was significantly greater with pump therapy than with MDI (−1.1 ± 1.2% vs −0.4 ± 1.1%; p < 0.001). The pump therapy group maintained this improvement to 12 months while the MDI group, which was switched to pump therapy, showed a 0.8% reduction: the final HbA1c level was identical in both arms. In the RP, total daily insulin dose (TDD) was 20.4% lower with pump therapy than with MDI and remained stable in the CP. The MDI–pump group showed a 19% decline in TDD, such that by 12 months TDD was equivalent in both groups. There were no differences in weight gain or ketoacidosis between groups. In the CP, one patient in each group experienced severe hypoglycaemia. Conclusions Pump therapy has a sustained durable effect on glycaemic control in uncontrolled type 2 diabetes. PMID:26854123

  13. Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

    PubMed Central

    Su, Chih-Ting

    2016-01-01

    Summary Insulin antibodies (IA) associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA) found in insulin autoimmune syndrome (IAS), which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%), high insulin concentration (111.9 IU/mL) and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly. Learning points: Insulin autoimmune syndrome (IAS) or IAS-like situation should be one of the differential diagnosis in patients with hyperinsulinemic hypoglycemia. Although less reported, insulin antibodies (IA) caused by exogenous insulin analog should be considered as the cause of hypoglycemia. Patients with suspected insulin autoimmune syndrome (IAS) should be screened for drugs related to autoimmunity to endogenous insulin. PMID:27933175

  14. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    PubMed

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K

    1991-07-01

    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  15. Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats.

    PubMed

    Naik, Bhagyashree; Nirwane, Abhijit; Majumdar, Anuradha

    2017-02-01

    There is strong evidence that mitochondrial dysfunction mediated oxidative stress results in aging and energy metabolism deficits thus playing a prime role in pathogenesis of Alzheimer's disease, neuronal death and cognitive dysfunction. Evidences accrued in empirical studies suggest the antioxidant, anticancer and anti-inflammatory activities of the phytochemical pterostilbene (PTS). PTS also exhibits favourable pharmacokinetic attributes compared to other stilbenes. Hence, in the present study, we explored the neuroprotective role of PTS in ameliorating the intracerebroventricular administered streptozotocin (STZ) induced memory decline in rats. PTS at doses of 10, 30 and 50 mg/kg, was administered orally to STZ administered Sprague-Dawley (SD) rats. The learning and memory tests, Morris water maze test and novel object recognition test were performed which revealed improved cognition on PTS treatment. Further, there was an overall improvement in brain antioxidant parameters like elevated catalase and superoxide dismutase activities, GSH levels, lowered levels of nitrites, lipid peroxides and carbonylated proteins. There was improved cholinergic transmission as evident by decreased acetylcholinesterase activities. The action of ATPases (Na(+) K(+), Ca(2+) and Mg(2+)) indicating the maintenance of cell membrane potential was also augmented. mRNA expression of battery of genes involved in cellular mitochondrial biogenesis and inflammation showed variations which extrapolate to hike in mitochondrial biogenesis and abated inflammation. The histological findings corroborated the effective role of PTS in countering STZ induced structural aberrations in brain.

  16. Intracerebroventricular D-galactose administration impairs memory and alters activity and expression of acetylcholinesterase in the rat.

    PubMed

    Rodrigues, André Felipe; Biasibetti, Helena; Zanotto, Bruna Stela; Sanches, Eduardo Farias; Pierozan, Paula; Schmitz, Felipe; Parisi, Mariana Migliorini; Barbé-Tuana, Florencia; Netto, Carlos Alexandre; Wyse, Angela T S

    2016-05-01

    Tissue accumulation of galactose is a hallmark in classical galactosemia. Cognitive deficit is a symptom of this disease which is poorly understood. The aim of this study was to investigate the effects of intracerebroventricular administration of galactose on memory (inhibitory avoidance and novel object recognition tasks) of adult rats. We also investigated the effects of galactose on acetylcholinesterase (AChE) activity, immunocontent and gene expression in hippocampus and cerebral cortex. Wistar rats received a single injection of galactose (4mM) or saline (control). For behavioral parameters, galactose was injected 1h or 24h previously to the testing. For biochemical assessment, animals were decapitated 1h, 3h or 24h after galactose or saline injection; hippocampus and cerebral cortex were dissected. Results showed that galactose impairs the memory formation process in aversive memory (inhibitory avoidance task) and recognition memory (novel object recognition task) in rats. The activity of AChE was increased, whereas the gene expression of this enzyme was decreased in hippocampus, but not in cerebral cortex. These findings suggest that these changes in AChE may, at least in part, to lead to memory impairment caused by galactose. Taken together, our results can help understand the etiopathology of classical galactosemia.

  17. Prototype micropump for insulin administration based on electrochemical bubble formation.

    PubMed

    Kabata, Ayumi; Okamura, Kentaro; Suzuki, Hiroaki; Kishigami, Yasuhiro; Kikuchi, Mariko; Haga, Makoto

    2008-11-01

    As part of the development of a percutaneous artificial pancreas islet, an insulin injection micropump was fabricated using micromachine techniques. The major components of the device were a thin-film, two-electrode system incorporated in a closed compartment, a silicone rubber diaphragm to separate an electrolyte solution from an insulin solution, a reservoir for insulin and a microneedle attached to the outlet. Hydrogen bubbles were formed on a platinum working electrode when current was applied. This caused the diaphragm to deform and to exert pressure on the insulin solution in the reservoir on the other side of the diaphragm. The injection of insulin was smooth and the injection rate could be controlled by the electrode potential or current. When the insulin solution was injected into streptozotocin-induced diabetic rats, a decrease in plasma glucose level (PGL) was observed which was dependent on the dose of insulin. No substantial difference was observed compared to manual injection.

  18. Effects of intracerebroventricular histamine injection on circadian activity phase entrainment during rapid illumination changes.

    PubMed

    Itowi, N; Yamatodani, A; Mochizuki, T; Wada, H

    1991-02-11

    Histamine is reported to have different effects on shifting the circadian activity phase depending on its circadian administration time (CT). The delay-sensitive period is CT 12-15, and the advance-sensitive period is CT 0-3. The activity phase of rats was entrained by a new light-dark cycle within a week in groups treated with either saline or i.c.v. histamine at CT 12-15. However, on treatment at CT 0-3 the activity phase of the group treated with histamine was entrained by the new light-dark cycle in half the period required for entrainment in the control group.

  19. Mechanism of renal effects of intracerebroventricular histamine in rabbits.

    PubMed

    Kook, Y J; Kim, K K; Yang, D K; Ahn, D S; Choi, B K

    1988-01-01

    Histamine, when given intracerebroventricularly (i.c.v.), has been reported to produce antidiuresis in the rabbit. In this study it was attempted to elucidate the mechanism involved in the effect. Histamine (H), 100 micrograms/kg i.c.v., produced antidiuresis with decreases in renal plasma flow and glomerular filtration rate in urethane-anesthetized rabbits. With larger doses, a tendency towards increased electrolyte excretion was noted in spite of decreased filtration. In the denervated kidney, marked diuresis and natriuresis were observed following i.c.v. H, whereas the contralateral innervated kidney responded with typical antidiuresis. Reserpinized rabbits also responded with marked natriuresis to i.c.v. H. Diphenhydramine (D), 250 micrograms/kg i.c.v., increased urine flow rate, sodium and potassium excretion, along with increase in renal perfusion. With 750 micrograms/kg i.c.v., marked natriuresis was observed in spite of decreased filtration. When H was given after D (250 micrograms/kg) the antidiuresis was completely abolished, and diuresis became more prominent. Cimetidine, 250 micrograms/kg i.c.v., elicited antidiuresis with decreases in renal hemodynamics, the pretreatment with cimetidine did not influence the antidiuresis by H and no natriuresis was noted. The present study suggests that histamine, given i.c.v., influences renal function in dual ways, i.e., antidiuresis by increasing the sympathetic tone to the kidney and diuresis due to some humoral natriuretic factor, the latter becoming apparent only when the former influence has been removed, and further suggests that H1-receptors might be involved in the nerve-mediated antidiuresis, whereas H2-receptors might mediate the humorally induced natriuresis and diuresis.

  20. 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

  1. Insulin-loaded microcapsules for in vivo delivery.

    PubMed

    Kim, Byung Soo; Oh, Jae Min; Hyun, Hoon; Kim, Kyung Sook; Lee, Sang Hyo; Kim, Yu Han; Park, Kinam; Lee, Hai Bang; Kim, Moon Suk

    2009-01-01

    Microencapsulation of insulin has been difficult, due to the high sensitivity of insulin to the harsh conditions that can occur during the microencapsulation process. We have developed a method of preparing insulin-loaded microcapsules by using a monoaxial ultrasonic atomizer to form microdroplets of insulin in aqueous solution surrounded by poly(lactic-co-glycolic acid) (PLGA) solution. Administration of these insulin-loaded microcapsules to type 1 diabetic rats maintained plasma insulin concentrations for 30 days, due to the sustained insulin release properties of the microcapsules. In contrast, plasma insulin concentrations after subcutaneous injection of insulin solution reached near zero levels within 2 days. Insulin solution showed only an immediate pharmacological effect, with no reduction of glycemia after 3 days, whereas insulin-loaded microcapsules maintained blood glucose levels at 100-200 mg/dL for 55 days. Molecular imaging using fluorescein isothiocyanate (FITC)-insulin-loaded microcapsules showed in vivo sustained release of the FITC-insulin in microcapsules. Using insulin-loaded microcapsules, we observed inflammation only immediately after injection, indicating that the rats adapted to long-term insulin release. In conclusion, insulin-loaded microcapsules may reduce nonrepetitive insulin administration and show sustained pharmacological performance.

  2. Influence of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist (WIN 55,212-2) and inverse agonist (AM 251) on the regulation of food intake and hypothalamic serotonin levels.

    PubMed

    Merroun, Ikram; Errami, Mohammed; Hoddah, Hanaa; Urbano, Gloria; Porres, Jesús M; Aranda, Pilar; Llopis, Juan; López-Jurado, María

    2009-05-01

    The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicle-injected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0.5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected.

  3. Intracerebroventricular streptozotocin exacerbates Alzheimer-like changes of 3xTg-AD mice.

    PubMed

    Chen, Yanxing; Liang, Zhihou; Tian, Zhu; Blanchard, Julie; Dai, Chun-Ling; Chalbot, Sonia; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2014-02-01

    Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3-6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase in tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease in synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.

  4. Pramlintide Injection

    MedlinePlus

    ... is used with mealtime insulin to control blood sugar levels in people who have diabetes. Pramlintide is only used to treat patients whose blood sugar could not be controlled by insulin or insulin ...

  5. Insulin effects on honeybee appetitive behaviour.

    PubMed

    Mengoni Goñalons, Carolina; Guiraud, Marie; de Brito Sanchez, María Gabriela; Farina, Walter M

    2016-10-01

    Worker honeybees (Apis mellifera) carry out multiple tasks throughout their adult lifespan. It has been suggested that the insulin/insulin-like signalling pathway participates in regulating behavioural maturation in eusocial insects. Insulin signalling increases as the honeybee worker transitions from nurse to food processor to forager. As behavioural shifts require differential usage of sensory modalities, our aim was to assess insulin effects on olfactory and gustatory responsiveness as well as on olfactory learning in preforaging honeybee workers of different ages. Adults were reared in the laboratory or in the hive. Immediately after being injected with insulin or vehicle (control), and focusing on the proboscis extension response, bees were tested for their spontaneous response to odours, sucrose responsiveness and ability to discriminate odours through olfactory conditioning. Bees injected with insulin have higher spontaneous odour responses. Sucrose responsiveness and odour discrimination are differentially affected by treatment according to age: whereas insulin increases gustatory responsiveness and diminishes learning abilities of younger workers, it has the opposite effect on older bees. In summary, insulin can improve chemosensory responsiveness in young workers, but also worsens their learning abilities to discriminate odours. The insulin signalling pathway is responsive in young workers, although they are not yet initiating outdoor activities. Our results show strong age-dependent effects of insulin on appetitive behaviour, which uncover differences in insulin signalling regulation throughout the honeybee worker's adulthood.

  6. Tocilizumab's effect on cognitive deficits induced by intracerebroventricular administration of streptozotocin in Alzheimer's model.

    PubMed

    Elcioğlu, H Kübra; Aslan, Ersin; Ahmad, Sarfraz; Alan, Saadet; Salva, Emine; Elcioglu, Ö Haluk; Kabasakal, Levent

    2016-09-01

    Neuroinflammation plays pivotal roles in the pathogenesis of Alzheimer's disease (AD). IL-6 is pleiotropic cytokine which plays significant pathological role in inflammatory diseases and causes prolonged inflammation. Additionally, IL-6 activates microglia cells and enhances the accumulation of amyloid-β peptides. Moreover, IL-6 signal transduction is mediated by membrane-bound and soluble IL-6 receptors. Tocilizumab which is a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody binds to both of these receptors and inhibits IL-6 signaling by this route. The objective was to investigate tocilizumab's potential effects in the treatment of AD. Male Sprague-Dawley rats were divided into three groups: sham (control), streptozotocin (STZ), and tocilizumab-STZ. We used a single dose of intracerebroventricular (ICV) tocilizumab, beginning 1 h prior to injection of STZ for 3 weeks. The rats in STZ and tocilizumab-STZ groups were given ICV-STZ (3 mg/kg). Behavioral parameters were evaluated on days 17-20 and the rats were sacrificed on day-21 to examine histopathological changes. STZ injection caused significant decrease in the mean escape latency in passive avoidance and also declined the performance improvement in Morris water maze tests. Tocilizumab-STZ group significantly improved learning and spatial memory functions by increasing RLT in the passive avoidance and by shortening escape latency in reaching the platform in the Morris water maze. Histopathological changes were examined using hematoxylin and eosin and immunohistochemical (IHC) stainings. IHC analysis revealed that while protein expressions of amyloid-ß (3.5 ± 0.2) and IL-6 (2.9 ± 0.4) showed intense immune-positivity in STZ group, amyloid-ß (1.3 ± 0.1) and IL-6 (1.5 ± 0.2) immunoreactivities were substantially decreased in tocilizumab treatment group. We conclude that tocilizumab treatment attenuated significantly STZ-induced cognitive impairment and histopathological changes

  7. Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

    PubMed Central

    Vora, J. P.; Owens, D. R.; Dolben, J.; Atiea, J. A.; Dean, J. D.; Kang, S.; Burch, A.; Brange, J.

    1988-01-01

    OBJECTIVE--To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. DESIGN--Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. SETTING--Study in normal people at a diabetes research unit and a university department of medical physics. SUBJECTS--Seven healthy male volunteers aged 20-39 not receiving any other drugs. INTERVENTIONS--After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. END POINT--To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U

  8. New forms of insulin and insulin therapies for the treatment of type 2 diabetes.

    PubMed

    Cahn, Avivit; Miccoli, Roberto; Dardano, Angela; Del Prato, Stefano

    2015-08-01

    Insulin is a common treatment option for many patients with type 2 diabetes, and is generally used late in the natural history of the disease. Its injectable delivery mode, propensity for weight gain and hypoglycaemia, and the paucity of trials assessing the risk-to-safety ratio of early insulin use are major shortcomings associated with its use in patients with type 2 diabetes. Development of new insulins-such as insulin analogues, including long-acting and short-acting insulins-now provide alternative treatment options to human insulin. These novel insulin formulations and innovative insulin delivery methods, such as oral or inhaled insulin, have been developed with the aim to reduce insulin-associated hypoglycaemia, lower intraindividual pharmacokinetic and pharmacodynamic variability, and improve imitation of physiological insulin release. Availability of newer glucose-lowering drugs (such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors) also offers the opportunity for combination treatment; the results of the first trials in this area of research suggest that such treatment might lead to use of reduced insulin doses, less weight gain, and fewer hypoglycaemic episodes than insulin treatment alone. These and future developments will hopefully offer better opportunities for individualisation of insulin treatment for patients with type 2 diabetes.

  9. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin....

  10. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin....

  11. Effect of licofelone--a dual COX/5-LOX inhibitor in intracerebroventricular streptozotocin-induced behavioral and biochemical abnormalities in rats.

    PubMed

    Kumar, Ashok; Sharma, Sorabh; Prashar, Ashwani; Deshmukh, Rahul

    2015-03-01

    The present study was designed to investigate the effect of licofelone-a dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitor in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficit and biochemical abnormalities in rats. ICV-STZ is a widely used model of sporadic Alzheimer's disease. In this study, STZ was administered intracerebroventricular (i.c.v.)-bilaterally 3 mg/kg in rats. The STZ-injected rats were treated with different doses of licofelone (2.5, 5, and 10 mg/kg, p.o.) for 21 days. Cognitive functions were assessed by using Morris water maze and passive avoidance task. Levels of malondialdehyde (MDA), nitrite, reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were determined to check oxidative stress and cholinergic function. Cytokine levels (IL-1β and TNF-α) were also determined as markers of neuroinflammation. Administration of STZ caused a significant increase in AChE activity and cognitive dysfunction. Increased oxidative stress and the proinflammatory cytokine levels were also observed following STZ administration in rats. Licofelone treatment attenuated STZ-induced cholinergic hypofunction and cognitive deficit in rats. In addition, licofelone attenuated STZ-induced oxidative stress and elevated cytokine levels. The cognitive enhancement following licofelone administration in STZ rats may be due to its ability to restore cholinergic functions or its antioxidant activity. These observed results suggest the therapeutic potential of dual COX/5-LOX inhibitors in neurodegenerative disorders associated with oxidative stress and cognitive impairment.

  12. Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold.

    PubMed

    Torsoni, Márcio A; Carvalheira, José B; Pereira-Da-Silva, Márcio; de Carvalho-Filho, Marco A; Saad, Mário J A; Velloso, Lício A

    2003-07-01

    Insulin and leptin act in the hypothalamus, providing robust anorexigenic signals. The exposure of homeothermic animals to a cold environment leads to increased feeding, accompanied by sustained low levels of insulin and leptin. In the present study, the initial and intermediate steps of the insulin-signaling cascade were evaluated in the hypothalamus of cold-exposed Wistar rats. By immunohistochemistry, most insulin receptor (IR) and insulin receptor substrate-2 (IRS-2) immunoreactivity localized to the arcuate nucleus. Basal levels of tyrosine phosphorylation of IR and IRS-2 were increased in cold-exposed rats compared with rats maintained at room temperature. However, after an acute, peripheral infusion of exogenous insulin, significantly lower increases of IR and IRS-2 tyrosine phosphorylation were detected in the hypothalamus of cold-exposed rats. Insulin-induced association of p85/phosphatidylinositol 3-kinase with IRS-2, Ser473 phosphorylation of Akt, and tyrosine phosphorylation of ERK was significantly reduced in the hypothalamus of cold-exposed rats. To test the hypothesis of functional impairment of insulin signaling in the hypothalamus, intracerebroventricularly cannulated rats were acutely treated with insulin, and food ingestion was measured over a period of 12 h. Cold-exposed animals presented a significantly lower insulin-induced reduction in food consumption compared with animals maintained at room temperature. Hence, the present studies reveal that animals exposed to cold are resistant, both at the molecular and the functional level, to the actions of insulin in the hypothalamus.

  13. Intracerebroventricular administration of chicken glucagon-like peptide-2 potently suppresses food intake in chicks.

    PubMed

    Honda, Kazuhisa; Saneyasu, Takaoki; Shimatani, Tomohiko; Aoki, Koji; Yamaguchi, Takuya; Nakanishi, Kiwako; Kamisoyama, Hiroshi

    2015-03-01

    Glucagon-related peptides, such as glucagon-like peptide (GLP)-1, GLP-2 and oxyntomodulin (OXM), are processed from an identical precursor proglucagon. In mammals, all of these peptides are suggested to be involved in the central regulation of food intake. We previously showed that intracerebroventricular administration of chicken OXM and GLP-1 significantly suppressed food intake in chicks. Here, we show that central administration of chicken GLP-2 potently suppresses food intake in chicks. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken GLP-2 significantly suppressed food intake in chicks. Plasma glucose concentration was significantly decreased by chicken GLP-2, whereas plasma nonesterified fatty acid concentration was significantly increased. Intracerebroventricular administration of chicken GLP-2 did not affect plasma corticosterone concentration. In addition, the anorexigenic effect of GLP-2 was not reversed by the corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, suggesting that CRF is not a downstream mediator of the anorexigenic pathway of GLP-2 in chicks. Intracerebroventricular administration of an equimolar amount of GLP-1 and GLP-2, but not OXM, significantly suppressed food intake in both broiler and layer chicks. All our findings suggest that GLP-2 functions as a potent anorexigenic peptide in the brain, as well as GLP-1, in chicks.

  14. Discovering novel carriers for oral insulin tablets: a pharmacoinformatics approach.

    PubMed

    Seenivasagam, R; Hemavathi, K; Sivakumar, G; Niranjan, Vidya

    2013-01-01

    Insulin is used medically to treat Type 1 diabetes mellitus most commonly injected subcutaneously for human beings. The realisation that insulin injections have become a part of life can be extremely harrowing for many diabetic patients. Using insulin therapeutically is not a new practice, but still delivery methods to make the process more bearable have not gained widespread prominence as of yet. Oral delivery of insulin in tablet form has always been a significant challenge for pharmaceutical researchers. This study is a prospect of oral insulin tablet through pharmacoinformatics approach.

  15. Exercise, Insulin Absorption Rates, and Artificial Pancreas Control

    NASA Astrophysics Data System (ADS)

    Frank, Spencer; Hinshaw, Ling; Basu, Rita; Basu, Ananda; Szeri, Andrew J.

    2016-11-01

    Type 1 Diabetes is characterized by an inability of a person to endogenously produce the hormone insulin. Because of this, insulin must be injected - usually subcutaneously. The size of the injected dose and the rate at which the dose reaches the circulatory system have a profound effect on the ability to control glucose excursions, and therefore control of diabetes. However, insulin absorption rates via subcutaneous injection are variable and depend on a number of factors including tissue perfusion, physical activity (vasodilation, increased capillary throughput), and other tissue geometric and physical properties. Exercise may also have a sizeable effect on the rate of insulin absorption, which can potentially lead to dangerous glucose levels. Insulin-dosing algorithms, as implemented in an artificial pancreas controller, should account accurately for absorption rate variability and exercise effects on insulin absorption. The aforementioned factors affecting insulin absorption will be discussed within the context of both fluid mechanics and data driven modeling approaches.

  16. Increased Clearance and Degradation of [3H]Insulin in Streptozotocin Diabetic Rats

    PubMed Central

    Philippe, Jacques; Halban, Philippe A.; Gjinovci, Asllan; Duckworth, William C.; Estreicher, Jurek; Renold, Albert E.

    1981-01-01

    The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since streptozotocin-diabetes in rats results in increased insulin binding to tissues in vitro, insulin pharmacokinetics in streptozotocin-diabetic rats were compared to controls, using semisynthetic [3H]insulin as the tracer. The initial distribution volume for [3H]insulin was elevated by 60% in diabetic rats. By contrast, no difference in initial distribution volume for [14C]inulin was observed, and the absolute values were lower than those found for [3H]insulin. The metabolic clearance rate of [3H]insulin was elevated by 44% in diabetic rats. That these differences were the result of increased binding of insulin to a specific receptor compartment in diabetic rats was shown by three additional experiments. The first involved receptor saturation by injection of 10 U native insulin 2 min before the tracer injection, resulting in identical [3H]insulin disappearance rates in the two groups of rats. The second consisted of displacing [3H]insulin from receptors by injecting 10 U unlabeled insulin 6 min after the tracer injection. Displacement of intact [3H]insulin from receptors and subsequent reappearance in the circulation occurred in both control and diabetic animals; however, such displacement was 25% greater in the diabetic rats. Finally, treatment of diabetic rats with insulin for 8 d normalized [3H]insulin clearance even though the tracer was injected at a time when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance. PMID:6451633

  17. [A case of leprechaunism with extreme insulin resistance due to a primary defect in insulin receptors].

    PubMed

    Goji, K; Takata, Y; Kobayashi, M

    1985-09-20

    This report describes a 3-month-old female infant with the typical physical features of leprechaunism. The patient demonstrated glucose intolerance and marked hyperinsulinemia (4600 microU/ml). Since an intravenous insulin injection (actrapid insulin: 0.15 U/kg) caused no significant decrease in the blood glucose level, the presence of insulin resistance was suggested. Neither insulin antibodies nor insulin receptor antibodies were were found in the patient's plasma, and other circulating insulin antagonists such as glucagon, growth hormone, and cortisol were within normal limits. [125I]Insulin binding to the erythrocytes from the patient was as low as 1.02% (control infants: 4.89 +/- 1.08% [mean +/- SD]). [125I]Insulin binding to the cultured transformed lymphocytes from the patient was similarly reduced to 3.58% (control: 20.9 +/- 2.71% [mean +/- SD]). From these findings we concluded that the insulin resistance was due to a primary defect in insulin receptors. Interestingly, transient remissions of the patient's glucose intolerance and hyperinsulinemia were observed during a year of follow-up study. The insulin tolerance test which was performed at the remission period showed an improvement in insulin resistance. However, the insulin binding defect to erythrocytes remained unchanged even at the remission period. The exact cause of these remissions was not clear and remained to be elucidated.

  18. Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

    PubMed Central

    Son, Sung Min; Cha, Moon-Yong; Choi, Heesun; Kang, Seokjo; Choi, Hyunjung; Lee, Myung-Shik; Park, Sun Ah; Mook-Jung, Inhee

    2016-01-01

    ABSTRACT The secretion of proteins that lack a signal sequence to the extracellular milieu is regulated by their transition through the unconventional secretory pathway. IDE (insulin-degrading enzyme) is one of the major proteases of amyloid beta peptide (Aβ), a presumed causative molecule in Alzheimer disease (AD) pathogenesis. IDE acts in the extracellular space despite having no signal sequence, but the underlying mechanism of IDE secretion extracellularly is still unknown. In this study, we found that IDE levels were reduced in the cerebrospinal fluid (CSF) of patients with AD and in pathology-bearing AD-model mice. Since astrocytes are the main cell types for IDE secretion, astrocytes were treated with Aβ. Aβ increased the IDE levels in a time- and concentration-dependent manner. Moreover, IDE secretion was associated with an autophagy-based unconventional secretory pathway, and depended on the activity of RAB8A and GORASP (Golgi reassembly stacking protein). Finally, mice with global haploinsufficiency of an essential autophagy gene, showed decreased IDE levels in the CSF in response to an intracerebroventricular (i.c.v.) injection of Aβ. These results indicate that IDE is secreted from astrocytes through an autophagy-based unconventional secretory pathway in AD conditions, and that the regulation of autophagy is a potential therapeutic target in addressing Aβ pathology. PMID:26963025

  19. Intracerebroventricular administration of C-type natriuretic peptide suppresses food intake via activation of the melanocortin system in mice.

    PubMed

    Yamada-Goto, Nobuko; Katsuura, Goro; Ebihara, Ken; Inuzuka, Megumi; Ochi, Yukari; Yamashita, Yui; Kusakabe, Toru; Yasoda, Akihiro; Satoh-Asahara, Noriko; Ariyasu, Hiroyuki; Hosoda, Kiminori; Nakao, Kazuwa

    2013-05-01

    C-type natriuretic peptide (CNP) and its receptor are abundantly distributed in the brain, especially in the arcuate nucleus (ARC) of the hypothalamus associated with regulating energy homeostasis. To elucidate the possible involvement of CNP in energy regulation, we examined the effects of intracerebroventricular administration of CNP on food intake in mice. The intracerebroventricular administration of CNP-22 and CNP-53 significantly suppressed food intake on 4-h refeeding after 48-h fasting. Next, intracerebroventricular administration of CNP-22 and CNP-53 significantly decreased nocturnal food intake. The increment of food intake induced by neuropeptide Y and ghrelin was markedly suppressed by intracerebroventricular administration of CNP-22 and CNP-53. When SHU9119, an antagonist for melanocortin-3 and melanocortin-4 receptors, was coadministered with CNP-53, the suppressive effect of CNP-53 on refeeding after 48-h fasting was significantly attenuated by SHU9119. Immunohistochemical analysis revealed that intracerebroventricular administration of CNP-53 markedly increased the number of c-Fos-positive cells in the ARC, paraventricular nucleus, dorsomedial hypothalamus, ventromedial hypothalamic nucleus, and lateral hypothalamus. In particular, c-Fos-positive cells in the ARC after intracerebroventricular administration of CNP-53 were coexpressed with α-melanocyte-stimulating hormone immunoreactivity. These results indicated that intracerebroventricular administration of CNP induces an anorexigenic action, in part, via activation of the melanocortin system.

  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

    2014-10-02

    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.

  1. Transgenic silkworms expressing human insulin receptors for evaluation of therapeutically active insulin receptor agonists.

    PubMed

    Matsumoto, Yasuhiko; Ishii, Masaki; Ishii, Kenichi; Miyaguchi, Wataru; Horie, Ryo; Inagaki, Yoshinori; Hamamoto, Hiroshi; Tatematsu, Ken-ichiro; Uchino, Keiro; Tamura, Toshiki; Sezutsu, Hideki; Sekimizu, Kazuhisa

    2014-12-12

    We established a transgenic silkworm strain expressing the human insulin receptor (hIR) using the GAL4/UAS system. Administration of human insulin to transgenic silkworms expressing hIR decreased hemolymph sugar levels and facilitated Akt phosphorylation in the fat body. The decrease in hemolymph sugar levels induced by injection of human insulin in the transgenic silkworms expressing hIR was blocked by co-injection of wortmannin, a phosphoinositide 3-kinase inhibitor. Administration of bovine insulin, an hIR ligand, also effectively decreased sugar levels in the transgenic silkworms. These findings indicate that functional hIRs that respond to human insulin were successfully induced in the transgenic silkworms. We propose that the humanized silkworm expressing hIR is useful for in vivo evaluation of the therapeutic activities of insulin receptor agonists.

  2. Insulin pumps and their use in pregnancy.

    PubMed

    Wollitzer, Adrienne D; Zisser, Howard; Jovanovic, Lois

    2010-06-01

    The prevalence of diabetes in pregnancy has continued to increase, both as obesity drives up the rate of glucose intolerance itself and as improvements in diabetes and infertility treatments allow more women with diabetes to become and remain pregnant into the third trimester. With this increase has come a concomitant increase in the number of pregnant women using insulin to control their blood glucose in pregnancy. This review seeks to identify advantages and disadvantages of insulin pump use in pregnancy, as compared to a more traditional multiple daily injection (MDI) insulin regimen. Insulin pumps have not yet been shown to offer superior glucose control compared to MDI insulin, and thus many healthcare practitioners and health insurance companies are hesitant to adopt such a practice; however, insulin pumps often facilitate ease of usage of insulin and promote postpartum insulin use when indicated. Although only a small percentage of pregnant women with diabetes in the United States currently use insulin pumps, we believe that insulin pumps may represent a superior mode of insulin delivery for many women with diabetes in pregnancy.

  3. Role of nitric oxide synthase inhibition in the acute hypertensive response to intracerebroventricular cadmium

    PubMed Central

    Demontis, Maria Piera; Varoni, Maria Vittoria; Volpe, Anna Rita; Emanueli, Costanza; Madeddu, Paolo

    1998-01-01

    In the rat, intracerebroventricular (i.c.v.) injection of cadmium, a pollutant with long biological half-life, causes a sustained increase in blood pressure at doses that are ineffective by peripheral route. Since cadmium inhibits calcium-calmodulin constitutive nitric oxide (NO) synthase in cytosolic preparations of rat brain, this mechanism may be responsible for the acute pressor action of this heavy metal.To test this possibility, we evaluated the effect of i.c.v. injection of 88 nmol cadmium in normotensive unanaesthetized Wistar rats, which were i.c.v. pre-treated with: (1) saline (control), (2) L-arginine (L-Arg), to increase the availability of substrate for NO biosynthesis, (3) D-arginine (D-Arg), (4) 3-[4-morpholinyl]-sydnonimine-hydrochloride (SIN-1), an NO donor, or (5) CaCl2, a cofactor of brain calcium-calmodulin-dependent cNOSI. In additional experiments, the levels of L-citrulline (the stable equimolar product derived from enzymatic cleavage of L-Arg by NO synthase) were determined in the brain of vehicle- or cadmium-treated rats.The pressor response to cadmium reached its nadir at 5 min (43±4 mmHg) and lasted over 20 min in controls. L-Citrulline/protein content was reduced from 35 up to 50% in the cerebral cortex, pons, hippocampus, striatus, hypothalamus (P<0.01) of cadmium-treated rats compared with controls. Central injection of NG nitro-L-arginine-methylester (L-NAME) also reduced the levels of L-citrulline in the brain.Both the magnitude and duration of the response were attenuated by 1.21 and 2.42 μmol SIN-1 (32±3 and 15±4 mmHg, P<0.05), or 1 μmol CaCl2 (6±4 mmHg, P<0.05). Selectivity of action exerted by SIN-1 was confirmed by the use of another NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). Both L-Arg and D-Arg caused a mild but significant attenuation in the main phase of the pressor response evoked by cadmium. However, only L-Arg reduced the magnitude of the delayed, pressor response. Despite their similarity in

  4. Intestinal micropatches for oral insulin delivery.

    PubMed

    Banerjee, Amrita; Wong, Jessica; Gogoi, Rohan; Brown, Tyler; Mitragotri, Samir

    2017-03-19

    Diabetes mellitus has become a major public health issue that has almost reached epidemic proportions worldwide. Injectable insulin has been typically utilized for the management of this chronic disease. However, lack of patient compliance with injectable formulations has spurred the development of oral insulin formulations, which although appealing, face several delivery challenges. We have developed novel mucoadhesive intestinal patches, several hundred micrometers in dimension (micropatches) that address the challenges of oral insulin delivery. The micropatches adhere to the intestinal mucosa, release their drug load rapidly within 30 min and are effective in lowering blood glucose levels in vivo. When insulin-loaded micropatches were administered with a permeation enhancer and protease inhibitor, a peak efficacy of 34% drop in blood glucose levels was observed within 3 h. Efficacy further improved to 41% when micropatches were administered in multiple doses. Here, we describe the design of micropatches as an oral insulin formulation and report their in vivo efficacy.

  5. Comparison of jet injector and insulin pen in controlling plasma glucose and insulin concentrations in type 2 diabetic patients.

    PubMed

    Guo, Lixin; Xiao, Xinhua; Sun, Xue; Qi, Cuijuan

    2017-01-01

    This study is conducted to investigate efficacy of an insulin jet injector and an insulin pen in treatment of type 2 diabetic patients. Sixty patients with type 2 diabetes were treated with rapid-acting insulin (regular insulin) and insulin analog (insulin aspart) using the jet injector and the pen in 4 successive test cycles. Postprandial glucose and insulin concentrations in blood were measured over time. Areas under curves of glucose and the insulin were calculated, and efficacy of 2 injection methods in treatment of the diabetes was compared. Regular insulin and insulin aspart administration by the jet injector showed significant decreases in plasma glucose levels as compared to the pen injection (P < 0.05). Postprandial plasma glucose excursions at the time points of 0.5 to 3 hours were obviously lower in the jet-treated patients than the pen-treated ones (P < 0.05). Postprandial plasma insulin levels were markedly higher in the jet-treated patients than the pen-treated ones (P < 0.05). Area under the glucose curve in the pen-treated patients was significantly increased as compared to the jet-treated ones (P < 0.01). Efficacy of the insulin jet injector in treatment of type 2 diabetic patients is obviously superior to the insulin pen in regulating plasma glucose and insulin levels.

  6. Comparison of jet injector and insulin pen in controlling plasma glucose and insulin concentrations in type 2 diabetic patients

    PubMed Central

    Guo, Lixin; Xiao, Xinhua; Sun, Xue; Qi, Cuijuan

    2017-01-01

    Abstract This study is conducted to investigate efficacy of an insulin jet injector and an insulin pen in treatment of type 2 diabetic patients. Sixty patients with type 2 diabetes were treated with rapid-acting insulin (regular insulin) and insulin analog (insulin aspart) using the jet injector and the pen in 4 successive test cycles. Postprandial glucose and insulin concentrations in blood were measured over time. Areas under curves of glucose and the insulin were calculated, and efficacy of 2 injection methods in treatment of the diabetes was compared. Regular insulin and insulin aspart administration by the jet injector showed significant decreases in plasma glucose levels as compared to the pen injection (P < 0.05). Postprandial plasma glucose excursions at the time points of 0.5 to 3 hours were obviously lower in the jet-treated patients than the pen-treated ones (P < 0.05). Postprandial plasma insulin levels were markedly higher in the jet-treated patients than the pen-treated ones (P < 0.05). Area under the glucose curve in the pen-treated patients was significantly increased as compared to the jet-treated ones (P < 0.01). Efficacy of the insulin jet injector in treatment of type 2 diabetic patients is obviously superior to the insulin pen in regulating plasma glucose and insulin levels. PMID:28072690

  7. Central injection of GalR1 agonist M617 facilitates GLUT4 expression in cardiac muscle of type 2 diabetic rats.

    PubMed

    Fang, Penghua; Shi, Mingyi; Zhu, Yan; Zhang, Zhenwen; Bo, Ping

    2015-05-01

    Although galanin has been shown to increase GLUT4 expression in the cardiac muscle of rats, there is no literature available about the effect of GalR1 on GLUT4 expression in the cardiac muscle of type 2 diabetic rats. The aim of this study was to determine whether intracerebroventricular injection of GalR1 agonist M617 would elevate GLUT4 expression in the cardiac muscle of type 2 diabetic rats. The rats tested were divided into four groups: rats from healthy and type 2 diabetic drug groups were injected with 10nM/kg/d M617 in 5μl artificial cerebrospinal fluid for 21days, while control received 5μl vehicle injections. The blood samples were analyzed for glucose and insulin concentration. Cardiac muscle was collected and processed for determination of GLUT4 mRNA expression and GLUT4 protein levels. The present findings showed that fasting blood glucose levels in both M617 treatment groups were lower compared with each control. The insulin levels in both M617 treatment groups were decreased compared with each control. Moreover, the GLUT4 content in the cardiac muscle in both drug groups was higher compared with each control. M617 treatment increased GLUT4 mRNA expression and GLUT4 protein levels compared with each control group. These observations suggest that GalR1 agonist M617, acting through its central GalR1, can promote GLUT4 expression and enhance GLUT4 content in the cardiac muscle of type 2 diabetic rats. Central GalR1 may play a significant role in regulation of glucose metabolic homeostasis in the cardiac muscle of type 2 diabetic rats.

  8. Inhaled insulin: A “puff” than a “shot” before meals

    PubMed Central

    Brashier, Dick B. S.; Khadka, Anjan; Anantharamu, Tejus; Sharma, Ashok Kumar; Gupta, A. K.; Sharma, Sushil; Dahiya, N.

    2015-01-01

    Diabetes is a metabolic disorder characterized by relative or absolute deficiency of insulin, resulting in hyperglycemia. The main treatment of diabetes relies on subcutaneous insulin administration by injection or continuous infusion to control glucose levels, besides oral hypoglycemic agents for type 2 diabetes. Novel routes of insulin administration are an area of research in the diabetes field as insulin injection therapy is burdensome and painful for many patients. Inhalational insulin is a potential alternative to subcutaneous insulin in the management of diabetes. The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium facilitates systemic delivery of insulin via pulmonary administration. Inhaled insulin has been recently approved by Food and Drug Administration (FDA). It is a novel, rapid-acting inhaled insulin with a pharmacokinetic profile that is different from all other insulin products and comparatively safer than the previous failed inhaled insulin (Exubera). PMID:26311994

  9. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2010-02-01

    foresee that with most new ways of insulin delivery the bioavailability/biopotency will be lower than with subcutaneous (SC) insulin administration. This in turn requires that more insulin has to be applied to induce the same metabolic (blood glucose lowering) effect in patients with diabetes. If the costs of insulin are of relevance for the price (this clearly depends on the source of insulin the individual company has to use) the price of the product will be higher relative to standard SC insulin therapy. The question is, clearly, what are the advantages of the new product? In times when SC insulin administration was painful and cumbersome it was clear that the ease of swallowing an insulin tablet was a good argument for many patients. With the invention of thin insulin needles that make the SC injection practically pain free in most cases, this argument of being 'convenient' becomes of limited relevance. However, for many patients (especially the public) the avoidance of 'injection' is an argument. The question is, how much is the patient (society) willing to pay for such a psychological 'advantage'? Most probably additional clear-cut clinical advantages must be demonstrable to convince the payers to reimburse a new product, especially when the price is higher than that of SC insulin. If, for example, postprandial glycaemic excursions are considerably better controlled because the pharmacodynamic (PD) effects are better than with SC injection of rapid-acting insulin analogues (this might be possible with inhaled Technosphere insulin), this would be a clinically relevant argument. Without such advantages, new products will have no market success. Most probably it will not be until one of the various ARIA developments (e.g. nasal insulin) makes it into a financially attractive product (sufficient return on investment) that more money will flow again in this area of research. The search for relevant articles about new ways to deliver insulin did not reveal very many

  10. Intentional overdose with insulin glargine and insulin aspart.

    PubMed

    Tofade, Toyin S; Liles, E Allen

    2004-10-01

    Reports of intentional massive overdoses of insulin are infrequent. A review of the literature revealed no reports of overdose attempts with either insulin glargine or insulin aspart. We report the case of a 33-year-old woman without diabetes mellitus who intentionally injected herself with an overdose of both products, which belonged to her husband. She arrived at the emergency department 15 hours after her suicide attempt, which took place the night before. Her husband had checked her blood glucose level throughout the night and had given her high-carbohydrate drinks and foods. The patient had a history of obsessive-compulsive disorder, major depression, and numerous suicide attempts. She recovered from the resulting hypoglycemia after 40 hours of dextrose infusion and was transferred to a mental health facility. The main danger associated with insulin overdose is the resultant hypoglycemia and its effects on the central nervous system; hypokalemia, hypophosphatemia, and hypomagnesemia also can develop with excess insulin administration. Dextrose infusion, with liberal oral intake when possible, and monitoring for electrolyte changes, making adjustments as needed, are recommended for the treatment of intentional insulin overdose.

  11. Bacopa monniera ameliorates cognitive impairment and neurodegeneration induced by intracerebroventricular-streptozotocin in rat: behavioral, biochemical, immunohistochemical and histopathological evidences.

    PubMed

    Khan, M Badruzzaman; Ahmad, Muzamil; Ahmad, Saif; Ishrat, Tauheed; Vaibhav, Kumar; Khuwaja, Gulrana; Islam, Fakhrul

    2015-02-01

    The standardized extract of Bacopa monniera (BM) is a complex mixture of ingredients with a uniquely wide spectrum of neuropharmacological influences upon the central nervous system including enhanced learning and memory with known antioxidant potential and protection of the brain from oxidative damage. The present study demonstrates the therapeutic efficacy of BM on cognitive impairment and oxidative damage, induced by intracerebroventricular injection of streptozotocin (ICV-STZ) in rat models. Male Wistar rats were pre-treated with BM at a selected dose (30 mg/Kg) given orally for 2 weeks and then were injected bilaterally with ICV-STZ (3 mg/Kg), while sham operated rats were received the same volume of vehicle. Behavioral parameters were subsequently monitored 2 weeks after the surgery using the Morris water maze (MWM) navigation task then were sacrificed for biochemical, immunohistochemical (Cu/Zn-SOD) and histopathological assays. ICV-STZ-infused rats showed significant loss in learning and memory ability, which were significantly improved by BM supplementation. A significant increase in thiobarbituric acid reactive species and a significant decrease in reduced glutathione, antioxidant enzymes in the hippocampus were observed in ICV-STZ rats. Moreover, decrease in Cu/Zn-SOD expression positive cells were observed in the hippocampus of ICV-STZ rats. BM supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. The data suggest that ICV-STZ might cause its neurotoxic effects via the production of free radicals. Our study demonstrates that BM is a powerful antioxidant which prevents cognitive impairment, oxidative damage, and morphological changes in the ICV-STZ-infused rats. Thus, BM may have therapeutic value for the treatment of cognitive impairment.

  12. Single-dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy.

    PubMed

    Lee, Wing C; Tsoi, Yuen K; Troendle, Frederick J; DeLucia, Michael W; Ahmed, Zeshan; Dicky, Chad A; Dickson, Dennis W; Eckman, Christopher B

    2007-08-01

    Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a devastating, degenerative neurological disorder. It is inherited as an autosomal recessive trait caused by loss-of-function mutations in the galactocerebrosidase (GALC) gene. Previously, we have shown that peripheral injection of recombinant GALC, administered every other day, results in a substantial improvement in early clinical phenotype in the twitcher mouse model of GLD. While we did detect active enzyme in the brain following peripheral administration, most of the administered enzyme was localized to the periphery. Given the substantial central nervous system (CNS) involvement in this disease, we were interested in determining whether or not a single-dose administration of the recombinant enzyme directly to the CNS, which could potentially be achieved clinically, would result in any substantial improvement. Following intracerebroventricular (i.c.v.) administration of GALC we noted a significant, 16.5%, reduction in the GALC substrate psychosine, the abnormal accumulation of which is believed to play a pivotal role in the CNS pathology observed in this disease. Moreover, recombinant GALC was found not only in periventricular regions but also at sites distant to the injection such as the cerebral cortex and cerebellum. Most importantly, animals receiving a single i.c.v. dose of the enzyme at postnatal day 20 survived up to 51 days, which compares favorably to the control twitcher animals, which normally only live to postnatal day 40/42. These results indicate that even a single i.c.v. administration of the recombinant enzyme can have significant clinical impact and suggests that other lysosomal storage disorders with significant CNS involvement may similarly benefit.

  13. Intracerebroventricular urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats

    PubMed Central

    Yeh, Chun; Ting, Ching-Heng; Doong, Ming-Luen; Chi, Chin-Wen; Lee, Shou-Dong; Chen, Chih-Yen

    2016-01-01

    Purpose Urocortin 3 is a key neuromodulator in the regulation of stress, anxiety, food intake, gut motility, and energy homeostasis, while ghrelin elicits feeding behavior and enhances gastric emptying, adiposity, and positive energy balance. However, the interplays between urocortin 3 and ghrelin on food intake and gastric emptying remain uninvestigated. Methods We examined the differential effects of central O-n-octanoylated ghrelin, des-Gln14-ghrelin, and urocortin 3 on food intake, as well as on charcoal nonnutrient semiliquid gastric emptying in conscious rats that were chronically implanted with intracerebroventricular (ICV) catheters. The functional importance of corticotropin-releasing factor (CRF) receptor 2 in urocortin 3-induced responses was examined by ICV injection of the selective CRF receptor 2 antagonist, astressin2-B. Results ICV infusion of urocortin 3 opposed central acyl ghrelin-elicited hyperphagia via CRF receptor 2 in satiated rats. ICV injection of O-n-octanoylated ghrelin and des-Gln14-ghrelin were equally potent in accelerating gastric emptying in fasted rats, whereas ICV administration of urocortin 3 delayed gastric emptying. In addition, ICV infusion of urocortin 3 counteracted central acyl ghrelin-induced gastroprokinetic effects via CRF receptor 2 pathway. Conclusion ICV-infused urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats. Our results clearly showed that enhancing ghrelin and blocking CRF receptor 2 signaling in the brain accelerated gastric emptying, which provided important clues for a new therapeutic avenue in ameliorating anorexia and gastric ileus found in various chronic wasting disorders. PMID:27757017

  14. Effect of Withania somnifera on insulin sensitivity in non-insulin-dependent diabetes mellitus rats.

    PubMed

    Anwer, Tarique; Sharma, Manju; Pillai, Krishna Kolappa; Iqbal, Muzaffar

    2008-06-01

    We investigated the effect of an aqueous extract of Withania somnifera (WS) on insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (100 mg/kg) to 2 days old rat pups. WS (200 and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e. 75 days after streptozotocin injection). A group of citrate control rats (group I) were also maintained that has received citrate buffer on the second day of their birth. A significant increase in blood glucose, glycosylated haemoglobin (HbA(1)c) and serum insulin levels were observed in NIDDM control rats. Treatment with WS reduced the elevated levels of blood glucose, HbA(1)c and insulin in the NIDDM rats. An oral glucose tolerance test was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with WS. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. WS treatment significantly improved insulin sensitivity index (K(ITT)) that was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas WS treatment significantly prevented the rise in HOMA-R in NIDDM-treated rats. Our data suggest that aqueous extract of WS normalizes hyperglycemia in NIDDM rats by improving insulin sensitivity.

  15. Insulin therapy in the elderly with type 2 diabetes.

    PubMed

    Eriksson, J G; Laine, M K

    2015-12-01

    Type 2 diabetes (T2D) is a progressive disorder and therefore many elderly people with T2D will require insulin therapy in order to reach treatment targets and to optimize quality of life. It is commonly assumed that insulin is underutilized in elderly T2 diabetics because of fear that it is too complicated to use. With the use of long-acting insulin analogues it has become much easier to use insulin in elderly patients as once daily pen injections. When basal insulin treatment is initiated in T2D it is often added to the oral medication. The use of basal insulin analogues (e.g. detemir and glargine) with relatively little peaking effects has made insulin therapy in elderly subjects a relatively straightforward process. Newer insulin analogues are also discussed. The use of prandial insulin in addition to basal insulin and use of premixed insulin analogues is also discussed and illustrated with patient cases. Avoidance of hypoglycemia is an important factor to consider when choosing therapeutic agents for elderly T2D diabetics. This is certainly also true when establishing glycemic goals. Therefore insulin must be used with caution and wisely and the motto "start low and go slow" is a good principle. Basal insulin therapy in combination with oral drugs, most often metformin ‑ is the most convenient initial regimen. However, all next steps, from one to two or even more daily injections in elderly T2D subjects should be considered carefully.

  16. The quest for physiologic insulin replacement.

    PubMed

    Owens, David R

    2004-11-01

    Historically, the objective of insulin replacement has been to simulate the 2 major components of insulin secretion in individuals without diabetes mellitus: the low-level basal secretion during the night and periods of fasting, and the prandial secretion in response to food intake. The variable pharmacokinetic and pharmacodynamic characteristics of conventional insulin preparations have made mimicking these physiologic profiles virtually impossible. Balancing the effects of diet, exercise, and the numerous factors contributing to intra- and inter-individual variations in insulin absorption and action, such as type, site of injection, and dosage of insulin, while avoiding the very serious side effect of hypoglycemia in seeking normoglycemia, presents a further challenge. Recently, these limitations have been addressed by recombinant DNA-mediated development of insulin analogues, such as rapid-acting insulin lispro, aspart and glulisine, and the long-acting insulin preparations, insulin glargine and detemir. The molecular structures of these analogues have produced time-action profiles that better approach prandial and basal insulin secretion, thus allowing for easier, safer, and more flexible treatment regimens.

  17. Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration.

    PubMed

    Cohen-Pfeffer, Jessica L; Gururangan, Sridharan; Lester, Thomas; Lim, Daniel A; Shaywitz, Adam J; Westphal, Manfred; Slavc, Irene

    2017-02-01

    Intrathecal delivery methods have been used for many decades to treat a broad range of central nervous system disorders. A literature review demonstrated that intracerebroventricular route is an established and well-tolerated method for prolonged central nervous system drug delivery in pediatric and adult populations. Intracerebroventricular devices were present in patients from one to 7156 days. The number of punctures per device ranged from 2 to 280. Noninfectious complication rates per patient (range, 1.0% to 33.0%) were similar to infectious complication rates (0.0% to 27.0%). Clinician experience and training and the use of strict aseptic techniques have been shown to reduce the frequency of complications.

  18. Effects of intravitreal insulin and insulin signaling cascade inhibitors on emmetropization in the chick

    PubMed Central

    Penha, Alexandra Marcha; Burkhardt, Eva; Schaeffel, Frank

    2012-01-01

    Purpose Intravitreal insulin has been shown to be a powerful stimulator of myopia in chickens, in particular if the retinal image is degraded or defocused. In most tissues, the insulin receptor activates two main signaling pathways: a) the mitogen-activated protein kinase (MAPK) cascade (e.g., mitogen-activated protein kinasem kinase [MEK] and extracellular regulated kinase [ERK]) and b) the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In the current study, insulin was injected, and these pathways were separately inhibited to determine which is activated when the retinal image is defocused by spectacle lenses. Methods Chicks were treated with either +7 D, −7 D, or no lenses. They were intravitreally injected with insulin, the MEK inhibitor U0126, the PI3K inhibitor Ly294002, or a combination of insulin and one of the inhibitors. Refractions and ocular dimension were measured at the beginning and after four days of treatment. The retinal proteins of the chicks were measured with western blots after 2 h and four days of treatment. Incubation occurred with anti-Akt1, anti-Erk1/2, anti-phospho-AktThr308, and anti-phospho-Erk1/2(Thr202/Tyr204) antibodies, and the ratio between the relative intensity of the phospho-form and the total-form was calculated. Results Chicks wearing positive lenses and injected with saline and with PI3K inhibitor compensated for the imposed defocus and became hyperopic. Insulin injections and insulin plus PI3K inhibitor injections prevented lens-induced hyperopia, whereas the MEK inhibitor alone and insulin plus MEK inhibitor had no effect. Obviously, the MEK inhibitor suppressed the effect of insulin on eye growth in the plus lens–treated animals. Chicks treated with negative lenses and injected with insulin, or with insulin plus MEK inhibitor, overcompensated for the imposed defocus. This effect of insulin was not detected in eyes injected with PI3K inhibitor plus insulin, suggesting that the PI3K inhibitor

  19. Insulin Glulisine (rDNA origin) Injection

    MedlinePlus

    ... the reservoir and change the tubing, needle, and infusion site (spot where the pump is attached to ... body) at least every 48 hours. If the infusion site is red, itchy, or thickened, tell your ...

  20. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... such as dexamethasone, methylprednisolone (Medrol), and prednisone (Rayos); sulfa antibiotics; terbutaline; and thyroid medications. Your doctor may ... may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online ( ...

  1. Insulin Glargine (rDNA origin) Injection

    MedlinePlus

    ... Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for ...

  2. Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics.

    PubMed

    Pozzilli, Paolo; Battelino, Tadej; Danne, Thomas; Hovorka, Roman; Jarosz-Chobot, Przemyslawa; Renard, Eric

    2016-01-01

    The level of glycaemic control necessary to achieve optimal short-term and long-term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid-acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health-related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid-acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost-effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid-acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients

  3. Anti-insulin antibody test

    MedlinePlus

    Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... Normally, there are no antibodies against insulin in your blood. ... different laboratories. Some labs use different measurements or ...

  4. Nanoparticle based insulin delivery system: the next generation efficient therapy for Type 1 diabetes.

    PubMed

    Sharma, Garima; Sharma, Ashish Ranjan; Nam, Ju-Suk; Doss, George Priya C; Lee, Sang-Soo; Chakraborty, Chiranjib

    2015-10-24

    Diabetic cases have increased rapidly in recent years throughout the world. Currently, for type-1 diabetes mellitus (T1DM), multiple daily insulin (MDI) injections is the most popular treatment throughout the world. At this juncture, researchers are trying to develop different insulin delivery systems, especially through oral and pulmonary route using nanocarrier based delivery system. This next generation efficient therapy for T1DM may help to improve the quality of life of diabetic patients who routinely employ insulin by the subcutaneous route. In this paper, we have depicted various next generation nanocarrier based insulin delivery systems such as chitosan-insulin nanoparticles, PLGA-insulin nanoparticles, dextran-insulin nanoparticles, polyalkylcyanoacrylated-insulin nanoparticles and solid lipid-insulin nanoparticles. Modulation of these insulin nanocarriers may lead to successful oral or pulmonary insulin nanoformulations in future clinical settings. Therefore, applications and limitations of these nanoparticles in delivering insulin to the targeted site have been thoroughly discussed.

  5. Salt preference elicited by chronic intracerebroventricular angiotensin II.

    PubMed

    Izumi, H; Nakamura, I

    1994-10-01

    1. Much more water was consumed than either 0.9% or 2.7% saline in response to various dipsogenic stimuli in untreated normal replete rats when they had free access to water, 0.9% and 2.7% saline. On the other hand, the rats drank more 0.9% saline than water and 2.7% saline when each solution is the sole drinking fluid offered. 2. A marked increase in preference for 0.9% saline was observed during the chronic i.c.v. injection of angiotensin II at a dose of 25 ng/hr for 7 consecutive days in the three bottle choice test. After the cessation of angiotensin II infusion, most rats (45 out of 50 rats) returned to drink much more water than 0.9% and 2.7% saline, similar to the drinking pattern of the 0.9% saline-treated control rats. However, some rats (5 out of 50 rats) still preferred 0.9% saline and this persisted for up to 3 months although these rats did not show a hypertensive state and an increase of plasma renin activity.

  6. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2011-02-01

    active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability/biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin. Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity/imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear 'advantage' can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that 'relevant' clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also

  7. The relationship between the frequency of self-monitoring of blood glucose and glycemic control in patients with type 1 diabetes mellitus on continuous subcutaneous insulin infusion or on multiple daily injections

    PubMed Central

    Murata, Takashi; Tsuzaki, Kokoro; Yoshioka, Fumi; Okada, Hiroshi; Kishi, Junichiro; Yamada, Kazunori; Sakane, Naoki

    2015-01-01

    Aims/Introduction We investigated the relationship between the frequency of self-monitoring of blood glucose (SMBG) and glycemic control in type 1 diabetes mellitus patients on continuous subcutaneous insulin infusion (CSII) or on multiple daily injections (MDI) using data management software. Materials and Methods We recruited 148 adult type 1 diabetes mellitus patients (CSII n = 42, MDI n = 106) and downloaded their SMBG records to the MEQNET™ SMBG Viewer software (Arkray Inc., Kyoto, Japan). The association between the SMBG frequency and the patients' hemoglobin A1c (HbA1c) levels was analyzed using the χ2-test and linear regression analysis was carried out to clarify their relationship. Results The odds ratio of achieving a target HbA1c level of <8% (63.9 mmol/mol) was significantly higher in subjects with SMBG frequencies of ≥3.5 times/day compared with those with SMBG frequencies of <3.5 times/day in the CSII group (odds ratio 7.00, 95% confidence interval 1.72–28.54), but not in the MDI group (odds ratio 1.35, 95% CI 0.62–2.93). A significant correlation between SMBG frequency and the HbA1c level was detected in the CSII group (HbA1c [%] = –0.24 × SMBG frequency [times/day] + 8.60 [HbA1c {mmol/L} = –2.61 × SMBG frequency {times/day} + 70.5], [r = –0.384, P = 0.012]), but not in the MDI group. Conclusions A SMBG frequency of <3.5 times per day appeared to be a risk factor for poor glycemic control (HbA1c ≥8%) in type 1 diabetes mellitus patients on CSII. PMID:26543543

  8. Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates mTOR signal pathways and protein translation in the rat frontal cortex.

    PubMed

    Kim, Se Hyun; Yu, Hyun-Sook; Park, Hong Geun; Ha, Kyooseob; Kim, Yong Sik; Shin, Soon Young; Ahn, Yong Min

    2013-08-01

    Intracerebroventricular (ICV) injection of ouabain, a specific Na/K-ATPase inhibitor, induces behavioral changes in rats in a putative animal model of mania. The binding of ouabain to Na/K-ATPase affects signaling molecules in vitro, including ERK1/2 and Akt, which promote protein translation. We have also reported that ERK1/2 and Akt in the brain are involved in the ouabain-induced hyperactivity of rats. In this study, rats were given an ICV injection of ouabain, and then their frontal cortices were examined to determine the effects of ouabain on the mTOR/p70S6K/S6 signaling pathway and protein translation, which are important in modifications of neural circuits and behavior. Rats showed ouabain-induced hyperactivity up to 8h following injection, and increased phosphorylation levels of mTOR, p70S6K, S6, eIF4B, and 4E-BP at 1, 2, 4, and 8h following ouabain injection. Immunohistochemical analyses revealed that increased p-S6 immunoreactivity in the cytoplasm of neurons by ouabain was evident in the prefrontal, cingulate, and orbital cortex. These findings suggested increased translation initiation in response to ouabain. The rate of protein synthesis was measured as the amount of [(3)H]-leucine incorporation in the cell-free extracts of frontal cortical tissues, and showed a significant increase at 8h after ouabain injection. These results suggest that ICV injection of ouabain induced activation of the protein translation initiation pathway regulated by ERK1/2 and Akt, and prolonged hyperactivity in rats. In conclusion, protein translation pathway could play an important role in ouabain-induced hyperactivity in a rodent model of mania.

  9. Intracerebroventricular administration of inosine is anticonvulsant against quinolinic acid-induced seizures in mice: an effect independent of benzodiazepine and adenosine receptors.

    PubMed

    Ganzella, Marcelo; Faraco, Rafael Berger; Almeida, Roberto Farina; Fernandes, Vinícius Fornari; Souza, Diogo Onofre

    2011-12-01

    Inosine (INO) has an anticonvulsant effect against seizures induced by antagonists of GABAergic system. Quinolinic acid (QA) is an agonist NMDA receptors implicated in the neurobiology of seizures. In the present study, we investigated the anticonvulsant effect of intracerebroventricular (i.c.v.) INO administration against QA-induced seizures in adult mice. We also investigated whether the benzodiazepines (BZ) or adenosine (ADO) receptors were involved in the INO effects. Animals were pretreated with an i.c.v. injection of either vehicle or INO before an i.c.v. administration of 4 μl QA (36.8 nmol). All animals pretreated with vehicle followed by QA presented seizures. INO protected against QA-induced seizures in a time and dose dependent manner (up to 60% at 400 nmol, 5 min before QA injection). Diazepam (DZ) and ADO (i.c.v.) also exhibited anticonvulsant effect against QA induced seizures. Additionally, i.p. administration of either flumazenil, a BZ receptor antagonist, or caffeine, an ADO receptor antagonist, did not change the anticonvulsant potency of INO i.c.v. injection, but completely abolished the DZ and ADO anticonvulsant effects, respectively. In conclusion, this study demonstrated that INO exert anticonvulsant effect against hyperactivity of the glutamatergic system independently of BZ or ADO receptors activation.

  10. Effect of isologous and autologous insulin antibodies on in vivo bioavailability and metabolic fate of immune-complexed insulin in Lou/M rats

    SciTech Connect

    Arquilla, E.R.; McDougall, B.R.; Stenger, D.P.

    1989-03-01

    The in vivo bioavailability, distribution, and metabolic fate of 125I-labeled insulin complexed to isologous and autologous antibodies were studied in inbred Lou/M rats. There was an impaired bioavailability of the 125I-insulin bound to the isologous and autologous antibodies. Very little of the 125I-insulin in these immune complexes could bind to insulin receptors on hepatocytes or renal tubular cells and be degraded, because the amounts of 125I from degraded 125I-insulin in the blood or secreted into the stomach were markedly attenuated in both cases for at least 30 min after injection. There was a simultaneous accumulation of 125I-insulin immune complexes in the liver and the kidneys of Lou/M rats injected with 125I-insulin complexed with isologous antibodies or when insulin-immunized Lou/M rats were injected with 125I-insulin during the same interval. The impaired bioavailability of immune-complexed insulin and altered distribution of radioactivity due to the accumulation of immune complexes in the liver and kidney were also observed in previous experiments in which Lewis rats were injected with xenogenic guinea pig and homologous insulin antibodies. These observations are therefore submitted as evidence that the Lou/M rat is a valid model in which to study the bioavailability of insulin immune complexed to isologous, homologous, and xenogenic antibodies and the metabolic fate of the respective insulin-antibody immune complexes.

  11. Space Grown Insulin Crystals Provide New Data on Diabetes

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Diabetic patients may someday reduce their insulin injections and lead more normal lives because of new insights gained through irnovative space research in which insulin crystals were grown on the Space Shuttle. Results from a 1994 insulin crystal growth experiment in space are leading to a new understanding of protein insulin. Lack of insulin is the cause of diabetes, a desease that accounts for one-seventh of the nation's health care costs. Dr. Marianna Long, associate director of the Center of Macromolecular Crystallography at the University of Alabama at Birmingham, is a co-investigator on the research. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  12. Space Grown Insulin Crystals Provide New Data on Diabetes

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Diabetic patients may someday reduce their insulin injections and lead more normal lives because of new insights gained through innovative space research in which insulin crystals were grown on the Space Shuttle. Results from a 1994 insulin crystals growth experiment in space are leading to a new understanding of protein insulin. Lack of insulin is the cause of diabetes, a disease that accounts for one-seventh of the nation's health care costs. Champion Deivanaygam, a researcher at the Center for Macromolecular Crystallography at the University of Alabama in Birmingham, assists in this work. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  13. INSULIN-INDUCED GLOMERULOSCLEROSIS IN THE RABBIT

    PubMed Central

    Mohos, Steven C.; Hennigar, Gordon R.; Fogelman, John A.

    1963-01-01

    An attempt has been made to induce intercapillary glomerulosclerosis in rabbits by immunization with insulin incorporated in Freund's adjuvant and followed by repeated challenges with subcutaneously given insulin. It was observed that lesions resembling human diabetic glomerulosclerosis with occasional nodule-like formation could be produced and that the challenge insulin injections produced proteinuria. The presence of a delayed type of hypersensitivity seemed necessary for the lesions to occur as did the dissemination of the immunizing material to the kidneys. The experiment also disclosed that intravenously given DIS-tagged insulin localizes in a subtly different kind of glomerular lesion with different staining properties. The significance of these findings and the possible role of insulin treatment in the pathogenesis of human diabetic glomerulosclerosis is discussed. PMID:14087614

  14. Molecular basis for insulin fibril assembly

    SciTech Connect

    Ivanova, Magdalena I.; Sievers, Stuart A.; Sawaya, Michael R.; Wall, Joseph S.; Eisenberg, David

    2009-12-01

    In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-{beta} spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 {angstrom} resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated {beta}-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.

  15. [The effect of nerobol and ecdysterone on insulin-dependent processes linked normally and in insulin resistance].

    PubMed

    Kosovskiĭ, M I; Syrov, V N; Mirakhmedov, M M; Katkova, S P; Khushbaktova, Z A

    1989-01-01

    The effect of substances with anabolic activity (metandienone and ecdysterone phytoecdysteroid) on the manifestation of insulin effects was studied on a model of insulin resistance in rats induced by injections of hydrocortisone or by insulin insufficiency caused by alloxan. The sensitivity of the body to i. v. infusion of insulin and the reactivity of isolated fatty tissue to the hormone were increased after administration of these substances to test animals. The above effects of steroids were determined by nonspecific synthesis of total proteins in cells rather than by an increase in insulin secretion.

  16. Cabazitaxel Injection

    MedlinePlus

    ... injection is used along with prednisone to treat prostate cancer (cancer of a male reproductive organ) that has ... cabazitaxel injection is usually used in men with prostate cancer. If used by pregnant women, cabazitaxel injection can ...

  17. Fondaparinux Injection

    MedlinePlus

    ... fondaparinux injection.Talk to your doctor about the risk of using fondaparinux injection. ... Fondaparinux injection is used to prevent deep vein thrombosis (DVT; a blood ... Xa inhibitors. It works by decreasing the clotting ability of the blood.

  18. Morphine Injection

    MedlinePlus

    Morphine injection is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Morphine injection comes as a solution (liquid) to inject intramuscularly (into a muscle) or intravenously (into a ...

  19. Dexamethasone Injection

    MedlinePlus

    Dexamethasone injection is used to treat severe allergic reactions. It is used in the management of certain types of ... gastrointestinal disease, and certain types of arthritis. Dexamethasone injection is also used for diagnostic testing. Dexamethasone injection ...

  20. Romidepsin Injection

    MedlinePlus

    Romidepsin injection is used to treat cutaneous T-cell lymphoma (CTCL; a group of cancers of the immune system ... one other medication given by mouth or by injection. Romidepsin injection is in a class of medications ...

  1. Ondansetron Injection

    MedlinePlus

    Zofran® Injection ... Ondansetron injection is used to prevent nausea and vomiting caused by cancer chemotherapy and surgery. Ondansetron is in a ... medications: or any of the ingredients in ondansetron injection. Ask your pharmacist for a list of the ...

  2. Intracerebroventricular Administration of Streptozotocin as an Experimental Approach to Depression: Evidence for the Involvement of Proinflammatory Cytokines and Indoleamine-2,3-Dioxygenase.

    PubMed

    Souza, Leandro Cattelan; Jesse, Cristiano R; de Gomes, Marcelo Gomes; Viana, Cristini Escobar; Mattos, Etiara; Silva, Neici Cáceres; Boeira, Silvana Peterini

    2017-02-02

    There is a lack of information about the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. Elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In this study, we report that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, measured by an increased duration in immobility time in the forced swimming test and decreased total time of grooming in the splash test. Indirect blockade of IDO activation with the cytokine inhibitor minocycline prevents the development of depressive-like behaviors and attenuates STZ-induced upregulation of proinflammatory cytokines in the hippocampus. Minocycline abrogates the increase in tryptophan and kynurenine levels as well as prevents serotonin dysfunction in the hippocampus of STZ-injected mice. These results suggest that hippocampal IDO activation in STZ-associated depressive-like behavior is mediated by proinflammatory cytokine-dependent mechanisms. Our study not only extends the evidence that IDO has a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets of novel therapeutic drugs for depression. In addition, our study provides new insights into the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in the preclinical research of depression.

  3. The insulin pump as murder weapon: a case report.

    PubMed

    Benedict, Butch; Keyes, Rusty; Sauls, F Clark

    2004-06-01

    Microprocessor-controlled insulin pumps designed for continuous delivery of short-acting insulin analogs into subcutaneous tissues offer several important potential benefits for diabetic patients. The delivery of other substances using these systems is technically feasible. We present a case of homicide involving lethal doses of etomidate and atracurium injected via the victim's insulin pump. This unique situation could be encountered by homicide investigators more frequently as the popularity of these systems continues to grow.

  4. Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity.

    PubMed

    Yi, Chun-Xia; Foppen, Ewout; Abplanalp, William; Gao, Yuanqing; Alkemade, Anneke; la Fleur, Susanne E; Serlie, Mireille J; Fliers, Eric; Buijs, Ruud M; Tschöp, Matthias H; Kalsbeek, Andries

    2012-02-01

    Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic-euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic-euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC-induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.

  5. Ibandronate Injection

    MedlinePlus

    Boniva® Injection ... Ibandronate injection is used to treat osteoporosis (a condition in which the bones become thin and weak and break ... Ibandronate injection comes as a solution (liquid) to be injected into a vein by a doctor or nurse in ...

  6. Leuprolide Injection

    MedlinePlus

    Leuprolide injection comes as a long-acting suspension (Lupron) that is injected intramuscularly (into a muscle) by a doctor or nurse in a medical ... Depot-4 month, Lupron Depot-6 Month). Leuprolide injection also comes as a long-acting suspension (Eligard) that is injected subcutaneously (just under ...

  7. Impact of intracerebroventricular obestatin on plasma acyl ghrelin, des-acyl ghrelin and nesfatin-1 levels, and on gastric emptying in rats.

    PubMed

    Chen, Chih-Yen; Lee, Wei-Jei; Chong, Keong; Lee, Shou-Dong; Liao, You-Di

    2012-07-01

    Obestatin, which is a putative 23-amino-acid peptide, is derived from the C-terminal part of the mammalian preproghrelin gene. Nesfatin-1 mRNA is co-expressed with ghrelin in gastric endocrine X/A-like cells; therefore, nesfatin-1 may also interact with preproghrelin gene products in the stomach. In this study, we investigated the impact of obestatin on the plasma levels of acyl ghrelin, des-acyl ghrelin and nesfatin-1, and on the gastric emptying of a solid nutrient meal 2 h after an intracerebroventricular (ICV) injection in conscious, fasted rats. The rats were implanted with ICV catheters. Plasma levels of acyl ghrelin, des-acyl ghrelin and nesfatin-1, expected to be co-expressed with obestatin, were measured, whereas the human/rat corticotropin-releasing factor (h/rCRF) was applied as an inhibitor of gastric emptying. The ICV administration of obestatin (0.1, 0.3 and 1.0 nmol/rat) did not modify the plasma acyl ghrelin and des-acyl ghrelin levels, the acyl ghrelin/des-acyl ghrelin ratio and nesfatin-1 concentrations. The ICV acute administration of obestatin had no influence on the 2-h rate of gastric emptying of a solid nutrient meal, but the ICV h/rCRF injection delayed it. The weight of food ingested 1 h before ICV injection significantly, but negatively correlated with the gastric emptying of a solid nutrient meal. Our study indicates that the ICV injection of obestatin does not change the 2-h rate of gastric emptying of a solid nutrient meal and the relatively weak interrelationships between ghrelin gene products and nesfatin-1. However, the weight of the ingested food negatively affects the gastric emptying of a solid nutrient meal in conscious, fasted rats.

  8. 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

  9. 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.

  10. Insulin reverses ammonia-induced anorexia and experimental cancer anorexia.

    PubMed

    Chance, W T; Thomas, I; Fischer, J E

    1994-01-01

    Previous experiments suggest that experimental cancer-induced anorexia is associated with hyperammonemia and that daily injections of insulin may attenuate the anorexia for several days. In the present study, we determined whether similar daily insulin treatments would correct anorexia induced by the infusion of ammonium salts and compared this feeding response with that of insulin-treated tumor-bearing (TB) rats. Daily treatment of control and anorectic TB rats with systemically administered insulin for six days increased feeding in all control rats and 40% of the TB rats. All insulin-treated groups exhibited equal degrees of hypoglycemia irrespective of anorexia. Basal concentrations of lactate and glucagon were elevated in saline-treated TB rats. Plasma lactate levels were normalized by insulin treatment, whereas glucagon was normalized only in the TB rats that fed to insulin and increased further in TB rats that did not feed to insulin. Elevated hypothalamic tyrosine was reduced in insulin-treated TB rats that ate, and 5-hydroxy-indoleacetic acid was increased further when the rats did not eat. Insulin also blocked anorexia resulting from the intravenous infusion of ammonium salts. Hypothalamic concentrations of tyrosine and tryptophan were increased by the ammonia infusion and reduced significantly in insulin-treated infused rats. These results indicate that insulin treatment can reverse experimental cancer-induced anorexia and hyperammonemia-induced anorexia. Neurochemical changes associated with these treatments are also similar, but not identical.

  11. Use of insulin in diabetes: a century of treatment.

    PubMed

    Shahani, Savita; Shahani, Lokesh

    2015-12-01

    Insulin is a key player in the control of hyperglycaemia for patients with type 1 diabetes mellitus and selected patients with type 2 diabetes mellitus. There have been many advances in insulin drug delivery from its first administration as a crude pancreatic extract till today. The traditional and most predictable method for administration of insulin is by subcutaneous injection. Currently available insulin delivery systems include insulin syringes, infusion pumps, jet injectors, and pens. The major drawback of insulin therapy is its invasive nature. Non-invasive delivery of insulin has long been a major goal for the treatment of diabetes mellitus. Although there have been improvements in insulin therapy since it was first conceived, it is still far from mimicking the physiological secretion of pancreatic β-cells, and research to find new insulin formulations and new routes of administration continues. This article reviews the emerging technologies, including insulin inhalers, insulin buccal spray, insulin pill, islet cell transplant, and stem cell therapy, as treatment options for diabetes mellitus.

  12. Incorporating a Generic Model of Subcutaneous Insulin Absorption into the AIDA v4 Diabetes Simulator 3. Early Plasma Insulin Determinations

    PubMed Central

    Lehmann, Eldon D.; Tarín, Cristina; Bondia, Jorge; Teufel, Edgar; Deutsch, Tibor

    2009-01-01

    Introduction AIDA is an interactive educational diabetes simulator that has been available without charge via the Internet for over 12 years. Recent articles have described the incorporation of a novel generic model of insulin absorption into AIDA as a way of enhancing its capabilities. The basic model components to be integrated have been overviewed, with the aim being to provide simulations of regimens utilizing insulin analogues, as well as insulin doses greater than 40 IU (the current upper limit within the latest release of AIDA [v4.3a]). Some preliminary calculated insulin absorption results have also recently been described. Methods This article presents the first simulated plasma insulin profiles from the integration of the generic subcutaneous insulin absorption model, and the currently implemented model in AIDA for insulin disposition. Insulin absorption has been described by the physiologically based model of Tarín and colleagues. A single compartment modeling approach has been used to specify how absorbed insulin is distributed in, and eliminated from, the human body. To enable a numerical solution of the absorption model, a spherical subcutaneous depot for the injected insulin dose has been assumed and spatially discretized into shell compartments with homogeneous concentrations, having as its center the injection site. The number of these compartments will depend on the dose and type of insulin. Insulin inflow arises as the sum of contributions to the different shells. For this report the first bench testing of plasma insulin determinations has been done. Results Simulated plasma insulin profiles are provided for currently available insulin preparations, including a rapidly acting insulin analogue (e.g., lispro/Humalog or aspart/Novolog), a short-acting (regular) insulin preparation (e.g., Actrapid), intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue (e.g., glargine/Lantus), as

  13. Intracerebroventricular 4-methylcatechol (4-MC) ameliorates chronic pain associated with depression-like behavior via induction of brain-derived neurotrophic factor (BDNF).

    PubMed

    Fukuhara, Kayoko; Ishikawa, Kozo; Yasuda, Seiko; Kishishita, Yusuke; Kim, Hae-Kyu; Kakeda, Takahiro; Yamamoto, Misa; Norii, Takafumi; Ishikawa, Toshizo

    2012-08-01

    Neuropathic pain concurrent with mood disorder from peripheral nerve injury is a serious clinical problem that significantly affects quality of life. Recent studies have suggested that a lack of brain-derived neurotrophic factor (BDNF) in the limbic system may cause this pain-emotion. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but the role of 4-MC-induced BDNF in pain-emotion is poorly understood. Thus, we assessed the possible involvement of BDNF in brain in depression-like behavior during chronic pain following peripheral nerve injury. In addition, we examined whether intracerebroventricular (i.c.v.) 4-MC prevents chronic pain in rats and produces an antidepressant effect. Sprague-Dawley rats implanted intracerebroventricularly with a PE-10 tube were subjected to chronic constriction injury (CCI). Pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli after CCI. We also used a forced swimming testing (FST; time of immobility, in seconds) from day 14 to day 21 after CCI. Modulation of pain and emotional behavior was performed by injection of PD0325901 (a MEK1/2 inhibitor). 4-MC (100 nM) was continuously administered i.c.v. for 3 days during the period from day 14 to day 21 after CCI. To block analgesic and antidepressant effects, anti-BDNF antibody or K252a (a TrkB receptor inhibitor) was injected in combination with 4-MC. Naloxone was also coadministered to confirm the analgesic effect of 4-MC. During the chronic stage after CCI, the rats showed a sustained decrease in PWL (thermal hyperalgesia) associated with extension of the time of immobility (depression-like behavior). PD0325901 significantly reduced the decrease in PWL and the increased time of immobility after CCI. The decreased PWL and increased time of immobility were also reduced by 4-MC and by treatment with an ERK1/2 inhibitor. These effects of 4-MC i.c.v. were reversed by anti-BDNF and K252a. The analgesic effect of 4-MC i.c.v. was also antagonized by

  14. [Insulin and glucocorticoid binding by blood cell receptors after hydrocortisone administration in rabbits].

    PubMed

    Tikhonova, N E; Tatarinova, G Sh

    1989-07-01

    Repeated i.v. administration of hydrocortisone (10 mg/kg) revealed an increase in the resistance against insulin although endogenous corticosterone was decreased in 33 male rabbits. The insulin- and dexamethasone-binding receptors of erythrocytes and mononuclear leucocytes. changed after 3-7 hydrocortisone injections, the binding increasing for insulin and diminishing for dexamethasone.

  15. Diabetes Mellitus and the Insulin Pump: What Teachers Need to Know

    ERIC Educational Resources Information Center

    Obringer, S. John; Coffey, Kenneth

    2006-01-01

    Diabetes is a condition where high amounts of glucose are found in the bloodstream due to impaired secretion of insulin. The hormone insulin was discovered by two physicians, Fredrick Banting and James Mcleod in 1921. Individuals with severe diabetes typically controlled their glucose level with multiple daily injections of insulin. Recently the…

  16. Albiglutide Injection

    MedlinePlus

    ... called incretin mimetics. It works by helping the pancreas to release the right amount of insulin when ... or have ever had pancreatitis (inflammation of the pancreas); severe stomach problems, including gastroparesis (slowed movement of ...

  17. Liraglutide Injection

    MedlinePlus

    ... called incretin mimetics. It works by helping the pancreas to release the right amount of insulin when ... suicide, changes in behavior, pancreatitis (inflammation of the pancreas); severe stomach problems, including gastroparesis (slowed movement of ...

  18. Lixisenatide Injection

    MedlinePlus

    ... called incretin mimetics. It works by stimulating the pancreas to secrete insulin when blood sugar levels are ... or problems digesting food; pancreatitis (swelling of the pancreas); gallstones (solid deposits that form in the gallbladder); ...

  19. Dulaglutide Injection

    MedlinePlus

    ... called incretin mimetics. It works by helping the pancreas to release the right amount of insulin when ... or have ever had pancreatitis (inflammation of the pancreas); severe stomach problems, including gastroparesis (slowed movement of ...

  20. Exenatide Injection

    MedlinePlus

    ... called incretin mimetics. It works by stimulating the pancreas to secrete insulin when blood sugar levels are ... other problems digesting food; pancreatitis (swelling of the pancreas), gallstones (solid deposits that form in the gallbladder), ...

  1. Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats.

    PubMed

    Li, Jun; Chen, Tao; Li, Kun; Yan, Hongtao; Li, Xiaowei; Yang, Yun; Zhang, Yulan; Su, Bingyin; Li, Fuxiang

    2016-05-01

    Non-insulin-dependent diabetes mellitus (NIDDM) is associated with chronic inflammatory activity and disrupted insulin signaling, leading to insulin resistance (IR). The present study investigated the benefits of neurolytic celiac plexus block (NCPB) on IR in a rat NIDDM model. Goto-Kakizaki rats fed a high-fat, high-glucose diet to induce signs of NIDDM were randomly divided into NCPB and control groups; these received daily bilateral 0.5% lidocaine or 0.9% saline injections into the celiac plexus, respectively. Following 14 and 28 daily injections, rats were subject to oral glucose tolerance tests (OGTTs) or sacrificed for the analysis of serum free fatty acids (FFAs), serum inflammatory cytokines and skeletal muscle insulin signaling. Compared with controls, rats in the NCPB group demonstrated significantly (P<0.05) lower baseline, 60-min and 120-min OGTT values, lower 120-min serum insulin, lower IR [higher insulin sensitivity index (ISI1) and lower ISI2) and lower serum FFAs, tumor necrosis factor-α, interleukin (IL)-1β and IL-6. Conversely, NCPB rats exhibited higher basal and insulin-stimulated skeletal muscle glucose uptake and higher skeletal muscle insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 expression. There were no differences between the groups in insulin receptor β (Rβ) or Akt expression; however Rβ-Y1162/Y1163 and Akt-S473 phosphorylation levels were higher and IRS-1-S307 phosphorylation were lower in NCPB rats than in the controls. These results indicate that NCPB improved insulin signaling and reduced IR, possibly by inhibiting inflammatory cytokine release.

  2. Insulin degludec/insulin aspart combination for the treatment of type 1 and type 2 diabetes.

    PubMed

    Dardano, Angela; Bianchi, Cristina; Del Prato, Stefano; Miccoli, Roberto

    2014-01-01

    Glycemic control remains the major therapeutic objective to prevent or delay the onset and progression of complications related to diabetes mellitus. Insulin therapy represents a cornerstone in the treatment of diabetes and has been used widely for achieving glycemic goals. Nevertheless, a large portion of the population with diabetes does not meet the internationally agreed glycemic targets. Moreover, insulin treatment, especially if intensive, may be associated with emergency room visits and hospitalization due to hypoglycemic events. Therefore, fear of hypoglycemia or hypoglycemic events represents the main barriers to the attainment of glycemic targets. The burden associated with multiple daily injections also remains a significant obstacle to initiating and maintaining insulin therapy. The most attractive insulin treatment approach should meet the patients' preference, rather than demanding patients to change or adapt their lifestyle. Insulin degludec/insulin aspart (IDegAsp) is a new combination, formulated with ultra-long-acting insulin degludec and rapid-acting insulin aspart, with peculiar pharmacological features, clinical efficacy, safety, and tolerability. IDegAsp provides similar, noninferior glycemic control to a standard basal-bolus regimen in patients with type 1 diabetes mellitus, with additional benefits of significantly lower episodes of hypoglycemia (particularly nocturnal) and fewer daily insulin injections. Moreover, although treatment strategy and patients' viewpoint are different in type 1 and type 2 diabetes, trial results suggest that IDegAsp may be an appropriate and reasonable option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled on maximal doses of conventional oral agents. This paper will discuss the role of IDegAsp combination as a novel treatment option in diabetic patients.

  3. Rhus coriaria ameliorates insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) rats.

    PubMed

    Anwer, Tarique; Sharma, Manju; Khan, Gyas; Iqbal, Muzaffar; Ali, Mohammad Sajid; Alam, Mohammad Sarfaraz; Safhi, Mohammed Mohsen; Gupta, Nakul

    2013-01-01

    We have investigated the effect of methanolic extract of Rhus coriaria (RC) on hyperinsulinemia, glucose intolerance and insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (STZ, 100 mg/kg) to 2 days old rat pups. RC (200 mg/kg and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e, 90 days after STZ injection). A group of citrate control rats were also maintained which has received citrate buffer on the 2nd day of their birth. There was a significant increase in blood glucose, glycosylated hemoglobin (HbA1c) and serum insulin levels were observed in NIDDM control rats. Treatment with RC reduced the elevated levels of blood glucose, HbA1c and insulin in the NIDDM rats. An oral glucose tolerance test (OGTT) was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with RC. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. RC treatment significantly improved insulin sensitivity index (K(ITT)) which was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas RC treatment significantly prevented the rise in HOMA-R in NIDDM treated rats. Our data suggest that methanolic extract of RC significantly delayed the onset of hyperinsulinemia and glucose intolerance and improved insulin sensitivity in NIDDM rats.

  4. Neurolytic celiac plexus block enhances skeletal muscle insulin signaling and attenuates insulin resistance in GK rats

    PubMed Central

    LI, JUN; CHEN, TAO; LI, KUN; YAN, HONGTAO; LI, XIAOWEI; YANG, YUN; ZHANG, YULAN; SU, BINGYIN; LI, FUXIANG

    2016-01-01

    Non-insulin-dependent diabetes mellitus (NIDDM) is associated with chronic inflammatory activity and disrupted insulin signaling, leading to insulin resistance (IR). The present study investigated the benefits of neurolytic celiac plexus block (NCPB) on IR in a rat NIDDM model. Goto-Kakizaki rats fed a high-fat, high-glucose diet to induce signs of NIDDM were randomly divided into NCPB and control groups; these received daily bilateral 0.5% lidocaine or 0.9% saline injections into the celiac plexus, respectively. Following 14 and 28 daily injections, rats were subject to oral glucose tolerance tests (OGTTs) or sacrificed for the analysis of serum free fatty acids (FFAs), serum inflammatory cytokines and skeletal muscle insulin signaling. Compared with controls, rats in the NCPB group demonstrated significantly (P<0.05) lower baseline, 60-min and 120-min OGTT values, lower 120-min serum insulin, lower IR [higher insulin sensitivity index (ISI1) and lower ISI2) and lower serum FFAs, tumor necrosis factor-α, interleukin (IL)-1β and IL-6. Conversely, NCPB rats exhibited higher basal and insulin-stimulated skeletal muscle glucose uptake and higher skeletal muscle insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 expression. There were no differences between the groups in insulin receptor β (Rβ) or Akt expression; however Rβ-Y1162/Y1163 and Akt-S473 phosphorylation levels were higher and IRS-1-S307 phosphorylation were lower in NCPB rats than in the controls. These results indicate that NCPB improved insulin signaling and reduced IR, possibly by inhibiting inflammatory cytokine release. PMID:27168847

  5. Insulin degludec and insulin degludec/insulin aspart in Ramadan: A single center experience

    PubMed Central

    Kalra, Sanjay

    2016-01-01

    This study aimed to document the utility and safety of insulin degludec (IDeg) and insulin degludec aspart (IDegAsp) in persons with type 2 diabetes, observing the Ramadan fast. An observational study was conducted at a single center, in the real world setting, on six persons who either switched to IDeg or IDegAsp a month before Ramadan or changed time of administration of IDegAsp at the onset of Ramadan, to keep the fast in a safe manner. Subjects were kept under regular monitoring and surveillance before, during, and after Ramadan, and counseled in an opposite manner. Four persons, who shifted from premixed insulin to IDegAsp, experienced a 12–18% dose reduction after 14 days. At the onset of Ramadan, the Suhur dose was reduced by 30%, and this remained unchanged during the fasting month. The Iftar dose had to be increased by 4 units. One person who shifted from neutral protamine hagedorn to IDeg demonstrated a 25% dose reduction at 20 days, without any further change in insulin requirement during Ramadan. One person who changed time of injection of IDegAsp from morning to night reported no change in dosage. No episode of major hypoglycemia was reported. IDeg and IDegAsp are effective, safe, and well-tolerated means of achieving glycemic control in persons with type 2 diabetes who wish to fast. PMID:27366727

  6. Restoring insulin production for type 1 diabetes.

    PubMed

    Tudurí, Eva; Bruin, Jennifer E; Kieffer, Timothy J

    2012-12-01

    Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.

  7. Central Administration of Insulin and Leptin Together Enhance Renal Sympathetic Nerve Activity and Fos Production in the Arcuate Nucleus

    PubMed Central

    Habeeballah, Hamza; Alsuhaymi, Naif; Stebbing, Martin J.; Jenkins, Trisha A.; Badoer, Emilio

    2017-01-01

    There is considerable interest in the central actions of insulin and leptin. Both induce sympatho-excitation. This study (i) investigated whether centrally administered leptin and insulin together elicits greater increases in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) than when given alone, and (ii) quantified the number of activated neurons in brain regions influencing SNA, to identify potential central sites of interaction. In anesthetised (urethane 1.4–1.6 g/kg iv) male Sprague-Dawley rats, RSNA, MAP, and HR were recorded following intracerebroventricular (ICV) saline (control; n = 5), leptin (7 μg; n = 5), insulin (500 mU; n = 4) and the combination of leptin and insulin; (n = 4). Following leptin or insulin alone, RSNA was significantly increased (74 and 62% respectively). MAP responses were not significantly different between the groups. Insulin alone significantly increased HR. Leptin alone also increased HR but it was significantly less than following insulin alone (P < 0.005). When leptin and insulin were combined, the RSNA increase (124%) was significantly greater than the response to either alone. There were no differences between the groups in MAP responses, however, the increase in HR induced by insulin was attenuated by leptin. Of the brain regions examined, only in the arcuate nucleus did leptin and insulin together increase the number of Fos-positive cell nuclei significantly more than leptin or insulin alone. In the lamina terminalis and rostroventrolateral medulla, leptin and insulin together increased Fos, but the effect was not greater than leptin alone. The results suggest that when central leptin and insulin levels are elevated, the sympatho-excitatory response in RSNA will be greater. The arcuate nucleus may be a common site of cardiovascular integration. PMID:28119622

  8. Golimumab Injection

    MedlinePlus

    ... body and causes pain, swelling, and damage) including: rheumatoid arthritis (condition in which the body attacks its own ... doctor.If golimumab injection is used to treat rheumatoid arthritis, it may also be injected intravenously (into a ...

  9. Adalimumab Injection

    MedlinePlus

    ... causes pain, swelling, and damage) including the following: rheumatoid arthritis (a condition in which the body attacks its ... If you are using adalimumab injection to treat rheumatoid arthritis, your doctor may tell you to inject the ...

  10. Aripiprazole Injection

    MedlinePlus

    ... aripiprazole injection and aripiprazole extended-release injection developed gambling problems or other intense urges or behaviors that ... even if you do not realize that your gambling or any other intense urges or unusual behaviors ...

  11. Teduglutide Injection

    MedlinePlus

    ... mix and inject it.Teduglutide comes as a kit containing vials of teduglutide powder for injection, prefilled syringes containing diluent (liquid to be mixed with teduglutide powder), needles to attach to the diluent syringe, dosing syringes ...

  12. Degarelix Injection

    MedlinePlus

    Degarelix injection is used to treat advanced prostate cancer (cancer that begins in the prostate [a male reproductive gland]). Degarelix injection is in a class of medications called gonadotropin-releasing hormone (GnRH) ...

  13. Cyclosporine Injection

    MedlinePlus

    ... injection is used with other medications to prevent transplant rejection (attack of the transplanted organ by the ... people who have received kidney, liver, and heart transplants. Cyclosporine injection should only be used to treat ...

  14. Colistimethate Injection

    MedlinePlus

    ... is used to treat certain infections caused by bacteria. Colistimethate injection is in a class of medications called antibiotics. It works by killing bacteria.Antibiotics such as colistimethate injection will not work ...

  15. Chloramphenicol Injection

    MedlinePlus

    ... treat certain types of serious infections caused by bacteria when other antibiotics cannot be used. Chloramphenicol injection ... antibiotics. It works by stopping the growth of bacteria..Antibiotics such as chloramphenicol injection will not work ...

  16. Estrogen Injection

    MedlinePlus

    ... forms of estrogen injection are used to treat hot flushes (hot flashes; sudden strong feelings of heat and sweating) ... If you are using estrogen injection to treat hot flushes, your symptoms should improve within 1 to ...

  17. Medroxyprogesterone Injection

    MedlinePlus

    ... Medroxyprogesterone injection is a very effective method of birth control but does not prevent the spread of human ... you have been using a different method of birth control and are switching to medroxyprogesterone injection, your doctor ...

  18. Etanercept Injection

    MedlinePlus

    ... areas causing pain and joint damage), chronic plaque psoriasis (a skin disease in which red, scaly patches ... etanercept injection is used to treat chronic plaque psoriasis, it may be injected twice a week during ...

  19. Levoleucovorin Injection

    MedlinePlus

    Levoleucovorin injection is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall) when methotrexate is used to to treat certain types of cancer. Levoleucovorin injection is also used to treat people ...

  20. Leucovorin Injection

    MedlinePlus

    Leucovorin injection is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall; cancer chemotherapy medication) when methotrexate is used to to treat certain types of cancer. Leucovorin injection is used to ...

  1. Teniposide Injection

    MedlinePlus

    ... in men. You should not become pregnant or breast-feed while you are receiving teniposide injection. If you or your partner become pregnant while receiving teniposide injection, call your doctor. Teniposide may harm the fetus.

  2. Ipilimumab Injection

    MedlinePlus

    ... are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while receiving ipilimumab injection, call your doctor. Ipilimumab injection may cause your baby to be born too early or to die before birth.

  3. Pralatrexate Injection

    MedlinePlus

    Pralatrexate injection is used to treat peripheral T-cell lymphoma (PTCL; a form of cancer that begins in a ... come back after treatment with other medications. Pralatrexate injection has not been shown to help people who ...

  4. Cyanocobalamin Injection

    MedlinePlus

    Cyanocobalamin injection is used to treat and prevent a lack of vitamin B12 that may be caused by any ... organs) and permanent damage to the nerves. Cyanocobalamin injection also may be given as a test to ...

  5. Paclitaxel Injection

    MedlinePlus

    Paclitaxel injection manufactured with human albumin is used to treat breast cancer that has not improved or that has come back after treatment with other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to ...

  6. Diphenhydramine Injection

    MedlinePlus

    Diphenhydramine injection is used to treat allergic reactions, especially for people who are unable to take diphenhydramine by mouth. ... is used also to treat motion sickness. Diphenhydramine injection is also used alone or along with other ...

  7. Peramivir Injection

    MedlinePlus

    Peramivir injection is used to treat some types of influenza infection ('flu') in people who have had symptoms of ... flu for no longer than 2 days. Peramivir injection is in a class of medications called neuraminidase ...

  8. Cefotetan Injection

    MedlinePlus

    Cefotetan injection is used to treat infections of the lungs, skin, bones, joints, stomach area, blood, female reproductive organs, and urinary tract. Cefotetan injection is also used before surgery to prevent infections. ...

  9. Mipomersen Injection

    MedlinePlus

    Mipomersen injection is used to decrease levels of cholesterol and other fatty substances in the blood in people who ... that removes LDL from the blood), but mipomersen injection should not be used along with this treatment. ...

  10. Romiplostim Injection

    MedlinePlus

    Romiplostim injection is used to increase the number of platelets (cells that help the blood to clot) in order ... low number of platelets in the blood). Romiplostim injection should only be used in people who cannot ...

  11. Hydrocortisone Injection

    MedlinePlus

    Hydrocortisone injection is used to treat symptoms of low corticosteroid levels (lack of certain substances that are usually produced ... also used to treat severe allergic reactions. Hydrocortisone injection is used in the management of multiple sclerosis ( ...

  12. Palivizumab Injection

    MedlinePlus

    Palivizumab injection is used to help prevent respiratory syncytial virus (RSV; common virus that can cause serious lung infections) ... or have certain heart or lung diseases. Palivizumab injection is not used to treat the symptoms of ...

  13. Naltrexone Injection

    MedlinePlus

    Naltrexone injection is used along with counseling and social support to help people who have stopped drinking large amounts of alcohol to avoid drinking again. Naltrexone injection is also used along with counseling and social ...

  14. Tesamorelin Injection

    MedlinePlus

    Tesamorelin injection is used to decrease the amount of extra fat in the stomach area in adults with human ... fat in certain areas of the body). Tesamorelin injection is not used to help with weight loss. ...

  15. Testosterone Injection

    MedlinePlus

    ... and testosterone pellet (Testopel) are forms of testosterone injection used to treat symptoms of low testosterone in ... are low before you begin to use testosterone injection. Testosterone enanthate (Delatestryl) and testosterone pellet (Testopel) are ...

  16. Tigecycline Injection

    MedlinePlus

    Tigecycline injection used to treat certain serious infections including community acquired pneumonia (a lung infection that developed in a ... area between the chest and the waist). Tigecycline injection should not be used to treat pneumonia that ...

  17. Eculizumab Injection

    MedlinePlus

    Eculizumab injection is used to treat paroxysmal nocturnal hemoglobinuria (PNH: a type of anemia in which too many red ... oxygen to all parts of the body). Eculizumab injection is also used to treat atypical hemolytic uremic ...

  18. Pembrolizumab Injection

    MedlinePlus

    Pembrolizumab injection is used to treat melanoma (a type of skin cancer) that cannot be treated with surgery or ... spread to other parts of the body. Pembrolizumab injection is also used to treat a certain type ...

  19. Methylprednisolone Injection

    MedlinePlus

    ... allergic reactions. Methylprednisolone injection is used in the management of multiple sclerosis (a disease in which the ... laboratory test, tell your doctor and the laboratory personnel that you are using methylprednisolone injection.If you ...

  20. Obinutuzumab Injection

    MedlinePlus

    Obinutuzumab injection is used with chlorambucil (Leukeran) to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells). Obinutuzumab injection is in a class of medications called ...

  1. Extension of time until cardiac arrest after injection of a lethal dose of pentobarbital in the hibernating Syrian hamster.

    PubMed

    Miyazawa, Seiji; Shiina, Takahiko; Takewaki, Tadashi; Shimizu, Yasutake

    2009-03-01

    The aim of the present study was to examine whether entry of peripherally injected drugs into the central nervous system is reduced during hibernation. When a lethal dose of pentobarbital was injected intraperitoneally, the time until cardiac arrest was significantly longer in hibernating hamsters than in active controls. The time difference was not a consequence of low body temperature or diminished circulation, because mimicking these parameters in artificial hypothermia did not prolong the time. In contrast, there was no difference in the time until cardiac arrest after intracerebroventricular injection of the anesthetic. These results indicate that entry of peripherally injected anesthetics into the central nervous system may be suppressed during hibernation.

  2. Insulin during pregnancy, labour and delivery.

    PubMed

    de Valk, Harold W; Visser, Gerard H A

    2011-02-01

    subcutaneous insulin administration (CSII (insulin pump)) over intensive insulin injection therapy (multiple-dose insulin (MDI)) on any maternal or foeto-neonatal end point. However, group sizes were far too small to allow assessment of superiority and issues such as manageability of the disease and quality of life were never assessed. These two issues are of major importance to patients. The first trimester is often the period of most hypoglycaemic events, and insulin therapy should be especially closely monitored and adjusted in this period. After midterm, insulin requirements increase. Continuous glucose monitoring can offer better insights into the glycaemic profile than self-monitoring of blood glucose levels by the patients but the place of these new monitoring techniques has yet to be established more clearly. Insulin therapy during labour means short-acting insulin adjusted to achieve glucose levels between 4 and 8 mmol l(-1) to prevent neonatal hypoglycaemia as much as possible. After delivery, glycaemic control must be relaxed to prevent hypoglycaemia, especially in women who breastfeed.

  3. Busulfan Injection

    MedlinePlus

    Busulfex® Injection ... Busulfan injection is used to treat a certain type of chronic myelogenous leukemia (CML; a type of cancer of ... of 16 doses) before bone marrow transplant.Busulfan injection may cause seizures during therapy with the medication. ...

  4. Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats.

    PubMed Central

    De Sarro, A; Ammendola, D; Zappala, M; Grasso, S; De Sarro, G B

    1995-01-01

    The epileptogenic activities of several beta-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various beta-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of beta-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mumol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggest that the beta-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the beta-lactam antibiotics. While the structure

  5. Effects of antidepressants and antihistaminics on catalepsy induced by intracerebroventricular administration of histamine in mice.

    PubMed

    Onodera, K

    1991-01-01

    The intracerebroventricular (icv) administration of histamine but not N-telemethylhistamine and 1-methyl-4-imidazole acetic acid induced catalepsy in mice. Histamine H1-receptor blockers such as cyproheptadine, mepyramine and diphenhydramine reduced histamine-induced catalepsy. However, astemizole which is known to be without central effects, did not reduce histamine-induced catalepsy. The icv pretreatment with histamine H2-receptor blockers, such as metiamide and cimetidine, also had no effect. Moreover, various antidepressants, both imipramine- and atypical-type drugs antagonized histamine-induced catalepsy to various degrees in this experiment. Thus, the induction of catalepsy by icv administration of histamine was mediated through histamine H1-receptors, and suggested that antidepressants reduced histamine-induced catalepsy via this mechanism. Histamine-induced catalepsy is a possible new animal model of depression which can also be used for evaluation of atypical antidepressants.

  6. 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.

  7. Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver.

    PubMed

    Okamoto, Maristela Mitiko; Anhê, Gabriel Forato; Sabino-Silva, Robinson; Marques, Milano Felipe dos Santos Ferreira; Freitas, Helayne Soares; Mori, Rosana Cristina Tieko; Melo, Karla Fabiana S; Machado, Ubiratan Fabres

    2011-10-01

    Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1.5, 3, 6, and 9 U/day) over 7 days. Insulinopenic-untreated rats and 6U- and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U- and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.

  8. A review of biodegradable polymeric systems for oral insulin delivery.

    PubMed

    Luo, Yue Yuan; Xiong, Xiang Yuan; Tian, Yuan; Li, Zi Ling; Gong, Yan Chun; Li, Yu Ping

    2016-07-01

    Currently, repeated routine subcutaneous injections of insulin are the standard treatment for insulin-dependent diabetic patients. However, patients' poor compliance for injections often fails to achieve the stable concentration of blood glucose. As a protein drug, the oral bioavailability of insulin is low due to many physiological reasons. Several carriers, such as macromolecules and liposomes have been used to deliver drugs in vivo. In this review article, the gastrointestinal barriers of oral insulin administration are described. Strategies for increasing the bioavailability of oral insulin, such absorption enhancers, enzyme inhibitors, enteric coatings are also introduced. The potential absorption mechanisms of insulin-loaded nanoparticles across the intestinal epithelium, including intestinal lymphatic route, transcellular route and paracellular route are discussed in this review. Natural polymers, such as chitosan and its derivates, alginate derivatives, γ-PGA-based materials and starch-based nanoparticles have been exploited for oral insulin delivery; synthetic polymers, such as PLGA, PLA, PCL and PEA have also been developed for oral administration of insulin. This review focuses on recent advances in using biodegradable natural and synthetic polymers for oral insulin delivery along with their future prospects.

  9. A comparative analysis of intraperitoneal versus intracerebroventricular administration of bromodeoxyuridine for the study of cell proliferation in the adult rat brain.

    PubMed

    Cifuentes, M; Pérez-Martín, M; Grondona, J M; López-Ávalos, M D; Inagaki, N; Granados-Durán, P; Rivera, P; Fernández-Llebrez, P

    2011-10-15

    Bromodeoxyuridine (BrdU) is the most widely used marker to detect proliferative cells in the adult brain. Here we analyse whether the route of administration of the tracer influences the number of labelled cells. For the intraperitoneal (ip) administration of BrdU, we performed two daily injections during 7 days, and for an intracerebroventricular (icv) delivery, it was continuously infused into one lateral ventricle for a 7 days period as well. After ip administration, cells labelled with BrdU were seen in the subventricular zone of the striatal wall of the lateral ventricle, the hippocampus and the neurohemal circumventricular organs. Also, the habenula and large myelinated tracts, such as the fornix and the corpus callosum, showed many BrdU-positive nuclei. Labelled nuclei were scarce in the parenchymal regions of the rest of the brain. In contrast, a significant increase in the number of BrdU-positive nuclei was observed in the parenchyma of the periventricular zones after icv administration of the marker, thus showing a greater availability of the tracer when it was administered directly into the ventricular cerebrospinal fluid. We suggest that the availability of BrdU in the vicinity of proliferating cells may depend on the permeability of the brain vessels to nucleosides in each location. By using double immunocytochemistry we found that neurons, astrocytes, oligodendrocytes, tanycytes and microglia had incorporated the tracer, demonstrating their proliferation capacity.

  10. Inhaled insulin--does it become reality?

    PubMed

    Siekmeier, R; Scheuch, G

    2008-12-01

    After more than 80 years of history the American and European Drug Agencies (FDA and EMEA) approved the first pulmonary delivered version of insulin (Exubera) from Pfizer/Nektar early 2006. However, in October 2007, Pfizer announced it would be taking Exubera off the market, citing that the drug had failed to gain market acceptance. Since 1924 various attempts have been made to get away from injectable insulin. Three alternative delivery methods where always discussed: Delivery to the upper nasal airways or the deep lungs, and through the stomach. From these, the delivery through the deep lungs is the most promising, because the physiological barriers for the uptake are the smallest, the inspired aerosol is deposited on a large area and the absorption into the blood happens through the extremely thin alveolar membrane. However, there is concern about the long-term effects of inhaling a growth protein into the lungs. It was assumed that the large surface area over which the insulin is spread out would minimize negative effects. But recent news indicates that, at least in smokers, the bronchial tumour rate under inhaled insulin seems to be increased. These findings, despite the fact that they are not yet statistical significant and in no case found in a non-smoker, give additional arguments to stop marketing this approach. Several companies worked on providing inhalable insulin and the insulin powder inhalation system Exubera was the most advanced technology. Treatment has been approved for adults only and patients with pulmonary diseases (e.g., asthma, emphysema, COPD) and smokers (current smokers and individuals who recently quitted smoking) were excluded from this therapy. Pharmacokinetics and pharmacodynamics of Exubera are similar to those found with short-acting subcutaneous human insulin or insulin analogs. It is thus possible to use Exubera as a substitute for short-acting human insulin or insulin analogs. Typical side effects of inhaled insulin were coughing

  11. Insulin therapy in children and adolescents with type 1 diabetes.

    PubMed

    Malik, Faisal S; Taplin, Craig E

    2014-04-01

    Treatment of type 1 diabetes mellitus (T1DM) requires lifelong administration of exogenous insulin. The primary goal of treatment of T1DM in children and adolescents is to maintain near-normoglycemia through intensive insulin therapy, avoid acute complications, and prevent long-term microvascular and macrovascular complications, while facilitating as close to a normal life as possible. Effective insulin therapy must, therefore, be provided on the basis of the needs, preferences, and resources of the individual and the family for optimal management of T1DM. To achieve target glycemic control, the best therapeutic option for patients with T1DM is basal-bolus therapy either with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Many formulations of insulin are available to help simulate endogenous insulin secretion as closely as possible in an effort to eliminate the symptoms and complications of hyperglycemia, while minimizing the risk of hypoglycemia secondary to therapy. When using MDI, basal insulin requirements are given as an injection of long- or intermediate-acting insulin analogs, while meal-related glucose excursions are controlled with bolus injections of rapid-acting insulin analogs. Alternatively, CSII can be used, which provides a 24-h preselected but adjustable basal rate of rapid-acting insulin, along with patient-activated mealtime bolus doses, eliminating the need for periodic injections. Both MDI treatment and CSII therapy must be supported by comprehensive education that is appropriate for the individual needs of the patient and family before and after initiation. Current therapies still do not match the endogenous insulin profile of pancreatic β-cells, and all still pose risks of suboptimal control, hypoglycemia, and ketosis in children and adolescents. The safety and success of a prescribed insulin regimen is, therefore, dependent on self-monitoring of blood glucose and/or a continuous glucose monitoring system

  12. Evaluating older patients with diabetes for insulin pump therapy.

    PubMed

    Stephens, Elizabeth A; Heffner, John

    2010-06-01

    The increasing prevalence of diabetes among elderly patients underscores the importance of matching the most effective therapy for diabetes self-management with patients' cognitive and motor skills, as these diminish with advancing age. Although many geriatric patients state interest in insulin pump therapy for tight glycemic control, few studies have examined the effectiveness, safety, and feasibility of insulin pumps compared to traditional injected insulin therapy in older age groups. It is important, therefore, for physicians to recognize the indications and the age-related barriers to insulin pump therapy in geriatric patients. Indications include glucose variability, hypoglycemia, and poor glycemic control with traditional insulin regimens. Common barriers include poor vision, dexterity, and cognitive status. Successful implementation of insulin pump therapy for older patients requires an experienced diabetes management team that can assess patient needs and tailor therapy in the context of age-related disabilities.

  13. Human insulin microcrystals with lactose carriers for pulmonary delivery.

    PubMed

    Lim, Se-Hwan; Park, Hye Won; Shin, Chang-Hoon; Kwon, Jai-Hyun; Kim, Chan-Wha

    2009-12-01

    Dry powder formulations for pulmonary delivery are attractive because many issues of solubility and stability can be minimized. Human insulin microcrystals with lactose carriers were produced for pulmonary delivery. The average particle diameter was 2.3 microm, with a narrow, monodispersed size distribution. The percentages of high molecular weight proteins (%HMWPs), other insulin-related compounds (%OIRCs), and A-21 desamido insulin (%D(es)) were very low throughout the microcrystal preparation process. Administration of the microcrystal powder by intratracheal insufflation significantly reduced the blood glucose levels of Sprague-Dawley rats. The percent minimum reductions of the blood glucose concentration (%MRBG) produced by the insulin microcrystal powder and by an insulin solution reached 40.4% and 33.4% of the initial glucose levels respectively, and their bioavailability relative to subcutaneous injection (F) was 15% and 10% respectively. These results confirm that the insulin microcrystal powder prepared is suitable for pulmonary delivery in an effective dosage form.

  14. H(1) and H(2) receptors in the locus ceruleus are involved in the intracerebroventricular histamine-induced carotid sinus baroreceptor reflex resetting in rats.

    PubMed

    Wang, Guo-Qing; Sun, Wan-Ping; Zhu, Yong-Jin; Zou, Rong; Zhou, Xi-Ping

    2006-07-01

    Objective To investigate the role of H(1) and H(2) receptors in the locus ceruleus (LC) in carotid sinus baroreceptor reflex (CSR) resetting induced by intracerebroventricular (i.c.v.) injection of histamine (HA). Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner in vivo. ISP-mean arterial pressure (MAP) relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H(1) or H(2) receptors selective antagonist, chlorpheniramine (CHL) or cimetidine (CIM) into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA (100 ng in 5 mu l) significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and obviously decreased the value of the reflex parameters such as MAP range and maximum gain (P < 0.05), but increased the threshold pressure, saturation pressure and ISP at maximum gain (P < 0.05). The pretreatment with CHL (0.5 mu g in 1 mu l) or CIM (1.5 mu g in 1 mu l) into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL (P < 0.05). Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly (P > 0.05). Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H(1) and H(2) receptors activities in the LC, especially by H(1) receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.

  15. Effect of insulin on Blattela germanica Linnacus

    PubMed Central

    Abolghasemi, E; Moosa, Kazem SH; Abolhasani, M; Davoudi, M

    2011-01-01

    Objective To determine the sensitivity of Blattela germanica L (B. germanica L) to differenct doses of insulin. Methods B. germanica were reared in laboratory conditions at (25±2) °C and (50±5)% relative humidity (RH), and exposure period of 12:12 L/D. Different concentrations, viz. 5, 10, 15, 20 and 25 µ of insulin N, R, (N+R) were prepared and injected to 10 treated cockroaches with another 10 cockroaches which were injected with normal saline as control group. Results Insulin N with a dose of 20 µ caused more than 70% mortality of B. germanica in this study. There was a significant difference between 20 µ of insulin N with other doses of 5, 10, 15 and 25 µ, and its comparison with other forms of medication also showed obvious difference (P<0.05). Conclusions It can be concluded that effective drug doses of insulin which can be used as posion bait or gel against German cockroaches could be utilized in the control of B. germanica in the future field studies. PMID:23569776

  16. Diabetes and Insulin

    MedlinePlus

    ... you have. There are three main types of diabetes: • Type 1 occurs when the pancreas stops making insulin. It ... but may occur later in life. People with type 1 diabetes need insulin to survive. Treatment includes changes in ...

  17. 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 ...

  18. Evidence-based clinical use of insulin premixtures

    PubMed Central

    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

  19. Preformed Seeds Modulate Native Insulin Aggregation Kinetics.

    PubMed

    Dutta, Colina; Yang, Mu; Long, Fei; Shahbazian-Yassar, Reza; Tiwari, Ashutosh

    2015-12-10

    Insulin aggregates under storage conditions via disulfide interchange reaction. It is also known to form aggregates at the site of repeated injections in diabetes patients, leading to injection amyloidosis. This has fueled research in pharmaceutical and biotechnology industry as well as in academia to understand factors that modulate insulin stability and aggregation. The main aim of this study is to understand the factors that modulate aggregation propensity of insulin under conditions close to physiological and measure effect of "seeds" on aggregation kinetics. We explored the aggregation kinetics of insulin at pH 7.2 and 37 °C in the presence of disulfide-reducing agent dithiothreitol (DTT), using spectroscopy (UV-visible, fluorescence, and Fourier transform infrared spectroscopy) and microscopy (scanning electron microscopy, atomic force microscopy) techniques. We prepared insulin "seeds" by incubating disulfide-reduced insulin at pH 7.2 and 37 °C for varying lengths of time (10 min to 12 h). These seeds were added to the native protein and nucleation-dependent aggregation kinetics was measured. Aggregation kinetics was fastest in the presence of 10 min seeds suggesting they were nascent. Interestingly, intermediate seeds (30 min to 4 h incubation) resulted in formation of transient fibrils in 4 h that converted to amorphous aggregates upon longer incubation of 24 h. Overall, the results show that insulin under disulfide reducing conditions at pH and temperature close to physiological favors amorphous aggregate formation and seed "maturity" plays an important role in nucleation dependent aggregation kinetics.

  20. All about Insulin Resistance

    MedlinePlus

    Toolkit No. 2 All About Insulin Resistance Insulin resistance is a condition that raises your risk for type 2 diabetes and heart disease. ... Diabetes Association, Inc. 1/15 Toolkit No. 2: All About Insulin Resistance continued J Order the smallest ...

  1. Insulin-loaded alginic acid nanoparticles for sublingual delivery.

    PubMed

    Patil, Nilam H; Devarajan, Padma V

    2016-01-01

    Alginic acid nanoparticles (NPs) containing insulin, with nicotinamide as permeation enhancer were developed for sublingual delivery. The lower concentration of proteolytic enzymes, lower thickness and enhanced retention due to bioadhesive property, were relied on for enhanced insulin absorption. Insulin-loaded NPs were prepared by mild and aqueous based nanoprecipitation process. NPs were negatively charged and had a mean size of ∼200 nm with low dispersity index. Insulin loading capacities of >95% suggested a high association of insulin with alginic acid. Fourier Transform Infra-Red Spectroscopy (FTIR) spectra and DSC (Differential Scanning Calorimetry) thermogram of insulin-loaded NPs revealed the association of insulin with alginic acid. Circular dichroism (CD) spectra confirmed conformational stability, while HPLC analysis confirmed chemical stability of insulin in the NPs. Sublingually delivered NPs with nicotinamide exhibited high pharmacological availability (>100%) and bioavailability (>80%) at a dose of 5 IU/kg. The high absolute pharmacological availability of 20.2% and bioavailability of 24.1% in comparison with subcutaneous injection at 1 IU/kg, in the streptozotocin-induced diabetic rat model, suggest the insulin-loaded alginic acid NPs as a promising sublingual delivery system of insulin.

  2. THE HYPOPHYSIS AND SECRETION OF INSULIN

    PubMed Central

    Houssay, B. A.; Foglia, V. G.; Smyth, F. S.; Rietti, C. T.; Houssay, A. B.

    1942-01-01

    The ability of the pancreas, from various types of dogs, to correct diabetic hyperglycemia has been studied (Table XI). The pancreas from one animal was united by a vascular union with the neck blood vessels of another dog which had been pancreatectomized for 20 hours. The time necessary to reduce the blood sugar level to 120 mg. per cent was determined. 1. Pancreas from 6 hypophysectomized dogs produced a normal insulin secretion, showing that an anterior pituitary hormone is not necessary for its production or maintenance. 2. In 14 of 17 normal dogs given anterior pituitary extract for 3 or more consecutive days and presenting diabetes (fasting blood sugar 150 mg. per cent or more) the pancreas showed diminished insulin production. 3. In animals which remained diabetic after discontinuing the injections of hypophyseal extract, the pancreas islands were markedly pathologic and the insulin secretion was practically nil. 4. When hyperglycemia existed on the 2nd to 5th day but fell later, the insulin secretion of 5 dogs was normal in 2, supernormal in 1, and less than normal in 2. Histologic examination showed a restoration of beta cells. 5. In 14 dogs resistant to the diabetogenic action of anterior pituitary extract, as shown by little or no change in blood sugar, the pancreatic secretion of insulin was normal in 6 cases, supernormal in 3, and subnormal in 5 cases. Clear signs of hyperfunction of B cells were observed. In 6 resistant animals a high blood sugar (150 mg. per cent) appeared shortly before transplanting, but insulin secretion was normal in 4, supernormal in 1, and subnormal in 1 case. 6. With one injection of extract and 1 day of hyperglycemia the capacity of the pancreas to secrete insulin was not altered. 7. A high blood sugar level lasting 4 days does not alter the islets. The hypophyseal extract acts, therefore, by some other mechanism. In normal dogs, the continuous intravenous infusion of glucose for 4 days maintained the blood sugar at levels as

  3. Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes

    PubMed Central

    Levy, Philip

    2007-01-01

    Context Type 2 diabetes is a progressive disease that is reaching epidemic proportions. Whereas most patients are initially managed with oral antidiabetic agents (OADs), the majority eventually require insulin to maintain glycemic control. The availability of insulin analogs (rapid-acting, long-acting, and premixed), with more predictable time-action profiles than human insulin preparations and simple-to-use insulin delivery devices, can help ease the transition to insulin therapy, which is often delayed until glycemic control has been inadequate for several years. >Objective To review the rationale for and strategies to initiate therapy with insulin analogs earlier in the course of type 2 diabetes. Practical barriers that must be overcome to successfully initiate insulin therapy in patients with type 2 diabetes are also briefly described. Design Narrative review of clinical evidence and current diabetes treatment guidelines. Setting and Patients Outpatients with type 2 diabetes inadequately managed with OADs alone. Interventions Three of the most common approaches to initiating insulin therapy with analogs are considered, with clinical evidence and detailed dosing algorithms provided. These approaches include: (1) addition of a basal insulin analog to oral therapy to reduce and stabilize fasting plasma glucose, (2) supplementation of oral therapy with a rapid-acting mealtime insulin analog to control postprandial glucose excursions, and (3) addition of or switching to a premixed insulin analog, which can be used to control both fasting and postprandial glucose in 1 injection. Conclusions Selection of appropriate insulin analog regimens and individualization of therapy can help patients achieve recommended glycemic goals while minimizing hypoglycemia. Education about the eventual need for insulin and improvements in insulin preparations and delivery systems at the time of diagnosis can also help overcome patient barriers. PMID:17955068

  4. Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice.

    PubMed

    Wen, Jing; Chen, Christopher Holden; Stock, Ariel; Doerner, Jessica; Gulinello, Maria; Putterman, Chaim

    2016-05-01

    Fn14, the sole known signaling receptor for the TNF family member TWEAK, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. There is increasing recognition of the importance of the TWEAK/Fn14 pathway in autoimmune neurologic conditions, including experimental autoimmune encephalomyelitis and neuropsychiatric lupus. Previously, we had found that Fn14 knockout lupus-prone MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To investigate whether this improvement in disease is secondary to inhibition of TWEAK/Fn14 signaling within the CNS or the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular (ICV) injection of Fc-TWEAK or an isotype matched control protein to C57Bl6/J non-autoimmune mice. We found that Fc-TWEAK injected C57Bl6/J mice developed significant depression-like behavior and cognitive dysfunction. Inflammatory mediators associated with lupus brain disease, including CCL2, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased blood brain barrier (BBB) permeability, as demonstrated by increased IgG deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex and hippocampus. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive dysfunction by acting within the CNS to enhance production of inflammatory mediators, promote disruption of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS.

  5. Atorvastatin Prevents Cognitive Deficits Induced by Intracerebroventricular Amyloid-β1-40 Administration in Mice: Involvement of Glutamatergic and Antioxidant Systems.

    PubMed

    Martins, Wagner C; dos Santos, Vanessa Valgas; dos Santos, Alessandra Antunes; Vandresen-Filho, Samuel; Dal-Cim, Tharine A; de Oliveira, Karen A; Mendes-de-Aguiar, Claudia B N; Farina, Marcelo; Prediger, Rui Daniel; Viola, Giordano Gubert; Tasca, Carla I

    2015-07-01

    Deposition of amyloid-β (Aβ) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Aβ-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Aβ1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Aβ1-40 administration. Aβ1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Aβ1-40 decreased hippocampal and cortical Na(+)-dependent glutamate uptake. However, Aβ1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Aβ1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Aβ1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Aβ1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Aβ in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex.

  6. Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose.

    PubMed

    Huang, Han-Chang; Zheng, Bo-Wen; Guo, Yu; Zhao, Jian; Zhao, Jiang-Yan; Ma, Xiao-Wei; Jiang, Zhao-Feng

    2016-04-05

    Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

  7. Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits.

    PubMed

    Lim, Kyungjoon; Burke, Sandra L; Head, Geoffrey A

    2013-03-01

    Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased blood pressure and RSNA during a HFD using specific antagonists. New Zealand White rabbits were implanted with an intracerebroventricular (ICV) catheter and RSNA electrode and placed on a normal or 13.5% HFD for 1 or 3 weeks. Blood pressure, heart rate, and RSNA were recorded before and for 90 minutes after ICV administration of a leptin antagonist (100 µg), insulin antagonist (0.5 U), or vehicle (50 µL) on separate days. Rabbits had higher blood pressure (+8%, +17%) and RSNA (+55%, +71%), at 1 and 3 weeks, respectively, of HFD compared with controls (n=7-11). ICV leptin antagonist reduced blood pressure by 9% and RSNA by 17% (P<0.001) after 3 weeks of HFD but had no effect at week 1. ICV administration of the insulin antagonist reduced blood pressure by ≈5% at both times (P<0.05) but there was no effect on RSNA. Leptin and insulin antagonist doses were confirmed to effectively block the pressor responses to ICV leptin and insulin, respectively. The elevation of blood pressure and RSNA induced by a HFD is predominantly mediated by central actions of leptin. Central actions of insulin contribute a smaller proportion of the hypertension but independently of RSNA.

  8. 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

  9. Peripheral Insulin Doesn't Alter Appetite of Broiler Chicks.

    PubMed

    Liu, Lei; Xu, Shaohua; Wang, Xiaojuan; Jiao, Hongchao; Lin, Hai

    2016-09-01

    An experiment was conducted to investigate the effect of peripheral insulin treatment on appetite in chicks. Six-d-age chicks with ad libitum feeding or fasting for 3 h before injection received a subcutaneous injection of 0, 1, 3, 5, 10, or 20 IU of insulin or vehicle (saline). The results showed peripheral insulin treatment (1 to 20 IU) did not alter significantly the feed intake in chicks under either ad libitum feeding or fasting conditions within 4 h (p>0.05). Compared with the control, plasma glucose concentration was significantly decreased after insulin treatment of 3, 5, 10, and 20 IU for 4 h in chicks with ad libitum feeding (p<0.05). In fasted chicks, 10 and 20 IU insulin treatments significantly decreased the plasma glucose level for 4 h (p<0.05). Peripheral insulin treatment of 10 IU for 2 or 4 h did not significantly affect the hypothalamic genes expression of neuropeptide Y, proopiomelanocortin, corticotropin-releasing factor and insulin receptors (p>0.05). All results suggest peripheral administration of insulin has no effect on appetite in chicks.

  10. 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

  11. Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3β decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model.

    PubMed

    Ponce-Lopez, Teresa; Liy-Salmeron, Gustavo; Hong, Enrique; Meneses, Alfredo

    2011-12-02

    Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3β (p-GSK3β) and total GSK3β levels were determined, and importantly GSK3β regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PFC) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3β levels, while total GSK3β did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100mg/kg), phenserine (1mg/kg), memantine (5mg/kg) and pioglitazone (30 mg/kg). The p-GSK3β levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3β levels in neither the hippocampus nor PFC. Total GSK3β levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3β levels, a kinase key of

  12. Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics

    PubMed Central

    Battelino, Tadej; Danne, Thomas; Hovorka, Roman; Jarosz‐Chobot, Przemyslawa; Renard, Eric

    2015-01-01

    Summary The level of glycaemic control necessary to achieve optimal short‐term and long‐term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid‐acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health‐related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid‐acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost‐effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid‐acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin

  13. Musculoskeletal Injection

    PubMed Central

    Wittich, Christopher M.; Ficalora, Robert D.; Mason, Thomas G.; Beckman, Thomas J.

    2009-01-01

    Patients commonly present to primary care physicians with musculoskeletal symptoms. Clinicians certified in internal medicine must be knowledgeable about the diagnosis and management of musculoskeletal diseases, yet they often receive inadequate postgraduate training on this topic. The musculoskeletal problems most frequently encountered in our busy injection practice involve, in decreasing order, the knees, trochanteric bursae, and glenohumeral joints. This article reviews the clinical presentations of these problems. It also discusses musculoskeletal injections for these problems in terms of medications, indications, injection technique, and supporting evidence from the literature. Experience with joint injection and the pharmacological principles described in this article should allow primary care physicians to become comfortable and proficient with musculoskeletal injections. PMID:19720781

  14. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

    PubMed

    Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei

    2015-02-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.

  15. Insulin secretion stimulated by allogeneic lymphocytes in an inbred strain of mice.

    PubMed Central

    García, J B; Venturino, M C; Alvarez, E; Fabiano de Bruno, L; Braun, M; Pivetta, O H; Basabe, J C

    1986-01-01

    Effects of intraperitoneal injection of allogeneic lymphocytes on insulin secretion were studied in incubated pancreas slices from BALB/c mice. Injection of allogeneic lymphocytes from C57BL/6J (H2b) mice increased insulin secretion, both in basal and 11-mM glucose-stimulated conditions. This effect was only present when at least 5 X 10(6) or 1 X 10(6) cells were injected (in basal and stimulated conditions, respectively). Glucose-induced insulin secretion (3.3-27.5 mM) was significantly increased in pancreata from mice injected with allogeneic lymphocytes. No effect was observed when glucose was not included in the incubation medium. Intraperitoneal injection of Dextran 70 produced no change in glucose-elicited insulin secretion. There were no differences in glucagon and somatostatin (SRIF) secretion obtained from pancreas of mice injected with allogeneic or syngeneic lymphocytes. Injection of allogeneic cells increases insulin secretion (basal and both phases of 11 mM glucose-stimulated secretion). Puromycin significantly inhibited the second phase of insulin secretion. These results suggest that: Injection of allogeneic lymphocytes raises both basal and glucose-stimulated insulin secretion. This effect seems to be connected with the major histocompatibility complex, and to be related to the number of allogeneic cells injected. Injection of allogeneic lymphocytes seems to sensitize the beta cell response to glucose stimulus. Neither glucagon nor SRIF secretion are altered by alloantigen injection. The stimulatory effect of allogeneic lymphocytes is related, at least in part, to insulin synthesis. PMID:2871044

  16. Basal insulin: beyond glycemia.

    PubMed

    Niswender, Kevin D

    2011-07-01

    Insulin is a pleiotropic hormone with numerous effects at the cellular, tissue, and organismal levels. Clinicians are familiar with physiological effects of insulin on carbohydrate metabolism, including stimulation of glucose uptake in skeletal muscle and the suppression of glucose production from the liver. Other metabolic effects of insulin include inhibiting the release of free fatty acids from adipose tissue and stimulating the incorporation of amino acids into proteins. Indeed, every organ in the body, including the brain, is a target for insulin action. Insulin resistance, typically defined with respect to glucose metabolism, is a condition in which normal levels of insulin do not trigger the signal for glucose disposition. The effects of insulin resistance and impaired insulin signaling have profound pathophysiologic effects, such as hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular and renal disease. An integrated view of insulin action in all of these tissues may yield improved therapeutic insight and possibly even illuminate new therapeutic opportunities. With the increase in the number of patients diagnosed with prediabetes and diabetes, an updated understanding of the disease and the pharmacologic armamentarium used to treat it is needed to improve outcomes. To help expand the clinical care provider's perspective, this article will provide a provocative discussion about the pathophysiology of diabetes, the role of insulin and insulin resistance, and the clinical efficacy potential of insulin. Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome.

  17. Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus.

    PubMed

    Dong, Hongxin; Csernansky, Cynthia A; Chu, Yunxiang; Csernansky, John G

    2003-10-10

    The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.

  18. Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation.

    PubMed

    Broetto, Núbia; Hansen, Fernanda; Brolese, Giovana; Batassini, Cristiane; Lirio, Franciane; Galland, Fabiana; Dos Santos, João Paulo Almeida; Dutra, Márcio Ferreira; Gonçalves, Carlos-Alberto

    2016-06-01

    Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are histological markers of Alzheimer's disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. Okadaic acid (OKA), a strong inhibitor of protein phosphatase 2A, has been used to induce dementia similar to AD in rats. We herein investigated the effect of intracerebroventricular (ICV) infusion of OKA (100 and 200ng) on hippocampal tau phosphorylation at Ser396, which is considered an important fibrillogenic tau protein site, and on glucose uptake, which is reduced early in AD. ICV infusion of OKA (at 200ng) induced a spatial cognitive deficit, hippocampal astrogliosis (based on GFAP increment) and increase in tau phosphorylation at site 396 in this model. Moreover, we observed a decreased glucose uptake in the hippocampal slices of OKA-treated rats. In vitro exposure of hippocampal slices to OKA altered tau phosphorylation at site 396, without any associated change in glucose uptake activity. Taken together, these findings further our understanding of OKA neurotoxicity, in vivo and vitro, particularly with regard to the role of tau phosphorylation, and reinforce the importance of the OKA dementia model for studying the neurochemical alterations that may occur in AD, such as NFTs and glucose hypometabolism.

  19. Effects of intracerebroventricular administration of N-acetylhistamine on body temperature in mice.

    PubMed

    Onodera, K; Shinoda, H; Imaizumi, M; Hiraki-Sakurai, E; Yamatodani, A

    1994-10-01

    The purpose of this study was to examine the effects of intracerebroventricular (i.c.v.) administration of N-acetylhistamine on rectal temperature, histamine level, histidine decarboxylase (HDC) activity, and the turnover rate of monoamines in mice. More than 60 micrograms of N-acetylhistamine induced hypothermia. The maximum effect of hypothermia was observed 20 min after administration of N-acetylhistamine (60-120 micrograms/mouse). A significant drop in rectal temperature of 3 degrees C was induced by 120 micrograms of N-acetylhistamine. Concurrent with the appearance of hypothermia, the histamine levels were increased. However, both histamine H1 and H2 antagonists did not prevent hypothermia. The i.c.v. administration of N-acetylhistamine inhibited HDC activity, but had no effect on the turnover rates of monoamines. These data confirmed that endogenous N-acetylhistamine may be a metabolite which lacks significant physiological roles, and demonstrated that exogenous N-acetylhistamine is not a good pharmacological tool for the study of the functions of the brain histaminergic system in mammals.

  20. Intracerebroventricular administration of neuronostatin induces depression-like effect in forced swim test of mice.

    PubMed

    Yang, Ai-min; Ji, Yue-ke; Su, Shu-fang; Yang, Shao-bin; Lu, Song-song; Mi, Ze-yun; Yang, Qing-zhen; Chen, Qiang

    2011-09-01

    Neuronostatin is a recently discovered endogenous bioactive peptide that is encoded by pro-mRNA of somatostatin. In the present study, we investigated the effect of neuronostatin on mood regulation in the forced swim test of mice. Our results showed intracerebroventricular (i.c.v.) administration of neuronostatin produced an increase in the immobility time, suggesting that neuronostatin induced depression-like effect. In order to rule out the possibility that neuronostatin had increased immobility time by a non-specific reduction in general activity, the effect of neuronostatin on locomotor activity was examined. Neuronostatin had no influence on locomotor activity in mice. In addition, the depression-like effect of neuronostatin was completely reversed by melanocortin 3/4 receptor antagonist SHU9119 or GABAA receptor antagonist bicuculline, but not by opioid receptor antagonist naloxone. These data suggested that the depression-like effect induced by i.c.v. administered neuronostatin was dependent upon the central melanocortin system and GABAA receptor. In conclusion, the results of this study report that neuronostatin induces depression-like effect. These findings reveal that neuronostatin is a new neuropeptide with an important role in regulating depressive behavior.

  1. Insulin secretion after injuries of differing severity in the rat.

    PubMed Central

    Frayn, K. N.

    1976-01-01

    The effects on insulin secretion of injuries of differing severity have been studied in the rat. The injuries used were dorsal scalds to 20% and 40% of the body surface area, and a 4-h period of bilateral hind-limb ischaemia. These injuries resulted in 48 h mortality rates of 0/10, 7/10 and 5/10 respectively. Rats were studied 1-5-2 h after scalding or removal of tourniquets. The blood glucose concentration was markedly raised after all these injuries, and the plasma insulin concentration was also raised, so that the insulin to glucose ratio in any group did not differ significantly from that in non-injured controls. Injection of glucose (0-5 g/kg i.v.) induced a rise in insulin concentration in all groups, although the insulin to glucose ratio after the lethal 40% scald was lower than in control rats. It was concluded that in the rat normal insulin secretion is maintained even after lethal injuries, although some suppression of the insulin response to exogenous glucose may occur. Insulin resistance is more important in the rat than impairment of insulin secretion even at an early stage after injury. PMID:782499

  2. Insulin pumps: from inception to the present and toward the future.

    PubMed

    Alsaleh, F M; Smith, F J; Keady, S; Taylor, K M G

    2010-04-01

    As an alternative to the usual insulin injections, insulin pumps have been introduced as an advanced method of insulin delivery for managing type 1 diabetes mellitus patients. This review documents the history of insulin pump development and the production of 'smart pumps' that offer patients greater dosing accuracy, flexibility, and ease of use. This has resulted in an increase in the number of insulin pump users around the world. This paper also provides a comprehensive survey of the pumps currently available on the market and their specifications. Unique features of each product and the drawbacks are addressed in the review. The future direction of insulin pump development is targeted toward closing the loop, to allow feedback control between an insulin pump and a glucose sensor, and hence finer adjustment of insulin delivery rates as required.

  3. Certolizumab Injection

    MedlinePlus

    ... has not improved when treated with other medications, rheumatoid arthritis (a condition in which the body attacks its ... continues. When certolizumab injection is used to treat rheumatoid arthritis, it is usually given every other week and ...

  4. Natalizumab Injection

    MedlinePlus

    ... prevent episodes of symptoms in people who have Crohn's disease (a condition in which the body attacks the ... If you are receiving natalizumab injection to treat Crohn's disease, your symptoms should improve during the first few ...

  5. Vedolizumab Injection

    MedlinePlus

    ... injection may cause serious allergic reactions during an infusion and for several hours afterward. A doctor or ... of the following symptoms during or after your infusion: rash; itching; swelling of the face, eyes, mouth, ...

  6. Panitumumab Injection

    MedlinePlus

    ... as a solution (liquid) to be given by infusion (injected into a vein). It is usually given ... doctor or nurse in a doctor's office or infusion center. Panitumumab is usually given once every 2 ...

  7. Methotrexate Injection

    MedlinePlus

    ... woman's uterus while she is pregnant), breast cancer, lung cancer, certain cancers of the head and neck; certain ... Methotrexate injection is also used along with rest, physical therapy and ... treat rheumatoid arthritis by decreasing the activity of the immune system.

  8. Alirocumab Injection

    MedlinePlus

    ... injection is used along with diet and certain cholesterol-lowering medications (HMG-CoA reductase inhibitors [statins]) in ... familial heterozygous hypercholesterolemia (an inherited condition in which cholesterol cannot be removed from the body normally) or ...

  9. Evolocumab Injection

    MedlinePlus

    ... injection is used along with diet and certain cholesterol-lowering medications, HMG-CoA reductase inhibitors (statins), in ... heterozygous hypercholesterolemia (HeFH; an inherited condition in which cholesterol cannot be removed from the body normally) or ...

  10. Pentamidine Injection

    MedlinePlus

    Pentamidine injection is used to treat pneumonia caused by a fungus called Pneumocystis carinii. It is in a class of medications called antiprotozoals. It works by stopping the growth of protozoa that can cause pneumonia.

  11. Oxytocin Injection

    MedlinePlus

    Oxytocin injection is used to begin or improve contractions during labor. Oxytocin also is used to reduce bleeding after childbirth. ... other medications or procedures to end a pregnancy. Oxytocin is in a class of medications called oxytocic ...

  12. Ibritumomab Injection

    MedlinePlus

    ... is in a class of medications called monoclonal antibodies with radioisotopes. It works by attaching to cancer ... you receive ibritumomab injection, your body may develop antibodies (substances in the blood that help the immune ...

  13. Ganciclovir Injection

    MedlinePlus

    ... problems, eye problems other than CMV retinitis, or kidney disease.tell your doctor if you are pregnant or plan to become pregnant. Ganciclovir injection may cause infertility (difficulty becoming pregnant). However, if you are a ...

  14. Bendamustine Injection

    MedlinePlus

    ... a type of cancer of the white blood cells). Bendamustine injection is also used to treat a ... that begins in a type of white blood cell that normally fights infection) that is slow spreading, ...

  15. Vancomycin Injection

    MedlinePlus

    ... medications called glycopeptide antibiotics. It works by killing bacteria that cause infections.Antibiotics such as vancomycin injection ... infection may not be completely treated and the bacteria may become resistant to antibiotics.

  16. Levofloxacin Injection

    MedlinePlus

    ... of antibiotics called fluoroquinolones. It works by killing bacteria that cause infections.Antibiotics such as levofloxacin injection ... infection may not be completely treated and the bacteria may become resistant to antibiotics.

  17. Doxycycline Injection

    MedlinePlus

    ... medications called tetracycline antibiotics. It works by killing bacteria that cause infections.Antibiotics such as doxycycline injection ... infection may not be completely treated and the bacteria may become resistant to antibiotics.

  18. Sumatriptan Injection

    MedlinePlus

    ... accompanied by nausea and sensitivity to sound and light). Sumatriptan injection is also used to treat the ... children. Store it at room temperature, away from light, excess heat, and moisture (not in the bathroom). ...

  19. Alemtuzumab Injection

    MedlinePlus

    ... injection, the medication is usually given three times weekly on alternate days (usually Monday, Wednesday, and Friday) ... that you eat foods that are rich in iron such as meats, leafy green vegetables, and fortified ...

  20. Epinephrine Injection

    MedlinePlus

    Epinephrine injection is used along with emergency medical treatment to treat life-threatening allergic reactions caused by ... or stings, foods, medications, latex, and other causes. Epinephrine is in a class of medications called alpha- ...

  1. Mitoxantrone Injection

    MedlinePlus

    ... medications to relieve pain in people with advanced prostate cancer who did not respond to other medications. Mitoxantrone ... doses). When mitoxantrone injection is used to treat prostate cancer, it is usually given once every 21 days. ...

  2. Trastuzumab Injection

    MedlinePlus

    ... with other medications to treat certain types of stomach cancer that have spread to other parts of the ... weeks. When trastuzumab injection is used to treat stomach cancer, it is usually given once every 3 weeks. ...

  3. Topotecan Injection

    MedlinePlus

    ... organs where eggs are formed) and small cell lung cancer (a type of cancer that begins in the ... topotecan injection is used to treat ovarian or lung cancer, it is usually given once a day for ...

  4. Palonosetron Injection

    MedlinePlus

    ... that may occur several days after receiving certain chemotherapy medications. Palonosetron injection is in a class of medications called 5-HT3 receptor antagonists. It works by blocking the action of serotonin, a natural ...

  5. Meropenem Injection

    MedlinePlus

    ... skin and abdominal (stomach area) infections caused by bacteria and meningitis (infection of the membranes that surround ... of medications called antibiotics. It works by killing bacteria that cause infection.Antibiotics such as meropenem injection ...

  6. Amikacin Injection

    MedlinePlus

    ... treat certain serious infections that are caused by bacteria such as meningitis (infection of the membranes that ... medications called aminoglycoside antibiotics. It works by killing bacteria.Antibiotics such as amikacin injection will not work ...

  7. Ertapenem Injection

    MedlinePlus

    ... abdominal (stomach area) infections, that are caused by bacteria. It is also used for the prevention of ... medications called carbapenem antibiotics. It works by killing bacteria.Antibiotics such as ertapenem injection will not work ...

  8. Moxifloxacin Injection

    MedlinePlus

    ... is used to treat certain infections caused by bacteria such as pneumonia; ; and , skin, and abdominal (stomach ... antibiotics called fluoroquinolones. It works by killing the bacteria that cause infections.Antibiotics such as moxifloxacin injection ...

  9. Cefepime Injection

    MedlinePlus

    ... is used to treat certain infections caused by bacteria including pneumonia, and skin, urinary tract, and kidney ... medications called cephalosporin antibiotics. It works by killing bacteria.Antibiotics such as cefepime injection will not work ...

  10. Cefazolin Injection

    MedlinePlus

    ... is used to treat certain infections caused by bacteria including skin, bone, joint, genital, blood, heart valve, ... medications called cephalosporin antibiotics. It works by killing bacteria.Antibiotics such as cefazolin injection will not work ...

  11. Daptomycin Injection

    MedlinePlus

    ... blood infections or serious skin infections caused by bacteria. Daptomycin injection is in a class of medications called cyclic lipopeptide antibiotics. It works by killing bacteria. Antibiotics will not work for treating colds, flu, ...

  12. Aztreonam Injection

    MedlinePlus

    ... to treat certain infections that are caused by bacteria, including respiratory tract (including pneumonia and bronchitis), urinary ... abdominal (stomach area) infections, that are caused by bacteria. Aztreonam injection also may be used before, during, ...

  13. Ceftazidime Injection

    MedlinePlus

    ... is used to treat certain infections caused by bacteria including pneumonia and other lower respiratory tract (lung) ... medications called cephalosporin antibiotics. It works by killing bacteria.Antibiotics such as ceftazidime injection will not work ...

  14. Tobramycin Injection

    MedlinePlus

    ... treat certain serious infections that are caused by bacteria such as meningitis (infection of the membranes that ... medications called aminoglycoside antibiotics. It works by killing bacteria.Antibiotics such as tobramycin injection will not work ...

  15. Ciprofloxacin Injection

    MedlinePlus

    ... is used to treat certain infections caused by bacteria such as pneumonia; and infections of the skin, ... of antibiotics called fluoroquinolones. It works by killing bacteria that cause infections.Antibiotics such as ciprofloxacin injection ...

  16. Gentamicin Injection

    MedlinePlus

    ... treat certain serious infections that are caused by bacteria such as meningitis (infection of the membranes that ... medications called aminoglycoside antibiotics. It works by killing bacteria.Antibiotics such as gentamicin injection will not work ...

  17. Ceftaroline Injection

    MedlinePlus

    ... infections and pneumonia (lung infection) caused by certain bacteria. Ceftaroline is in a class of medications called cephalosporin antibiotics. It works by killing bacteria.Antibiotics such as ceftaroline injection will not work ...

  18. Daclizumab Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS; a disease in which ... injections. Before you use daclizumab yourself the first time, read the written instructions that come with it. ...

  19. Risperidone Injection

    MedlinePlus

    ... release (long-acting) injection is used to treat schizophrenia (a mental illness that causes disturbed or unusual ... do not already have diabetes. If you have schizophrenia, you are more likely to develop diabetes than ...

  20. Acyclovir Injection

    MedlinePlus

    ... chickenpox in the past) in people with weak immune systems. It is also used to treat first-time ... from time to time) in people with normal immune systems. Acyclovir injection is used to treat herpes simplex ...

  1. Omalizumab Injection

    MedlinePlus

    ... steroids. Omalizumab is also used to treat chronic hives without a known cause that cannot successfully be ... is not used to treat other forms of hives or allergic conditions. Omalizumab injection is in a ...

  2. Pegloticase Injection

    MedlinePlus

    ... doctor if you have glucose-6-phosphate dehydrogenase (G6PD) deficiency (an inherited blood disease). Your doctor may test you for G6PD deficiency before you start to receive pegloticase injection. If ...

  3. Lacosamide Injection

    MedlinePlus

    ... with other medications to control certain types of seizures in people who cannot take oral medications. Lacosamide ... If you suddenly stop using lacosamide injection, your seizures may happen more often. Your doctor will probably ...

  4. Oxacillin Injection

    MedlinePlus

    ... injection is in a class of medications called penicillins. It works by killing bacteria.Antibiotics such as ... and pharmacist if you are allergic to oxacillin; penicillins; cephalosporin antibiotics such as cefaclor, cefadroxil, cefazolin, cefdinir, ...

  5. Nafcillin Injection

    MedlinePlus

    ... injection is in a class of medications called penicillins. It works by killing bacteria.Antibiotics such as ... and pharmacist if you are allergic to nafcillin; penicillins; cephalosporin antibiotics such as cefaclor, cefadroxil, cefazolin, cefdinir, ...

  6. Ampicillin Injection

    MedlinePlus

    ... injection is in a class of medications called penicillins. It works by killing bacteria.Antibiotics such as ... and pharmacist if you are allergic to ampicillin; penicillins; cephalosporin antibiotics such as cefaclor, cefadroxil, cefazolin (Ancef, ...

  7. Naloxone Injection

    MedlinePlus

    ... emergency medical treatment to reverse the life-threatening effects of a known or suspected opiate (narcotic) overdose. ... is also used after surgery to reverse the effects of opiates given during surgery. Naloxone injection is ...

  8. Omacetaxine Injection

    MedlinePlus

    ... or cannot take these medications due to side effects. Omacetaxine injection is in a class of medications ... a treatment cycle if you experience serious side effects of the medication or if blood tests show ...

  9. Methylnaltrexone Injection

    MedlinePlus

    ... injection is used to treat constipation caused by opioid (narcotic) pain medications in patients with chronic (on-going) pain that is not caused by ... by protecting the bowel from the effects of opioid (narcotic) medications.

  10. Denosumab Injection

    MedlinePlus

    ... menstrual periods), who have an increased risk for fractures (broken bones) or who cannot take or did ... receiving certain treatments that increase their risk for fractures. Denosumab injection (Xgeva) is used to reduce fractures ...

  11. Rasburicase Injection

    MedlinePlus

    ... break down) in people with certain types of cancer who are being treated with chemotherapy medications. Rasburicase injection is in a class of medications called enzymes. It works by breaking down uric acid so that the body can eliminate it.

  12. Gemcitabine Injection

    MedlinePlus

    ... with surgery. Gemcitabine is also used to treat cancer of the pancreas that has spread to other parts of the ... 4 weeks. When gemcitabine is used to treat cancer of pancreas it may be injected once every week. The ...

  13. Doxercalciferol Injection

    MedlinePlus

    Doxercalciferol injection is used to treat secondary hyperparathyroidism (a condition in which the body produces too much parathyroid hormone [PTH; a natural substance needed to control the amount of calcium in ...

  14. Granisetron Injection

    MedlinePlus

    ... that may occur after surgery. Granisetron extended-release (long-acting) injection is used with other medications to prevent nausea and vomiting caused by cancer chemotherapy that may occur immediately ...

  15. Fluconazole Injection

    MedlinePlus

    ... injection is used to treat fungal infections, including yeast infections of the mouth, throat, esophagus (tube leading ... by fungus. Fluconazole is also used to prevent yeast infections in patients who are likely to become ...

  16. Docetaxel Injection

    MedlinePlus

    ... allergic to docetaxel injection or drugs made with polysorbate 80, an ingredient found in some medications. Ask ... if a medication you are allergic to contains polysorbate 80. If you experience any of the following ...

  17. Haloperidol Injection

    MedlinePlus

    ... emotions). Haloperidol injection is also used to control motor tics (uncontrollable need to repeat certain body movements) ... people who have Tourette's disorder (condition characterized by motor or verbal tics). Haloperidol is in a class ...

  18. Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin.

    PubMed

    Salkovic-Petrisic, Melita; Osmanovic-Barilar, Jelena; Knezovic, Ana; Hoyer, Siegfried; Mosetter, Kurt; Reutter, Werner

    2014-02-01

    Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD.

  19. Biosimilar Insulin and Costs

    PubMed Central

    Heinemann, Lutz

    2015-01-01

    The costs for insulin treatment are high, and the steady increase in the number of patients with diabetes on insulin presents a true challenge to health care systems. Therefore, all measures to lower these costs are welcomed by patients, physicians, and health care providers. The market introduction of biosimilar insulins presents an option to lower treatment costs as biosimilars are usually offered at a lower price than the originator product. However, the assumption that a drastic reduction in insulin prices will take place, as was observed with many generic drugs, is most probably not realistic. As the first biosimilar insulin has now been approved in the EU, this commentary discusses a number of aspects that are relevant when it comes to the potential cost reduction we will see with the use of biosimilar insulins. PMID:26350722

  20. Adipokines and insulin action

    PubMed Central

    Knights, Alexander J; Funnell, Alister PW; Pearson, Richard CM; Crossley, Merlin; Bell-Anderson, Kim S

    2014-01-01

    Obesity is a major public health concern and a strong risk factor for insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The last two decades have seen a reconsideration of the role of white adipose tissue (WAT) in whole body metabolism and insulin action. Adipose tissue-derived cytokines and hormones, or adipokines, are likely mediators of metabolic function and dysfunction. While several adipokines have been associated with obese and insulin-resistant phenotypes, a select group has been linked with insulin sensitivity, namely leptin, adiponectin, and more recently, adipolin. What is known about these insulin-sensitizing molecules and their effects in healthy and insulin resistant states is the subject of this review. There remains a significant amount of research to do to fully elucidate the mechanisms of action of these adipokines for development of therapeutics in metabolic disease. PMID:24719781

  1. Injection overview

    SciTech Connect

    Prestwich, S.

    1983-12-01

    The test program was initiated at the Raft River Geothermal Field in southern Idaho in September 1982. A series of eight short-term injection and backflow tests, followed by a long-term injection test, were conducted on one well in the field. Tracers were added during injection and monitored during backflow as well. The principal objective was to determine if tracers could be effectively used as a means to assess reservoir characteristics in a one-well test. The test program resulted in a unique data set which shows promise as a means to improve understanding of the reservoir characteristics. In December 1982, an RFP was issued to obtain an industrial partner to obtain follow-on data on the injection/backflow technique in a second field, and to study any alternate advanced concepts for injection testing which the industrial community might recommend. The East Mesa Geothermal Field was selected for the second test series. Two wells were utilized for testing, and a series of ten tests were conducted in July and August 1983, aimed principally at further evaluation of the injection/backflow technique.

  2. Immunologic insulin resistance.

    PubMed

    Davidson, J K; DeBra, D W

    1978-03-01

    The efficacy of sulfated beef insulin for plasma glucose control in 35 patients with immunologic insulin resistance was studied. Patients were on a mean dose of 550 U./day (range 200--2,000) of U-500 regular beef insulin. Mean maximum 125I-insulin-binding capacity was 191 mU./ml. serum (range 13--1,080). Mean in vivo half-life (T 1/2) of 125I-regular beef insulin was 614 minutes (range 114--1,300), as against a mean T 1/2 of 13.9 minutes (range 11.8--16.5) in normal controls. Treatment was successful in 34 patients and unsuccessful in one with lipoatrophic diabetes. The mean initial dose of sulfated insulin was 89 U./day (range 15--400) and at three months was 66 U./day (range 20--400). Twenty-eight patients who responded and survived have been on sulfated insulin for a mean of 39 months (range 2-66) and are on a mean dose of 25 U./day (range 0--100). The mean maximum binding capacity fell to 9 mU./ml. (range 0--34) during therapy (p less than 0.01). Mean 125I-insulin T 1/2 fell from 614 to 249 minutes after sulfated insulin therapy (p less than 0.001). A comparative study of 15 patients on consecutive days showed a 35 sulfated insulin T 1/2 of 60 minutes (range 15--94) and a mean 125I-regular insulin T 1/2 of 246 minutes (range 62--560, p less than 0.001). These results indicate that sulfated insulin is less antigenic than regular beef insulin and combines less avidly with human antibodies to regular beef insulin. The response to sulfated insulin therapy was significantly better than the response reported by other investigators to pork insulin or to steroid therapy in similar patients.

  3. Insulin resistance and atherosclerosis

    PubMed Central

    Semenkovich, Clay F.

    2006-01-01

    Considerable evidence supports the association between insulin resistance and vascular disease, and this has led to wide acceptance of the clustering of hyperlipidemia, glucose intolerance, hypertension, and obesity as a clinical entity, the metabolic syndrome. While insulin resistance, by promoting dyslipidemia and other metabolic abnormalities, is part of the proatherogenic milieu, it is possible that insulin resistance itself in the vascular wall does not promote atherosclerosis. Recent findings suggest that insulin resistance and atherosclerosis could represent independent and ultimately maladaptive responses to the disruption of cellular homeostasis caused by the excess delivery of fuel. PMID:16823479

  4. A Micro-PIV Study of the Pulsed Micro-Flows Driven by an Insulin Pump

    NASA Astrophysics Data System (ADS)

    Wang, Bing; Demuren, Ayodeji; Gyuricsko, Eric; Hu, Hui

    2009-11-01

    In recent years, there is a surge in the popularity of using insulin pump or continuous subcutaneous insulin infusion therapy, as opposed to multiple daily injections by insulin syringe or an insulin pen. Some case studies have suggested that insulin delivery failure may be caused by precipitation of insulin within the infusion set. Speculation also exists that the flow of insulin through an insulin infusion set may be reduced or inhibited by air bubbles entrained into the micro-sized tubing system since there are chances that air be introduced into the insulin reservoir during the filling process. In the present study, a microscopic Particle Image Velocimtry (micro-PIV) system was used to characterize the transient behavior of the pulsed micro-flows inside the micro-sized tubing system of an insulin infusion set with insulin pump operating in basal mode (i.e., pulsed insulin pumping). The effects of the air bubbles entrained into the micro-sized tubing system on the insulin delivery process were assessed based on the micro-PIV measurements.

  5. Naringenin ameliorates Alzheimer's disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) caused by the intracerebroventricular-streptozotocin in rat model.

    PubMed

    Khan, M Badruzzaman; Khan, Mohd Moshahid; Khan, Andleeb; Ahmed, Md Ejaz; Ishrat, Tauheed; Tabassum, Rizwana; Vaibhav, Kumar; Ahmad, Ajmal; Islam, Fakhrul

    2012-12-01

    Oxidative stress is involved in Alzheimer's disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) as well as age related cognitive deficit. The present study was designed to investigate the pre-treatment effects of naringenin (NAR), a polyphenolic compound on cognitive dysfunction, oxidative stress in the hippocampus, and hippocampal neuron injury in a rat model of AD-TNDCI. The rats were pre-treated with NAR at a selective dose (50mg/kg, orally) for 2 weeks followed by intracerebroventricular-streptozotocin (ICV-STZ) (3mg/kg; 5μl per site) injection bilaterally. Behavioral alterations were monitored after 2 weeks from the lesion using passive avoidance test and Morris water maze paradigm. Three weeks after the lesion, the rats were sacrificed for measuring non-enzymatic [4-hydroxynonenal (4-HNE), malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H(2)O(2)), protein carbonyl (PC), reduced glutathione (GSH)] content and enzymatic [glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and Na(+)/K(+)-ATPase] activity in the hippocampus, and expression of choline acetyltransferase (ChAT) positive neuron, and histopathology of hippocampal neurons. The non-enzymatic level and enzymatic activity was significantly increased and decreased, respectively, with striking impairments in spatial learning and memory, loss of ChAT positive neuron and severe damage to hippocampal neurons in the rat induced by ICV-STZ. These abnormalities were significantly improved by NAR pre-treatment. The study suggests that NAR can protect against cognitive deficits, neuronal injury and oxidative stress induced by ICV-STZ, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD-TNDCI.

  6. Degranulation, density, and distribution of mast cells in the rat thalamus: a light and electron microscopic study in basal conditions and after intracerebroventricular administration of nerve growth factor.

    PubMed

    Florenzano, F; Bentivoglio, M

    2000-09-04

    In the adult rat brain mast cells reside selectively in the thalamus. We investigated thalamic mast cells stained by acidic toluidine blue or pinacyanol, and with histamine immunocytochemistry, focusing on their state of activity revealed by degranulation. Mast cells exhibited perivascular prevalence and high quantitative variability, between cases and in different sections, with no asymmetry or topographical selectivity in thalamic nuclei. Pinacyanol, alone or with erythrosine, stained mast cells with higher sensitivity than toluidine blue. However, toluidine blue was highly predictive of pinacyanol staining and provided the best resolution of mast cell cytoplasmic features. Histamine immunocytochemistry labeled 61% of pinacyanol-stained mast cells. Intensely toluidine blue-stained granulated cells, as well as cells exhibiting different degrees of degranulation that paralleled lighter staining, were observed. The response of thalamic mast cells to intracerebroventricular administration of nerve growth factor (NGF) and control cytochrome-c injections was evaluated after 2, 24, and 72 hours. No obvious changes in mast cell number or distribution were found after treatment, but massive degranulation was frequently observed after NGF administration. Significant decrease of staining intensity of mast cells, supporting enhanced degranulation, was documented in NGF-treated animals by quantitative image analysis. Ultrastructural features of mast cell degranulation, with granule coalescence and matrix dissolution, were detected in untreated and NGF-treated cases. The findings point out that mast cells are active in the thalamus in basal conditions and that NGF has the potential to elicit long-lasting degranulation of thalamic mast cells in vivo, exerting a direct effect and/or priming these cells to react to endogenous stimuli.

  7. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

    PubMed

    Paul, Gesine; Zachrisson, Olof; Varrone, Andrea; Almqvist, Per; Jerling, Markus; Lind, Göran; Rehncrona, Stig; Linderoth, Bengt; Bjartmarz, Hjalmar; Shafer, Lisa L; Coffey, Robert; Svensson, Mikael; Mercer, Katarina Jansson; Forsberg, Anton; Halldin, Christer; Svenningsson, Per; Widner, Håkan; Frisén, Jonas; Pålhagen, Sven; Haegerstrand, Anders

    2015-03-02

    BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

  8. The effects of intracerebroventricular infusion of apelin-13 on reproductive function in male rats.

    PubMed

    Sandal, Suleyman; Tekin, Suat; Seker, Fatma Burcu; Beytur, Ali; Vardi, Nigar; Colak, Cemil; Tapan, Tuba; Yildiz, Sedat; Yilmaz, Bayram

    2015-08-18

    Apelin is a novel bioactive peptide as the endogenous ligand for APJ. Apelin and APJ have also been identified in the testis, hypothalamic nuclei such as arcuate, supraoptic and paraventricular nuclei, implicating roles in the control of reproduction. Therefore, the present study was designed to investigate the effects of chronic central infusion of apelin-13 on LH, FSH and testosterone levels and testis morphology. 21 Wistar-Albino male rats received continuous intracerebroventricular infusion via Alzet osmotic mini pumps filled artificial cerebrospinal fluid (vehicle) or apelin-13 at concentrations of 1 or 10 nmol (10 μl/h) for seven days. At the last 90 min of the infusion period, the blood samples were collected at 15 min intervals (0-90 min) for LH and FSH analyses. At the last sampling point, the blood samples were analyzed for testosterone levels. Infusion of high dose apelin-13 significantly suppressed LH release compared with the vehicle values at 30, 60 and 75 min (p<0.05). However, FSH levels did not significantly differ among the groups. Serum testosterone levels in high dose apelin-13 group were statistically lower than the control group (p<0.05). In addition, histological examination showed that infusion of high dose apelin-13 significantly decreased the number of Leydig cells compared with the control and lower dose apelin-13 groups (p<0.05, p<0.01). Our results suggest that apelin-13 may play a role in the central regulation and decreases testosterone release by suppressing LH secretion. Thus, antagonists of the apelin receptor may, therefore, be useful for pharmaceuticals in the treatment of infertility.

  9. Embelin Attenuates Intracerebroventricular Streptozotocin-Induced Behavioral, Biochemical, and Neurochemical Abnormalities in Rats.

    PubMed

    Arora, Rimpi; Deshmukh, Rahul

    2016-10-15

    Embelin, the main active constituent of Embelia ribes, has been reported to possess various pharmacological actions, including anti-inflammatory, antioxidant, anticonvulsant, and neuroprotective. The present study was designed to investigate neuroprotective mechanisms and therapeutic potential of embelin against intracerebroventricular streptozotocin (ICV-STZ)-induced experimental sporadic dementia in rats. STZ was infused bilaterally at the dose of (3 mg/kg/1 μl/1 min) ICV on day first and third. Spatial and non-spatial memory was evaluated using Morris water maze and object recognition task in rats. Embelin (2.5, 5, and 10 mg/kg, i.p.) was administrated for 14 days from seventh day onwards after first ICV-STZ infusion in rats. On day 22, rats were sacrificed and hippocampal brain regions were used to identify biochemical, neurochemical, and neuroinflammatory alterations. STZ-infused rats showed significant learning and memory deficit which was associated with an increase in oxidative stress (lipid peroxidation and nitrite), compromised antioxidant defense (reduced glutathione), neurotransmitter alterations (AChE, dopamine, noradrenaline, 5-hydroxytryptamine, gama amino butyric acid, and glutamate), and elevation in neuroinflammatory cytokine (IL-1 β, IL-6, and TNF-α) levels. Embelin dose dependently attenuated STZ-induced cognitive deficit and biochemical alterations and restored hippocampal neurochemical levels. The observed protective effect might be attributed to the antioxidant and anti-inflammatory potential of embelin and its ability to restore hippocampal neurochemistry. Thus, the outcomes of the current study suggest therapeutic potential of embelin in cognitive disorders such as sporadic Alzheimer's disease (SAD).

  10. The role of hypothalamic mTORC1 signaling in insulin regulation of food intake, body weight, and sympathetic nerve activity in male mice.

    PubMed

    Muta, Kenjiro; Morgan, Donald A; Rahmouni, Kamal

    2015-04-01

    Insulin action in the brain particularly the hypothalamus is critically involved in the regulation of several physiological processes, including energy homeostasis and sympathetic nerve activity, but the underlying mechanisms are poorly understood. The mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the control of diverse cellular functions, including sensing nutrients and energy status. Here, we examined the role of hypothalamic mTORC1 in mediating the anorectic, weight-reducing, and sympathetic effects of central insulin action. In a mouse hypothalamic cell line (GT1-7), insulin treatment increased mTORC1 activity in a time-dependent manner. In addition, intracerebroventricular (ICV) administration of insulin to mice activated mTORC1 pathway in the hypothalamic arcuate nucleus, a key site of central action of insulin. Interestingly, inhibition of hypothalamic mTORC1 with rapamycin reversed the food intake- and body weight-lowering effects of ICV insulin. Rapamycin also abolished the ability of ICV insulin to cause lumbar sympathetic nerve activation. In GT1-7 cells, we found that insulin activation of mTORC1 pathway requires phosphatidylinositol 3-kinase (PI3K). Consistent with this, genetic disruption of PI3K in mice abolished insulin stimulation of hypothalamic mTORC1 signaling as well as the lumbar sympathetic nerve activation evoked by insulin. These results demonstrate the importance of mTORC1 pathway in the hypothalamus in mediating the action of insulin to regulate energy homeostasis and sympathetic nerve traffic. Our data also highlight the key role of PI3K as a link between insulin receptor and mTORC1 signaling in the hypothalamus.

  11. 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.

  12. A Review of the Security of Insulin Pump Infusion Systems

    PubMed Central

    Paul, Nathanael; Kohno, Tadayoshi; Klonoff, David C

    2011-01-01

    Insulin therapy has enabled patients with diabetes to maintain blood glucose control to lead healthier lives. Today, rather than injecting insulin manually using syringes, a patient can use a device such as an insulin pump to deliver insulin programmatically. This allows for more granular insulin delivery while attaining blood glucose control. Insulin pump system features have increasingly benefited patients, but the complexity of the resulting system has grown in parallel. As a result, security breaches that can negatively affect patient health are now possible. Rather than focus on the security of a single device, we concentrate on protecting the security of the entire system. In this article, we describe the security issues as they pertain to an insulin pump system that includes an embedded system of components, which include the insulin pump, continuous glucose management system, blood glucose monitor, and other associated devices (e.g., a mobile phone or personal computer). We detail not only the growing wireless communication threat in each system component, but also describe additional threats to the system (e.g., availability and integrity). Our goal is to help create a trustworthy infusion pump system that will ultimately strengthen pump safety, and we describe mitigating solutions to address identified security issues. PMID:22226278

  13. A review of the security of insulin pump infusion systems.

    PubMed

    Paul, Nathanael; Kohno, Tadayoshi; Klonoff, David C

    2011-11-01

    Insulin therapy has enabled patients with diabetes to maintain blood glucose control to lead healthier lives. Today, rather than injecting insulin manually using syringes, a patient can use a device such as an insulin pump to deliver insulin programmatically. This allows for more granular insulin delivery while attaining blood glucose control. Insulin pump system features have increasingly benefited patients, but the complexity of the resulting system has grown in parallel. As a result, security breaches that can negatively affect patient health are now possible. Rather than focus on the security of a single device, we concentrate on protecting the security of the entire system. In this article, we describe the security issues as they pertain to an insulin pump system that includes an embedded system of components, which include the insulin pump, continuous glucose management system, blood glucose monitor, and other associated devices (e.g., a mobile phone or personal computer). We detail not only the growing wireless communication threat in each system component, but also describe additional threats to the system (e.g., availability and integrity). Our goal is to help create a trustworthy infusion pump system that will ultimately strengthen pump safety, and we describe mitigating solutions to address identified security issues.

  14. A Review of the Security of Insulin Pump Infusion Systems

    SciTech Connect

    Klonoff, David C.; Paul, Nathanael R; Kohno, Tadayoshi

    2011-01-01

    Insulin therapy has enabled diabetic patients to maintain blood glucose control to lead healthier lives. Today, rather than manually injecting insulin using syringes, a patient can use a device, such as an insulin pump, to programmatically deliver insulin. This allows for more granular insulin delivery while attaining blood glucose control. The insulin pump system features have increasingly benefited patients, but the complexity of the resulting system has grown in parallel. As a result security breaches that can negatively affect patient health are now possible. Rather than focus on the security of a single device, we concentrate on protecting the security of the entire system. In this paper we describe the security issues as they pertain to an insulin pump system that includes an embedded system of components including the insulin pump, continuous glucose management system, blood glucose monitor, and other associated devices (e.g., a mobile phone or personal computer). We detail not only the growing wireless communication threat in each system component, but we also describe additional threats to the system (e.g., availability and integrity). Our goal is to help create a trustworthy infusion pump system that will ultimately strengthen pump safety, and we describe mitigating solutions to address identified security issues both for now and in the future.

  15. Chromium and insulin resistance.

    PubMed

    Anderson, Richard A

    2003-12-01

    Insulin resistance leads to the inability of insulin to control the utilization and storage of glucose. It is associated initially with elevated levels of circulating insulin followed by glucose intolerance which may progress to type 2 diabetes, hyperlipidaemia, hypertension, obesity and cardiovascular diseases. While the causes of these diseases are multifactorial, one nutrient that is associated with all of these abnormalities is Cr. In the presence of Cr, in a biologically active form, much lower levels of insulin are required. Modern diets, which are often high in refined carbohydrates, are not only low in Cr, but lead to enhanced Cr losses. In response to the consumption of refined carbohydrates, there is a rapid rise in blood sugar leading to elevations in insulin that cause a mobilization of Cr. Once mobilized, Cr is not reabsorbed but lost via the urine leading to decreased Cr stores. Several studies involving both human subjects and experimental animals have reported improvements in insulin sensitivity, blood glucose, insulin, lipids, haemoglobin A1c, lean body mass and related variables in response to improved Cr nutrition. However, not all studies have reported beneficial effects associated with improved Cr nutrition. Well-controlled human studies are needed to document an unequivocal effect of Cr on insulin sensitivity in human subjects. Studies need to involve a significant number of subjects with insulin resistance, glucose intolerance or early stages of diabetes, who have not been taking supplements containing Cr for at least 4 months, and involve at least 400 to 600 microg supplemental Cr daily or more. Studies should be at least 4 months to document sustained effects of supplemental Cr on insulin resistance and related variables. Cr is a nutrient and not a therapeutic agent and therefore will only be of benefit to those whose problems are due to suboptimal intake of Cr.

  16. Role of insulin in the growth of fetal rat tissues.

    PubMed

    Cooke, P S; Nicoll, C S

    1984-02-01

    The effect of insulin on the growth of fetal rat tissues was investigated using a transplant system. Paws from 15-day-old fetal rats were transplanted under the kidney capsule of 1-month-old syngeneic hosts, where they grew and differentiated normally. After 11 days of incubation, growth of transplants in hosts made diabetic by streptozotocin injection was reduced by 37% compared to growth in nondiabetic controls, but tissue differentiation and bone formation were normal in the absence of insulin. Injections of insulin (2 U, twice daily) into diabetic hosts restored paw growth to normal. Growth of transplants in hypophysectomized (HX) and in HX-diabetic hosts was reduced to the same degree (i.e. by 65%). Thus, the growth decrements produced by host hypophysectomy and diabetes are not additive. In contrast to the results with insulin-deficient hosts, the transplants failed to differentiate normally in the HX hosts. Injections of exogenous insulin (3 U, twice daily) to produce transient hyperinsulinemia failed to increase transplant growth in intact hosts over 11 days of incubation. The transplants were exposed to frequent periods of hyperglycemia and hyperinsulinemia by injecting 0.66 g glucose/100 g BW four times per day into intact hosts during 6 days of incubation. This treatment also failed to stimulate transplant growth. These results indicate that normal growth of transplanted fetal paw tissue is partially dependent on insulin, but whether the insulin acts directly or indirectly to support growth is not known. Supranormal insulin levels or frequent periods of hyperglycemia with hyperinsulinemia are not capable of producing overgrowth of the fetal paws. The HX, diabetic, and HX-diabetic host rats did not grow, as judged by tail length increase, and they lost weight. Accordingly, the juvenile host tissues have an obligatory dependence on insulin and GH for normal growth, but the fetal tissue is only partially dependent, because the paw transplants continued to

  17. [Management of type 1 diabetes (insulin, diet, sport): "Dorchy's recipes"].

    PubMed

    Dorchy, Harry

    2010-01-01

    The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications by maintaining blood glucose concentrations close to the normal range and an HbA1c level under 7%. The number of daily insulin injections, 2 or > or = 4, by itself does not necessarily give better results, but the 4-injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided. Due to their pharmakokinetic characteristics, fast-acting and long-acting insulin analogues have specific indications in both the twice-daily injection regimen and the basal-bolus insulin therapy. They improve quality of life, without necessarily reducing HbA1c. Dietary recommendations issued over the last few years are the same for diabetic and non-diabetic individuals in order to avoid degenerative diseases. In the twice-daily free-mix regimen, the allocation of carbohydrates throughout the day is essential. There is no linear correlation between the metabolization of x grams of glucose by y units of insulin and carbohydrate counting is a piece of nonsense. Glycamic changes during exercise depend largely on blood insulin levels. In the young diabetic, during insulin deficiency, and therefore in a poor degree of metabolic control, i.e. hyperglycemic and ketotic, exercise accentuates hyperglycemia and ketosis, leading to extreme fatigue. If the insulin dosage is too high, the increase in muscular assimilation, combined with the shutdown of liver glucose production, may result in a severe hypoglycemia. During the recovery period, the repletion of muscular and hepatic glycogen stores may also provoke an hypoglycemia during hours after the cessation of muscular work.

  18. Pegaptanib Injection

    MedlinePlus

    ... if you have or have ever had diabetes, high blood pressure, a heart attack, or a stroke.tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using pegaptanib injection, ...

  19. Ramucirumab Injection

    MedlinePlus

    ... doctor if you have or have ever had high blood pressure, a wound that has not healed, or liver disease.tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. Ramucirumab injection may harm your unborn baby. You ...

  20. Reslizumab Injection

    MedlinePlus

    ... the infusion or for a short period of time after the infusion has finished.You will receive each injection of reslizumab in a doctor's office or medical facility. You will stay in the office for some time after you receive the medication so your doctor ...

  1. Dexrazoxane Injection

    MedlinePlus

    ... are used to treat or prevent certain side effects that may be caused by chemotherapy medications. Dexrazoxane ... Dexrazoxane injection may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: pain or swelling in the place ...

  2. Influence of Unweighting on Insulin Signal Transduction in Muscle

    NASA Technical Reports Server (NTRS)

    Tischler, Marc E.

    2002-01-01

    Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

  3. Histidine augments the suppression of hepatic glucose production by central insulin action.

    PubMed

    Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-Ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

    2013-07-01

    Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

  4. Simultaneous determination of insulin and its analogues in pharmaceutical formulations by micellar electrokinetic chromatography.

    PubMed

    Lamalle, Caroline; Servais, Anne-Catherine; Radermecker, Régis P; Crommen, Jacques; Fillet, Marianne

    2015-01-01

    A simple and efficient MEKC method was developed to simultaneously determine human insulin, its five analogues, the main degradation products and the excipients usually present in injection formulations. A very fast method with a total analysis time of 3 min was then successfully validated for the analysis of human insulin and the quality control of commercial formulations was carried out.

  5. Management of insulin pump therapy in children with type 1 diabetes.

    PubMed

    Abdullah, Nadeem; Pesterfield, Claire; Elleri, Daniela; Dunger, David B

    2014-12-01

    Insulin pump therapy is a current treatment option for children and adolescents with type 1 diabetes. Insulin pumps can provide a greater flexibility in insulin administration and meal planning, as compared with multiple insulin injections, and they may be particularly suitable for the paediatric age group. Many young people with diabetes have integrated insulin pumps into their daily practice. The use of insulin pumps can also be supplemented by the information retrieved from continuous glucose monitoring in the sensor-augmented pump therapy, which may improve glycaemic control. In this review, we describe the principles of pump therapy and summarise features of commercially available insulin pumps, with focus on practical management and the advantages and disadvantages of this technology.

  6. The role of insulin pump therapy for type 2 diabetes mellitus.

    PubMed

    Landau, Zohar; Raz, Itamar; Wainstein, Julio; Bar-Dayan, Yosefa; Cahn, Avivit

    2017-01-01

    Many patients with type 2 diabetes fail to achieve adequate glucose control despite escalation of treatment and combinations of multiple therapies including insulin. Patients with long-standing type 2 diabetes often suffer from the combination of severe insulin deficiency in addition to insulin resistance, thereby requiring high doses of insulin delivered in multiple injections to attain adequate glycemic control. Insulin-pump therapy was first introduced in the 1970s as an approach to mimic physiological insulin delivery and attain normal glucose in patients with type 1 diabetes. The recent years have seen an increase in the use of this technology for patients with type 2 diabetes. This article summarizes the clinical studies evaluating insulin pump use in patients with type 2 diabetes and discusses the benefits and shortcomings of pump therapy in this population. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Impact of the Type of Continuous Insulin Administration on Metabolism in a Diabetic Rat Model

    PubMed Central

    Schaschkow, A.; Dal, S.; Langlois, A.; Seyfritz, E.; Sookhareea, C.; Bietiger, W.; Peronet, C.; Jeandidier, N.; Pinget, M.; Sigrist, S.

    2016-01-01

    Exogenous insulin is the only treatment available for type 1 diabetic patients and is mostly administered by subcutaneous (SC) injection in a basal and bolus scheme using insulin pens (injection) or pumps (preimplanted SC catheter). Some divergence exists between these two modes of administration, since pumps provide better glycaemic control compared to injections in humans. The aim of this study was to compare the impacts of two modes of insulin administration (single injections of long-acting insulin or pump delivery of rapid-acting insulin) at the same dosage (4 IU/200 g/day) on rat metabolism and tissues. The rat weight and blood glucose levels were measured periodically after treatment. Immunostaining for signs of oxidative stress and for macrophages was performed on the liver and omental tissues. The continuous insulin delivery by pumps restored normoglycaemia, which induced the reduction of both reactive oxygen species and macrophage infiltration into the liver and omentum. Injections controlled the glucose levels for only a short period of time and therefore tissue stress and inflammation were elevated. In conclusion, the insulin administration mode has a crucial impact on rat metabolic parameters, which has to be taken into account when studies are designed. PMID:27504460

  8. 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.

  9. 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

  10. Infliximab and insulin resistance.

    PubMed

    Ursini, Francesco; Naty, Saverio; Grembiale, Rosa Daniela

    2010-06-01

    Insulin resistance is the most important pathophysiologic feature of obesity, type 2 diabetes mellitus and prediabetic states. TNF-alpha, a proinflammatory cytokine, plays a pivotal role in the pathogenesis of inflammation-associated insulin resistance during the course of rheumatic diseases. Therapies aimed at neutralizing TNF-alpha, such as the monoclonal antibody infliximab, represent a novel approach for the treatment of rheumatic diseases and allow to obtain significant results in terms of control of the inflammatory process. In this article we reviewed the scientific evidence published in the literature about a potential role of TNF-alpha blockade in improving insulin resistance in non-diabetic rheumatic patients.

  11. Relative hypoglycemia of rectal insulin suppositories containing deoxycholic acid, sodium taurocholate, polycarbophil, and their combinations in diabetic rabbits.

    PubMed

    Hosny, E A

    1999-06-01

    In this study, insulin suppositories containing 50 U insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose concentrations was observed, and the relative hypoglycemias were calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.) injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and 42.2%, respectively. The most pronounced effect was observed with the addition of polycarbophil to the suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced a 56% relative hypoglycemia compared with subcutaneous injection. These suppository formulations could be very promising alternatives to the current insulin injections, being roughly half as efficacious as subcutaneous injection.

  12. TREATMENT OF TYPE 2 DIABETES WITH BIPHASIC INSULIN ANALOGUES

    PubMed Central

    Rizvi, Ali A.

    2016-01-01

    The majority of patients with Type 2 diabetes require insulin therapy for treating hyperglycaemia. There are several regimens available for insulin initiation and maintenance. Insulin analogues have been developed to mimic normal physiology as closely as possible. Biphasic analogues can target both fasting and postprandial hyperglycaemia, with the added advantage of being premixed and thus convenient for the patient. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes, thus providing both basal and prandial coverage. Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections. Awareness of the advantages and limitations of biphasic insulin analogues can assist clinicians in their appropriate use for the treatment of patients with Type 2 diabetes. PMID:27918600

  13. Determinants of intensive insulin therapeutic regimens in patients with type 1 diabetes: data from a nationwide multicenter survey in Brazil

    PubMed Central

    2014-01-01

    Background To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D). Methods This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups. Results We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). The majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001). Conclusions Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits. PMID:24920963

  14. Intracerebroventricular administration of nerve growth factor induces gliogenesis in sensory ganglia, dorsal root, and within the dorsal root entry zone.

    PubMed

    Schlachetzki, Johannes C M; Pizzo, Donald P; Morrissette, Debbi A; Winkler, Jürgen

    2014-01-01

    Previous studies indicated that intracerebroventricular administration of nerve growth factor (NGF) leads to massive Schwann cell hyperplasia surrounding the medulla oblongata and spinal cord. This study was designed to characterize the proliferation of peripheral glial cells, that is, Schwann and satellite cells, in the trigeminal ganglia and dorsal root ganglia (DRG) of adult rats during two weeks of NGF infusion using bromodeoxyuridine (BrdU) to label dividing cells. The trigeminal ganglia as well as the cervical and lumbar DRG were analyzed. Along the entire neuraxis a small number of dividing cells were observed within these regions under physiological condition. NGF infusion has dramatically increased the generation of new cells in the neuronal soma and axonal compartments of sensory ganglia and along the dorsal root and the dorsal root entry zone. Quantification of BrdU positive cells within sensory ganglia revealed a 2.3- to 3-fold increase in glial cells compared to controls with a similar response to NGF for the different peripheral ganglia examined. Immunofluorescent labeling with S100β revealed that Schwann and satellite cells underwent mitosis after NGF administration. These data indicate that intracerebroventricular NGF infusion significantly induces gliogenesis in trigeminal ganglia and the spinal sensory ganglia and along the dorsal root entry zone as well as the dorsal root.

  15. Amyloid-β induces hepatic insulin resistance in vivo via JAK2.

    PubMed

    Zhang, Yi; Zhou, Ben; Deng, Bo; Zhang, Fang; Wu, Jingxia; Wang, Yuangao; Le, Yingying; Zhai, Qiwei

    2013-04-01

    Amyloid-β (Aβ), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Aβ can induce insulin resistance in cultured hepatocytes by activating the JAK2/STAT3/SOCS-1 signaling pathway. Amyloid precursor protein and presenilin 1 double-transgenic AD mouse models with increased circulating Aβ level show impaired glucose/insulin tolerance and hepatic insulin resistance. However, whether Aβ induces hepatic insulin resistance in vivo is still unclear. Here we show C57BL/6J mice intraperitoneally injected with Aβ42 exhibit increased fasting blood glucose level, impaired insulin tolerance, and hepatic insulin signaling. Moreover, the APPswe/PSEN1dE9 AD model mice intraperitoneally injected with anti-Aβ neutralizing antibodies show decreased fasting blood glucose level and improved insulin sensitivity. Injection of Aβ42 activates hepatic JAK2/STAT3/SOCS-1 signaling, and neutralization of Aβ in APPswe/PSEN1dE9 mice inhibits liver JAK2/STAT3/SOCS-1 signaling. Furthermore, knockdown of hepatic JAK2 by tail vein injection of adenovirus inhibits JAK2/STAT3/SOCS-1 signaling and improves glucose/insulin tolerance and hepatic insulin sensitivity in APPswe/PSEN1dE9 mice. Our results demonstrate that Aβ induces hepatic insulin resistance in vivo via JAK2, suggesting that inhibition of Aβ signaling is a new strategy toward resolving insulin resistance and T2DM.

  16. Insulin Resistance and Prediabetes

    MedlinePlus

    ... especially sleep apnea; and cigarette smoking. 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 ...

  17. 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.

  18. Clinical study on local application of low-dose insulin for promoting wound healing after operation for deep burns

    PubMed Central

    Zeng, Ming; Zhi, Yan; Liu, Wenjun; Zhang, Wei; Xu, Jinxiong

    2016-01-01

    Transplanted free skin flaps are often needed to treat deep burns; their survival, however, is less than optimal. This study examined whether local low-dose insulin injections can promote flap survival and wound healing after surgery. A total of 165 patients who underwent free skin flap transplantation for simple deep burns were enrolled in the study and divided into 5 groups of 33 patients each: Blank control group (no local subcutaneous drug injections), saline control group (saline injections), low-dose insulin group (0.5 units regular insulin injections), medium-dose group (1.0 units regular insulin injections) and high-dose group (2.0 units regular insulin injections). Wound healing and flap survival conditions were assessed and compared among groups. The best wound healing rate found was that of the low-dose insulin injection group where all the parameters measured improved significantly: The healing time was shorter; the blood flow volume, the flap survival, the number of fibroblasts and new vessels increased; the re-epithelialization occurred faster; the infiltration of inflammatory cells was reduced; the expression levels of heat shock protein-90, vascular endothelial growth factor, transforming growth factor-β and interleukin-1 were higher; and the plasma glucose levels only fluctuated slightly. The results clearly demonstrate that a local low-dose insulin regime after flap transplantation can accelerate the healing time and improve the surgical outcome without exerting detrimental secondary effects on the glucose plasma level of deep burn patients. PMID:27882141

  19. Developing a Commercial Air Ultrasonic Ceramic Transducer to Transdermal Insulin Delivery

    PubMed Central

    Jabbari, Nasrollah; Asghari, Mohammad Hossein; Ahmadian, Hassan; Mikaili, Peyman

    2015-01-01

    The application of low-frequency ultrasound for transdermal delivery of insulin is of particular public interest due to the increasing problem of diabetes. The purpose of this research was to develop an air ultrasonic ceramic transducer for transdermal insulin delivery and evaluate the possibility of applying a new portable and low-cost device for transdermal insulin delivery. Twenty-four rats were divided into four groups with six rats in each group: one control group and three experimental groups. Control group (C) did not receive any ultrasound exposure or insulin (untreated group). The second group (T1) was treated with subcutaneous insulin (Humulin® R, rDNA U-100, Eli Lilly and Co., Indianapolis, IN) injection (0.25 U/Kg). The third group (T2) topically received insulin, and the fourth group (T3) received insulin with ultrasound waves. All the rats were anesthetized by intraperitoneal injection of ketamin hydrochloride and xylazine hydrochloride. Blood samples were collected after anesthesia to obtain a baseline glucose level. Additional blood samples were taken every 15 min in the whole 90 min experiment. In order for comparison the changes in blood glucose levels” to “ In order to compare the changes in blood glucose levels. The statistical multiple comparison (two-sided Tukey) test showed a significant difference between transdermal insulin delivery group (T2) and subcutaneous insulin injection group (T1) during 90 min experiment (P = 0.018). In addition, the difference between transdermal insulin delivery group (T2) and ultrasonic transdermal insulin delivery group (T3) was significant (P = 0.001). Results of this study demonstrated that the produced low-frequency ultrasound from this device enhanced the transdermal delivery of insulin across hairless rat skin. PMID:26120571

  20. Developing a Commercial Air Ultrasonic Ceramic Transducer to Transdermal Insulin Delivery.

    PubMed

    Jabbari, Nasrollah; Asghari, Mohammad Hossein; Ahmadian, Hassan; Mikaili, Peyman

    2015-01-01

    The application of low-frequency ultrasound for transdermal delivery of insulin is of particular public interest due to the increasing problem of diabetes. The purpose of this research was to develop an air ultrasonic ceramic transducer for transdermal insulin delivery and evaluate the possibility of applying a new portable and low-cost device for transdermal insulin delivery. Twenty-four rats were divided into four groups with six rats in each group: one control group and three experimental groups. Control group (C) did not receive any ultrasound exposure or insulin (untreated group). The second group (T1) was treated with subcutaneous insulin (Humulin(®) R, rDNA U-100, Eli Lilly and Co., Indianapolis, IN) injection (0.25 U/Kg). The third group (T2) topically received insulin, and the fourth group (T3) received insulin with ultrasound waves. All the rats were anesthetized by intraperitoneal injection of ketamin hydrochloride and xylazine hydrochloride. Blood samples were collected after anesthesia to obtain a baseline glucose level. Additional blood samples were taken every 15 min in the whole 90 min experiment. In order for comparison the changes in blood glucose levels" to " In order to compare the changes in blood glucose levels. The statistical multiple comparison (two-sided Tukey) test showed a significant difference between transdermal insulin delivery group (T2) and subcutaneous insulin injection group (T1) during 90 min experiment (P = 0.018). In addition, the difference between transdermal insulin delivery group (T2) and ultrasonic transdermal insulin delivery group (T3) was significant (P = 0.001). Results of this study demonstrated that the produced low-frequency ultrasound from this device enhanced the transdermal delivery of insulin across hairless rat skin.

  1. Studying the Hurdles of Insulin Prescription (SHIP©): development, scoring and initial validation of a new self-administered questionnaire

    PubMed Central

    Martinez, Luc; Consoli, Silla M; Monnier, Louis; Simon, Dominique; Wong, Olivier; Yomtov, Bernard; Guéron, Béatrice; Benmedjahed, Khadra; Guillemin, Isabelle; Arnould, Benoit

    2007-01-01

    Background Although insulin therapy is well-accepted by symptomatic diabetic patients, it is still often delayed in less severe patients, in whom injectable insulin remains under-used. A better understanding of patients' perception of insulin would eventually help physicians to adopt the most appropriate dialogue when having to motivate patients to initiate or to intensify insulin injection. Methods The 'Studying the Hurdles of Insulin Prescription' (SHIP) questionnaire was developed based on a list of concepts derived from three diabetic patients' focus groups, and was included into two cross-sectional studies with similar design: SHIP Oral study and SHIP Premix study. Diabetic patients treated with oral hypoglycaemic agents (OHA; n = 1,494) and patients already treated with insulin (n = 1,150) completed the questionnaire at baseline, 6- and 12 months. Psychometric properties were assessed: 1) structure analysis by Principal Component Analysis (PCA) with Varimax rotation, 2) internal consistency reliability (Cronbach's alpha), and 3) concurrent validity (Spearman correlation coefficients with the Fear of Self-Injecting (FSI) score of the Diabetes Fear of Injecting and Self-testing Questionnaire. Reluctance/motivation towards insulin was assessed. Scores' ability to predict patients' insulin injection reluctance/motivation and initiation/intensification was evaluated with the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC). Results PCA analysis confirmed the structure of the 14 items grouped into 3 dimensions: 'acceptance and motivation', 'fear and constraints', and 'restraints and barriers' towards insulin injection. Internal consistency reliability was excellent (Cronbach's alpha > 0.70); concurrent validity was good. The three scores were significantly predictive of patients' reluctance/motivation towards insulin injection initiation, as they were of patients' actual switch, except for the 'restraints and barriers' dimension. 'Acceptance and

  2. [New insulin types in type 1 diabetes mellitus].

    PubMed

    Mesa, Jordi

    2015-07-20

    Since its discovery almost a century ago, insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus. Although progress in the synthesis of new formulations has been remarkable, the physiological profile of insulin is still different from that observed with preparations available nowadays. In the last decade, the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal/bolus patterns, the most physiological ones until now. Despite the benefits of basal analogues, glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated. Improvement has been achieved especially in terms of duration and rate of hypoglycemia, the main limiting factor of intensive therapy. This article reviews the available data concerning the new basal insulin analogues, degludec, pegylated lispro and glargine U300, and new formulations currently under development.

  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.

  4. [INSULIN GLARGINE 300 U/mL (TOUJEO®)].

    PubMed

    Scheen, A J

    2016-02-01

    This article presents a new formulation of insulin glargine concentrated at 300 U/mL (Gla-300). It is commercialized under the trade name of Toujeo® in an optimized pre-filled SoloStar™ pen for the treatment of type 1 and type 2 diabetes in adults. Besides a threefold higher concentration compared to the classical insulin Lantus® (100 U/mL or Gla-100), both pharmacokinetic and pharmacodynamic profiles of Gla-300 are flatter and longer (more than 24 hours) and have a lesser intra-/inter-variability, which makes them more reproducible. Overall, Toujeo® offers the same hypoglycaemic efficacy and the same safety profile when compared with Lantus®. However, a lower risk of hypoglycaemia, especially at night, a slightly smaller weight gain and a better flexibility in the time of injection have been reported. The two insulin formulations are not bioequivalent and the daily insulin requirement is slightly higher with insulin Gla-300 than with insulin Gla-100. The shift from an already available basal insulin towards Toujeo® may require a dose adjustment and a reinforcement of blood glucose monitoring.

  5. Considerations in insulin delivery device selection.

    PubMed

    Valentine, Virginia; Kruger, Davida F

    2010-06-01

    Recent guidelines from the American Diabetes Association and the European Association for the Study of Diabetes promote the use of insulin sooner rather than later in patients with type 2 diabetes to achieve goal range glucose control (< 7%) but remain silent on a recommendation for delivery system. Even though there is widespread consensus among experts and payers that people with type 2 diabetes should use insulin earlier to achieve tight control, it still remains an elusive goal. Benefits of pen-type delivery devices include accurate dosing, faster and easier setting of dose and injection times, and increased patient acceptance and adherence. Before healthcare professionals can recommend a delivery device, it is critical they understand not only the medication in the device but also the various features and benefits to the different devices available and how those impact the patient. We will present considerations to assist in making appropriate device selection, to optimize patient success.

  6. Gallbladder edema in type 1 diabetic patient due to delayed-type insulin allergy.

    PubMed

    Kawasaki, Fumiko; Kamei, Shinji; Tatsumi, Fuminori; Hamamoto, Sumiko; Shimoda, Masashi; Tawaramoto, Kazuhito; Shigeto, Makoto; Kanda, Yukiko; Hashiramoto, Mitsuru; Matsuki, Michihiro; Kaku, Kohei

    2009-01-01

    A 29-year-old woman was diagnosed as having type 1 diabetes mellitus and received insulin aspart and NPH insulin (NovolinN). On day 22, she had leg edema and right abdominal pain. The serum hepatobiliary enzyme levels were markedly elevated. Computed tomography revealed gallbladder edema. After an injection of human regular insulin and NPH insulin (HumacartN), the elevated liver enzyme levels were no longer observed. Challenge testing demonstrated that protamine was the cause of her allergy. Furthermore, tests revealed increased VEGF levels. This is an extremely rare case with a delayed-type protamine allergy caused by NovolinN resulting in gallbladder edema.

  7. Insulin-induced hypoglycaemia is co-ordinately regulated by liver and muscle during acute and chronic insulin stimulation in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Polakof, Sergio; Skiba-Cassy, Sandrine; Choubert, Georges; Panserat, Stéphane

    2010-05-01

    The relative glucose intolerance of carnivorous fish species is often proposed to be a result of poor peripheral insulin action or possibly insulin resistance. In the present study, data from aortic cannulated rainbow trout receiving bovine insulin (75 mIU kg(-1)) injections show for the first time their ability to clear glucose in a very efficient manner. In another set of experiments, mRNA transcripts and protein phosphorylation status of proteins controlling glycaemia and glucose-related metabolism were studied during both acute and chronic treatment with bovine insulin. Our results show that fasted rainbow trout are well adapted at the molecular level to respond to increases in circulating insulin levels, and that this hormone is able to potentially improve glucose distribution and uptake by peripheral tissues. After acute insulin administration we found that to counter-regulate the insulin-induced hypoglycaemia, trout metabolism is strongly modified. This short-term, efficient response to hypoglycaemia includes a rapid, coordinated response involving the reorganization of muscle and liver metabolism. During chronic insulin treatment some of the functions traditionally attributed to insulin actions in mammals were observed, including increased mRNA levels of glucose transporters and glycogen storage (primarily in the muscle) as well as decreased mRNA levels of enzymes involved in de novo glucose production (in the liver). Finally, we show that the rainbow trout demonstrates most of the classic metabolic adjustments employed by mammals to efficiently utilize glucose in the appropriate insulin context.

  8. An update on the treatment of type 1 and type 2 diabetes mellitus: focus on insulin detemir, a long-acting human insulin analog.

    PubMed

    Raslova, Katarina

    2010-06-01

    Basal insulin analogs are used to minimize unpredictable processes of NPH insulin. Modification of the human insulin molecule results in a slower distribution to peripheral target tissues, a longer duration of action with stable concentrations and thus a lower rate of hypoglycemia. Insulin detemir is a basal insulin analog that provides effective therapeutic options for patients with type 1 and type 2 diabetes. For glycemic control, no significant differences were found in HbA1c levels compared with NPH and insulin glargine. It is comparable with insulin glargine in significantly reducing rates of all types of hypoglycemia. Clinical studies have demonstrated that detemir is responsible for significantly lower within-subject variability and no or less weight gain than NPH insulin and glargine. Recent pharmacodynamic studies have shown that detemir can be used once daily in many patients with diabetes. Together with patient-friendly injection devices and dose adjustments, it provides a treatment option with the potential to lower the key barriers of adherence to insulin therapy in type 2 diabetes. Recent guidelines for treatment of type 2 diabetes suggest starting intensive therapy of hyperglycemia at an early stage of diabetes and recommend therapeutic options that provide the possibility of reaching HbA1c goals individually, with a low risk of hypoglycemia or other adverse effects of treatment. The properties of insulin detemir match these requirements.

  9. Mouse models of insulin resistance.

    PubMed

    Hribal, Marta Letizia; Oriente, Francesco; Accili, Domenico

    2002-05-01

    The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic beta-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and beta-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic beta-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic beta-cells.

  10. II - Insulin processing in mitochondria.

    PubMed

    Camberos, María Del Carmen; Pérez, Adriana A; Passicot, Gisel A; Martucci, Lucía C; Wanderley, María I; Udrisar, Daniel P; Cresto, Juan C

    2016-10-01

    Our objective was to know how insulin is processing in mitochondria; if IDE is the only participant in mitochondrial insulin degradation and the role of insulin degradation on IDE accumulation in mitoplasts. Mitochondria and its fractions were isolated as described by Greenwalt. IDE was purified and detected in immunoblot with specific antibodies. High insulin degradation was obtained through addition to rat's diet of 25 g/rat of apple and 10 g/rat of hard-boiled eggs, 3 days a week. Mitochondrial insulin degradation was assayed with 5 % TCA, insulin antibody or Sephadex G50 chromatography. Degradation was also assayed 60 min at 37 °C in mitochondrial fractions (IMS and Mx) with diet or not and without IDE. Degradation in fractions precipitated with ammonium sulfates (60-80 %) were studied after mitochondrial insulin incubation (1 ng. insulin during 15 min, at 30 °C) or with addition of 2.5 mM ATP. Supplementary diet increased insulin degradation. High insulin did not increase mitoplasts accumulation and did not decrease mitochondrial degradation. High insulin and inhibition of degradation evidence insulin competition for a putative transport system. Mitochondrial incubation with insulin increased IDE in matrix as observed in immunoblot. ATP decreased degradation in Mx and increased it in IMS. Chromatography of IMS demonstrated an ATP-dependent protease that degraded insulin, similar to described by Sitte et al. Mitochondria participate in insulin degradation and the diet increased it. High insulin did not accomplish mitochondrial decrease of degradation or its accumulation in mitoplasts. Mitochondrial incubation with insulin increased IDE in matrix. ATP suggested being a regulator of mitochondrial insulin degradation.

  11. The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation.

    PubMed

    Stern, Sarah A; Chen, Dillon Y; Alberini, Cristina M

    2014-10-01

    Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms.

  12. The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

    PubMed Central

    Stern, Sarah A.; Chen, Dillon Y.

    2014-01-01

    Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms. PMID:25227250

  13. 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

  14. 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)

  15. Coffee improves insulin-stimulated Akt phosphorylation in liver and skeletal muscle in diabetic KK-A(y) mice.

    PubMed

    Kobayashi, Misato; Matsuda, Yuji; Iwai, Hiroshi; Hiramitsu, Masanori; Inoue, Takashi; Katagiri, Takao; Yamashita, Yoko; Ashida, Hitoshi; Murai, Atsushi; Horio, Fumihiko

    2012-01-01

    Coffee has an anti-diabetic effect, specifically the amelioration of both hyperglycemia and insulin resistance, in KK-A(y) mice, a type 2 diabetes animal model. To investigate coffee's effect on insulin signaling in liver, skeletal muscle, and adipose tissue (epididymal fat), we assayed the tyrosine phosphorylation of insulin receptor (IR) and serine phosphorylation of Akt. In Expt. 1, we assayed insulin signaling under nonfasting conditions in KK-A(y) mice that ingested water or coffee for 4 wk. Coffee ingestion ameliorated the development of hyperglycemia but did not affect insulin signaling in liver or skeletal muscle under such conditions. In Expt. 2, we assayed insulin signaling under basal and insulin-stimulated conditions in KK-A(y) mice that ingested water or coffee for 3 wk. The levels of tyrosine phosphorylation of insulin receptor in response to insulin injection in insulin-sensitive tissues were not different between mice that drank water and those that drank coffee. Coffee ingestion significantly increased the insulin-induced serine phosphorylation of Akt in liver and skeletal muscle, but not in epididymal fat, of KK-A(y) mice. Our results also indicated that coffee ingestion may contribute to the improvement of insulin resistance and hyperglycemia in KK-A(y) mice via the activation of Akt in insulin signaling in liver and skeletal muscle.

  16. Insulin attenuates atrophy of unweighted soleus muscle by amplified inhibition of protein degradation

    NASA Technical Reports Server (NTRS)

    Tischler, M. E.; Satarug, S.; Aannestad, A.; Munoz, K. A.; Henriksen, E. J.

    1997-01-01

    Unweighting atrophy of immature soleus muscle occurs rapidly over the first several days, followed by slower atrophy coinciding with increased sensitivity to insulin of in vitro protein metabolism. This study determined whether this increased sensitivity might account for the diminution of atrophy after 3 days of tall-cast hindlimb suspension. The physiological significance of the increased response to insulin in unweighted muscle was evaluated by analyzing in vivo protein metabolism for day 3 (48 to 72 hours) and day 4 (72 to 96 hours) of unweighting in diabetic animals either injected with insulin or not treated. Soleus from nontreated diabetic animals showed a similar loss of protein during day 3 (-16.2%) and day 4 (-14.5%) of unweighting, whereas muscle from insulin-treated animals showed rapid atrophy (-14.5%) during day 3 only, declining to just -3.1% the next day. Since fractional protein synthesis was similar for both day 3 (8.6%/d) and day 4 (7.0%/d) of unweighting in insulin-treated animals, the reduction in protein loss must be accounted for by a slowing of protein degradation due to circulating insulin. Intramuscular (IM) injection of insulin (600 nmol/L) stimulated in situ protein synthesis similarly in 4-day unweighted (+56%) and weight-bearing (+90%) soleus, even though unweighted muscle showed a greater in situ response of 2-deoxy-[3H]glucose uptake to IM injection of either insulin (133 nmol/L) or insulin-like growth factor-I (IGF-I) (200 nmol/L) than control muscle. These findings suggest that unweighted muscle is selectively more responsive in vivo to insulin, and that the slower atrophy after 3 days of unweighting was due to an increased effect of insulin on inhibiting protein degradation.

  17. Effects of intracerebroventricular administration of 5-(glutathion-S-yl)-alpha-methyldopamine on brain dopamine, serotonin, and norepinephrine concentrations in male Sprague-Dawley rats.

    PubMed

    Miller, R T; Lau, S S; Monks, T J

    1996-03-01

    alpha-Methyldopamine (alpha-MeDA) is a metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine (MDA) and 3,4-(+/-)-(methylenedioxy)methamphetamine (MDMA). alpha-MeDA readily oxidizes, and in the presence of glutathione (GSH) it forms 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA]. Since GSH conjugates of many polyphenols are biologically (re)active, we investigated the role of 5-(glutathion-S-yl)-alpha-MeDA in the acute and long-term neurochemical changes observed after administration of MDA. Intracerebroventricular (icv) administration of 5-(glutathion-S-yl)-alpha-MeDA (720 nmol) to male Sprague-Dawley rats produced behavioral changes similar to those reported after subcutaneous administration of MDA. Thus, animals became hyperactive and aggressive and displayed forepaw treading and Straub tails, behaviors usually seen after administration of serotonin (5-HT) releasers, and consistent with a role for 5-(glutathion-S-yl)-alpha-MeDA in some of the behavioral alterations seen after administration of MDA and MDMA. In addition to the behavioral changes, 5-(glutathion-S-yl)-alpha-MeDA also caused short-term alterations in the dopaminergic, serotonergic, and noradrenergic systems. An increase in dopamine synthesis appears to be a prerequisite for the long-term depletion of brain 5-HT following MDMA administration. However, although 5-(glutathion-S-yl)-alpha-MeDA reproduced some of the effects of MDA on the dopaminergic system and was capable of causing acute increases in 5-HT turnover, a single icv injection of 5-(glutathion-S-yl)-alpha-MeDA did not result in long-term serotonergic toxicity. Thus, although acute stimulation of dopamine turnover may be necessary for long-term serotonergic toxicity, such changes are not sufficient to produce these effects. The effects of a multiple dosing schedule of 5-(glutathion-S-yl)-alpha-MeDA will therefore require investigation before we can define a role for this metabolite in

  18. Ketogenesis evaluation in perfused liver of diabetic rats submitted to short-term insulin-induced hypoglycemia.

    PubMed

    Barrena, Helenton Cristhian; Gazola, Vilma Aparecida Ferreira Godoi; Furlan, Maria Montserrat Diaz Pedrosa; Garcia, Rosângela Fernandes; de Souza, Helenir Medri; Bazotte, Roberto Barbosa

    2009-08-01

    Ketogenesis, inferred by the production of acetoacetate plus ss-hydroxybutyrate, in isolated perfused livers from 24-h fasted diabetic rats submitted to short-term insulin-induced hypoglycemia (IIH) was investigated. For this purpose, alloxan-diabetic rats that received intraperitoneal regular insulin (IIH group) or saline (COG group) injection were compared. An additional group of diabetic rats which received oral glucose (gavage) (100 mg kg(-1)) 15 min after insulin administration (IIH + glucose group) was included. The studies were performed 30 min after insulin (1.0 U kg(-1)) or saline injection. The ketogenesis before octanoate infusion was diminished (p < 0.05) in livers from rats which received insulin (COG vs. IIH group) or insulin plus glucose (COG vs. IIH + glucose group). However, the liver ketogenic capacity during the infusion of octanoate (0.3 mM) was maintained (COG vs. IIH group and COG vs. IIH + glucose group). In addition, the blood concentration of ketone bodies was not influenced by the administration of insulin or insulin plus glucose. Taken together, the results showed that inspite the fact that insulin and glucose inhibits ketogenesis, livers from diabetic rats submitted to short-term IIH which received insulin or insulin plus glucose showed maintained capacity to produce acetoacetate and ss-hydroxybutyrate from octanoate.

  19. Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer's Disease.

    PubMed

    Uekawa, Ken; Hasegawa, Yu; Senju, Satoru; Nakagata, Naomi; Ma, Mingjie; Nakagawa, Takashi; Koibuchi, Nobutaka; Kim-Mitsuyama, Shokei

    2016-04-23

    This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer's disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer's disease.

  20. Do perceptions of insulin pump usability impact attitudes toward insulin pump therapy? A pilot study of individuals with type 1 and insulin-treated type 2 diabetes.

    PubMed

    Chamberlain, James J; Gilgen, Emily

    2015-01-01

    We assessed the impact of perceived insulin pump usability on attitudes toward insulin pump therapy in diabetic individuals currently treated with multiple daily insulin injections (MDI). This comparative, single-arm study recruited 28 adults with type 1 (n = 16) and insulin-treated type 2 diabetes (n = 12) to evaluate 2 current insulin pumps: Medtronic Revel 723 (Pump 1), Asante Snap Insulin Pump (Pump 2). Participants were randomized 1:1 to 1 of 2 assessment sequences: Pump 1 followed by Pump 2; and Pump 2 followed by Pump 1. Structured observational protocols were utilized to assess participants' ability and time required to learn/perform common tasks associated with pump setup/use. Participants used a modified version of the System Usability Scale (SUS) and investigator-developed questionnaires to rate pump usability and task difficulty; pre-post questionnaires assessed changes in attitudes toward insulin pump therapy. All participants completed the study. SUS scores showed Pump 2 to be more usable than Pump 1 on all usability attributes. Participants rated Pump 2 more positively than Pump 1, overall mean SUS scores of 5.7 versus 4.1 respectively, F(1, 52) = 32.7, P < .001, and SUS scores were higher if participants used the Pump 2 last, 5.3 versus 4.4 for Pump 1 last, F(1, 52) = 10.8, P < .01. Pump 2 was preferred for all tasks: manual bolus (86%), bolus calculation (71%), managing basal rates (93%), interpreting alarms (96%), transferring settings (100%), changing insulin and infusion sets (93%), all P < .05. Perceptions of pump usability can directly impact acceptance and use of features that may benefit those who wear them. Simpler pump devices that decrease perceptions of complexity may encourage broader use of this technology.

  1. Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery

    PubMed Central

    Matteucci, Elena; Giampietro, Ottavio; Covolan, Vera; Giustarini, Daniela; Fanti, Paolo; Rossi, Ranieri

    2015-01-01

    Insulin is a life-saving medication for people with type 1 diabetes, but traditional insulin replacement therapy is based on multiple daily subcutaneous injections or continuous subcutaneous pump-regulated infusion. Nonphysiologic delivery of subcutaneous insulin implies a rapid and sustained increase in systemic insulin levels due to the loss of concentration gradient between portal and systemic circulations. In fact, the liver degrades about half of the endogenous insulin secreted by the pancreas into the venous portal system. The reverse insulin distribution has short- and long-term effects on glucose metabolism. Thus, researchers have explored less-invasive administration routes based on innovative pharmaceutical formulations, which preserve hormone stability and ensure the therapeutic effectiveness. This review examines some of the recent proposals from clinical and material chemistry point of view, giving particular attention to patients’ (and diabetologists’) ideal requirements that organic chemistry could meet. PMID:26124635

  2. Lipolytic responses induced by intracerebroventricular administration of histamine in the rat.

    PubMed

    Bugajski, J; Janusz, Z

    1981-04-01

    Histamine (10-50 microgram) administered intraventricularly in conscious rats induced an increase in serum-free fatty acids. The maximum, significant increase appeared 30-60 min after administration. Histamine H1-receptor antagonists, mepyramine and chloropyramine, when injected 2 h prior to histamine, abolished considerably hyperlipaemic responses to histamine. H2-Receptor antagonists, metiamide and cimetidine, given i.c.v. only moderately diminished histamine-induced hyperlipaemia. Histamine injected i.c.v. also increased serum corticosterone levels considerably. This elevation was prevented significantly by the H1-receptor antagonist, mepyramine, but not by the H2-receptor blocker, cimetidine. It seems likely that histamine given i.c.v. induces lipolysis through the release of ACTH, one of the known lipid-mobilizing hormones. The central lipid-mobilizing mechanism after histamine depends more on activation of H1- than H2-receptors.

  3. The osmotically and histamine-induced enhancement of the plasma vasopressin level is diminished by intracerebroventricularly administered orexin in rats.

    PubMed

    Kis, Gyöngyi K; Molnár, Andor H; Daruka, Leila; Gardi, János; Rákosi, Kinga; László, Ferenc; László, Ferenc A; Varga, Csaba

    2012-04-01

    The effects of the centrally administered neuropeptides orexin-A on water intake and vasopressin (VP) secretion were studied in male Wistar rats (180-250 g). Different doses (10, 30, and 90 μg/10 μl) of the orexins and the specific orexin receptor-1 (OX(1)) antagonist SB 408124 (30 μg/10 μl) were administered intracerebroventricularly (i.c.v.) under anaesthesia, and the water consumption was measured during 6 h. A plasma VP level elevation was induced by histamine (10 mg/kg) or 2.5% NaCl (10 ml/kg) administered intraperitoneally (i.p.). The plasma VP levels were measured by radioimmunoassay. Increased water consumption was observed after the administration of 30 μg/10 μl orexin-A. There were no changes in basal VP secretion after the administration of different doses of the orexins. A significant increase in plasma VP concentration was detected following histamine administration. After 2.5% NaCl administration, there was a moderate VP level enhancement. Intracerebroventricularly administered orexin-A (30 μg/10 μl) blocked the VP level increase induced by either histamine or 2.5% NaCl administration. The inhibitory effects were prevented by the specific OX(1) receptor antagonist. In conclusion, the orexins increased water consumption. After 30 μg/10 μl orexin-A administration, the polydipsia was more pronounced. The OX(1) receptor antagonist significantly decreased the polydipsia. Histamine or hyperosmotic VP release enhancement was blocked by previously administered orexin. This inhibition was not observed following OX(1) receptor antagonist administration. Our results suggest that the effects of the orexins on water consumption or blockade of the histamine and osmosis-induced VP level increase are mediated by the OX(1) receptor.

  4. Effects of systemic Thalidomide and intracerebroventricular Etanercept and Infliximab administration in a Streptozotocin induced dementia model in rats.

    PubMed

    Kübra Elçioğlu, H; Kabasakal, Levent; Tufan, Fatih; Elçioğlu, Ömer H; Solakoglu, Seyhun; Kotil, Tugba; Karan, Mehmet Akif

    2015-03-01

    Tumor necrosis factor-alpha (TNF-α) upregulation enhances amyloid β (Aβ) induced neurotoxicity in Alzheimer's disease (AD). Intracerebroventricular streptozotocin (STZ) administration causes pathological changes and cognitive deficits similar to those seen in AD by causing impairment of brain glucose and energy metabolism. Recent reports indicate a protective role of Thalidomide, Etanercept, and Infliximab, all of which have anti-TNF-α activity, against cognitive and neuropathological changes in experimental and clinical studies. We aimed to investigate the protective effects of Thalidomide, Etanercept, and Infliximab in a rat model of intracerebroventricular STZ-induced dementia. Sprague-Dawley rats (250-300g) were separated to sham (n=6) and STZ (n=24) groups. The STZ group was divided into four groups (STZ, STZ-thalidomide, STZ-etanercept, and STZ-infliximab). Morris's water maze (MWM) and passive avoidance (PA) tests were performed. At the end of the third week, brain tissues were obtained. Histopathological analysis, immunohistochemistry, and electron microscopic examinations were done. The improvement performance of the STZ group was significantly reduced in the MWM test (p<0.001). Compared with the STZ, STZ-thalidomide, STZ-etanercept, and STZ-infliximab groups had significantly better performance (p<0.001, <0.05 and <0.05, respectively) in the MWM test. STZ administration caused a significant decrease in the mean escape latency in PA reflex (p<0.001). Thalidomide, Etanercept, and Infliximab were associated with better PA reflexes compared to the STZ group (p<0.001 for all). Morphological and immunohistochemical results showed increased neurodegenerative changes compared to sham group. Our findings are in line with the findings reported in the literature and encourage further studies with TNF-α antagonists, in particular Thalidomide.

  5. Does one-to-one demonstration with insulin pads by health-care providers improves the insulin administration techniques among diabetic patients of a Tertiary Care Teaching Hospital in South India?

    PubMed Central

    Kapoor, Urvasi; Ramasamy, Gomathi; Selvaraj, Kalaiselvi; Sahoo, Jaya Prakash; Kar, Sitanshu Sekhar

    2016-01-01

    Objectives: The study was aimed to capture the effect of using injection pads as a tool in educating the diabetic patients who were on insulin. The attitude and practice of the patients in storage of insulin vials and disposal of insulin syringes were also assessed. Materials and Methods: A facility based Quasi-experimental study was carried out among the diabetic patients on insulin, attending diabetic clinic in endocrinology OPD in a tertiary care hospital, Puducherry. One to one intervention was given to the study participants or their attendants (who were involved in injecting insulin), by a trained investigator regarding all the steps of insulin administration. The insulin administration practices before and immediately after the intervention was assessed using a checklist. Results: In total 91 patients were included for the study with mean (SD) age of 53.9 (10.6) years and of them 76% were females. The attitude and practices of the study participants, such as hand washing before handling insulin, checking the expiry date, storage of insulin, inspection of injection site, rolling and cleaning the vial, withdrawal of the syringe up to the required dose, pushing the plunger after inserting the syringe into the vial, checking and removal of air bubbles, cleaning the injection site and allow to dry and injection technique improved significantly after the intervention (P < 0.05). Conclusion: This study findings shows that using injection pads for educating patients helps them to practise better insulin administration. The findings from the study can be applied in routine care and has to be explored further in diabetic patient management. PMID:27867877

  6. The effects of caerulein on insulin secretion in anaesthetized dogs.

    PubMed

    Bertaccini, G; De Caro, G; Melchiorri, P

    1970-09-01

    1. Insulin concentration changes in pancreatico-duodenal venous plasma were studied in anaesthetized dogs injected with caerulein.2. Rises in insulin concentration were elicited by rapid intravenous injection of caerulein, as well as by intravenous infusion. Threshold doses were 10 ng/kg and 0.5-1 (ng/kg)/min respectively.3. At the highest dose used (500 ng/kg by rapid intravenous injection and (25 ng/kg)/min by intravenous infusion) the increase in immuno-reactive insulin release was approximately 7 to 9 times the base levels.4. Adrenalectomy potentiated the effects of intravenous infusion of caerulein.5. On a molar basis, caerulein was 2-3 times as active as pancreozymin.6. It is concluded that caerulein is a potent stimulant of pancreatic islets in the dog and that it may be considered as a model peptide, capable of being substituted for pancreozymin in any experiment.7. The mechanism of the insulin stimulating effect of caerulein is discussed. The possibility of a direct "beta-cytotropic" effect of the peptide is suggested.

  7. Self-assembled lecithin/chitosan nanoparticles for oral insulin delivery: preparation and functional evaluation

    PubMed Central

    Liu, Liyao; Zhou, Cuiping; Xia, Xuejun; Liu, Yuling

    2016-01-01

    Purpose Here, we investigated the formation and functional properties of self-assembled lecithin/chitosan nanoparticles (L/C NPs) loaded with insulin following insulin–phospholipid complex preparation, with the aim of developing a method for oral insulin delivery. Methods Using a modified solvent-injection method, insulin-loaded L/C NPs were obtained by combining insulin–phospholipid complexes with L/C NPs. The nanoparticle size distribution was determined by dynamic light scattering, and morphologies were analyzed by cryogenic transmission electron microscopy. Fourier transform infrared spectroscopy analysis was used to disclose the molecular mechanism of prepared insulin-loaded L/C NPs. Fast ultrafiltration and a reversed-phase high-performance liquid chromatography assay were used to separate free insulin from insulin entrapped in the L/C NPs, as well as to measure the insulin-entrapment and drug-loading efficiencies. The in vitro release profile was obtained, and in vivo hypoglycemic effects were evaluated in streptozotocin-induced diabetic rats. Results Our results indicated that insulin-containing L/C NPs had a mean size of 180 nm, an insulin-entrapment efficiency of 94%, and an insulin-loading efficiency of 4.5%. Cryogenic transmission electron microscopy observations of insulin-loaded L/C NPs revealed multilamellar structures with a hollow core, encircled by several bilayers. In vitro analysis revealed that insulin release from L/C NPs depended on the L/C ratio. Insulin-loaded L/C NPs orally administered to streptozotocin-induced diabetic rats exerted a significant hypoglycemic effect. The relative pharmacological bioavailability following oral administration of L/C NPs was 6.01%. Conclusion With the aid of phospholipid-complexation techniques, some hydrophilic peptides, such as insulin, can be successfully entrapped into L/C NPs, which could improve oral bioavailability, time-dependent release, and therapeutic activity. PMID:26966360

  8. Effect of intravenous infusion of recombinant ovine leptin on feed intake and serum concentrations of GH, LH, insulin, IGF-1, cortisol, and thyroxine in growing prepubertal ewe lambs.

    PubMed

    Morrison, C D; Wood, R; McFadin, E L; Whitley, N C; Keisler, D H

    2002-04-01

    In sheep, serum concentrations of leptin change congruently with increases or decreases in nutritional status, while intracerebroventricular infusions of leptin dramatically suppress feed intake in well-fed lambs, and may also increase growth hormone (GH), and/or luteinizing hormone (LH) in undernourished lambs. The objective of the present study was to determine the effects of peripherally delivered ovine leptin, via intravenous infusions, on feed intake and serum concentrations of GH, LH, insulin, IGF-1, cortisol, and thyroxine. Twelve ewe lambs weighing 29.4 +/- 0.7 kg were infused intravenously with a linearly increasing dose of leptin or saline (n = 6 per group) for 10 days, reaching a maximum dose delivered of 0.5mg/h on day 10. Feed intake was assessed twice daily, and blood samples were collected every 10 min for 6 h on days 0, 2, 5, 8, and 10. Serum concentrations of leptin increased in leptin-treated lambs by day 2 (P = 0.05), and continued to increase to concentrations 9-fold greater than saline-infused lambs by day 10 (P < 0.001). Despite the substantial increase in serum leptin, feed intake did not differ between leptin and saline-infused lambs except on day 3.5 (P = 0.01). Furthermore, intravenous infusions of leptin did not significantly influence serum concentrations of insulin, cortisol, IGF-1, thyroxine, LH, or GH. Collectively, these observations contrast with the potent hypophagic effects of leptin when delivered intracerebroventricularly into well-fed lambs. The reasons for the disparate response of lambs treated intravenously with leptin, versus that reported for lambs treated intracerebroventricularly with leptin are not known, but may provide insight into the mechanism(s) of leptin resistance.

  9. 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

  10. The effect of fasting, diet, and actinomycin D on insulin secretion in the rat

    PubMed Central

    Grey, N. J.; Goldring, S.; Kipnis, D. M.

    1970-01-01

    The present studies were performed to elucidate the mechanisms responsible for the impairment of glucose-stimulated insulin secretion observed in fasting. Rats fasted for 48 hr displayed marked impairment in their insulin secretory response to both oral and intravenous glucose. Glucose-stimulated insulin secretion was restored within 24 hr by refeeding; actinomycin D given before refeeding blocked the expected return of normal glucose-stimulated insulin secretion despite adequate food intake. Fasted rats refed a diet devoid of carbohydrate failed to display a return of normal insulin secretory responsiveness to oral glucose in contrast to rats fed isocalorically a high carbohydrate diet. Differences in insulin secretion in fed, fasted, and fasted-refed rats could not be attributed to changes in pancreatic insulin content. There was no significant difference in the insulin secretory response to aminophylline of fed, fasted, or fasted-refed rats. The intermittent pulsing of fasted rats with hyperglycemic episodes by the injection of small amounts of glucose (500 mg) intraperitoneally every 8 hr ameliorated the impairment of glucose-stimulated insulin secretion characteristic of the fasting state. These results suggest that the impairment of glucose-stimulated insulin secretion during fasting and its restoration by refeeding are regulated by changes in a glucose-inducible enzyme system in the pancreatic beta cell. PMID:5441542

  11. Adipocyte JAK2 mediates growth hormone–induced hepatic insulin resistance

    PubMed Central

    Corbit, Kevin C.; Camporez, João Paulo G.; Tran, Jennifer L.; Wilson, Camella G.; Lowe, Dylan A.; Nordstrom, Sarah M.; Ganeshan, Kirthana; Perry, Rachel J.; Weiss, Ethan J.

    2017-01-01

    For nearly 100 years, growth hormone (GH) has been known to affect insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here, we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extrahepatic, adipose tissue–dependent mechanism. PMID:28194444

  12. Colon targeting: an emerging frontier for oral insulin delivery.

    PubMed

    Patel, Mayur Mahendrakumar

    2013-06-01

    Subcutaneous administration of insulin is associated with several limitations such as discomfort, local pain, irritation, infections, immune reactions and lipoatrophy as well as lipohypertrophy manifestations at the injection site. To overcome these drawbacks, enormous research is currently going on worldwide for designing of an alternative noninvasive route of administration. Pulmonary and oral route seem to be the most promising ones, with respect to the market value. However, after the letdown by pulmonary delivery of insulin, oral colon targeted delivery of insulin has gained tremendous interest among researchers. Although bioavailability remains a challenge for oral colon specific delivery of insulin, the employment of protease inhibitors, permeation enhancers and polymeric delivery systems have proved to be advantageous to overcome the said problem. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the strategies employed for attaining non-erratic bioavailability of insulin, and to highlight some of the formulation technologies that have been developed for attaining oral colon-specific delivery of insulin.

  13. Insulin gene therapy for type 1 diabetes mellitus.

    PubMed

    Handorf, Andrew M; Sollinger, Hans W; Alam, Tausif

    2015-04-01

    Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of pancreatic β cells. Current treatments for patients with type 1 diabetes mellitus include daily insulin injections or whole pancreas transplant, each of which are associated with profound drawbacks. Insulin gene therapy, which has shown great efficacy in correcting hyperglycemia in animal models, holds great promise as an alternative strategy to treat type 1 diabetes mellitus in humans. Insulin gene therapy refers to the targeted expression of insulin in non-β cells, with hepatocytes emerging as the primary therapeutic target. In this review, we present an overview of the current state of insulin gene therapy to treat type 1 diabetes mellitus, including the need for an alternative therapy, important features dictating the success of the therapy, and current obstacles preventing the translation of this treatment option to a clinical setting. In so doing, we hope to shed light on insulin gene therapy as a viable option to treat type 1 diabetes mellitus.

  14. Attributes Influencing Insulin Pen Preference Among Caregivers and Patients With Diabetes Who Require Greater Than 20 Units of Mealtime Insulin

    PubMed Central

    Wang, Tao; Conrad, Kenneth A.; van Brunt, Kate; Rees, Tina M.

    2016-01-01

    Background: This study compared patient preference for Humalog® KwikPen™ 200 units/mL (insulin lispro; hereafter, IL 200 pen; Eli Lilly and Company, Indianapolis, IN) versus the Humalog KwikPen 100 units/mL (insulin lispro; hereafter, IL 100 pen; Eli Lilly and Company, Indianapolis, IN) in patients with diabetes requiring >20 units of mealtime insulin and diabetes caregivers. This study also determined which attributes had the greatest influence on pen preference selection. Methods: In this 2-period, crossover, simulated-use study, 106 participants were randomized to 1 of 8 sequences that varied the pen order (IL 100 pen or IL 200 pen) and dosing order (15 units = low dose or 50 units = high dose) for a total of 4 simulated injections. Participants then completed a self-administered questionnaire to select their overall preference between the 2 pens and then rated the importance of 11 pen attributes in contributing to their overall preference. Results: Of the 90 participants expressing an overall preference, significantly more preferred the IL 200 pen to the IL 100 pen (IL 200 pen: 80 respondents; IL 100 pen: 10 respondents; 95% confidence interval [0.81, 0.94], P < .0001). The total amount of insulin in the pen, the ease in pressing the injection button, and the amount of fluid injected were key attributes influencing IL 200 pen preference. Conclusions: Based on these key attributes, the IL 200 pen was significantly preferred over the IL 100 pen by patients with diabetes who require >20 daily mealtime insulin units or diabetes caregivers and may improve the injection experience for these patients. PMID:26920640

  15. Increased insulin translation from an insulin splice-variant overexpressed in diabetes, obesity, and insulin resistance.

    PubMed

    Minn, Alexandra H; Lan, Hong; Rabaglia, Mary E; Harlan, David M; Peculis, Brenda A; Attie, Alan D; Shalev, Anath

    2005-03-01

    Type 2 diabetes occurs when pancreatic beta-cells become unable to compensate for the underlying insulin resistance. Insulin secretion requires beta-cell insulin stores to be replenished by insulin biosynthesis, which is mainly regulated at the translational level. Such translational regulation often involves the 5'-untranslated region. Recently, we identified a human insulin splice-variant (SPV) altering only the 5'-untranslated region and conferring increased translation efficiency. We now describe a mouse SPV (mSPV) that is found in the cytoplasm and exhibits increased translation efficiency resulting in more normal (prepro)insulin protein per RNA. The RNA stability of mSPV is not increased, but the predicted secondary RNA structure is altered, which may facilitate translation. To determine the role of mSPV in insulin resistance and diabetes, mSPV expression was measured by quantitative real-time RT-PCR in islets from three diabetic and/or insulin-resistant, obese and nonobese, mouse models (BTBRob/ob, C57BL/6ob/ob, and C57BL/6azip). Interestingly, mSPV expression was significantly higher in all diabetic/insulin-resistant mice compared with wild-type littermates and was dramatically induced in primary mouse islets incubated at high glucose. This raises the possibility that the mSPV may represent a compensatory beta-cell mechanism to enhance insulin biosynthesis when insulin requirements are elevated by hyperglycemia/insulin resistance.

  16. Use of an implantable pump for controlled subcutaneous insulin delivery in healthy cats.

    PubMed

    Zini, E; Padrutt, I; Macha, K; Riederer, A; Pesaresi, M; Lutz, T A; Reusch, C E

    2017-01-01

    The aim of this study was to examine the safety and reliability of a research-grade implantable pump for controlled delivery of insulin glargine in cats. For this purpose, a small telemetrically controlled drug delivery pump with a refillable reservoir was implanted into the subcutaneous tissues of the dorsal neck in 10 clinically healthy cats. The reservoir was filled with insulin glargine, and the pump was programmed to deliver four boluses of 0.25 IU/kg, 2-3 weeks apart. As a control, insulin glargine (0.25 IU/kg) was injected SC. Blood glucose and plasma insulin glargine concentrations were measured before each bolus and SC injection and for 8 h afterward. Cats were monitored for signs of discomfort. Pumps were easily implanted and well tolerated by all cats. The experiment was completed in five of 10 cats. In four, the pump failed because of technical reasons; another cat developed severe hypoglycaemia attributable to insulin leakage. Overall, plasma insulin glargine increased after six of eight (75%) initial boluses and after one of 16 (6%) successive boluses. Glucose decreased after seven of eight (88%) initial boluses and after four of 16 (25%) successive boluses. Only the first bolus significantly increased plasma insulin glargine (P = 0.008) and decreased glucose (P = 0.008). Of 20 SC injections, 10 (50%) increased plasma insulin glargine (P <0.001) and 12 (60%) decreased glucose (P <0.001). The pump did not cause discomfort in cats, but life-threatening hypoglycaemia occurred in one. Frequent device problems suggest that the pump needs improvements. Because successive boluses did not increase plasma insulin glargine, this type of insulin may not be appropriate with the pump.

  17. Anti-idiotype guinea pig antibodies as response to insulin immunization.

    PubMed

    Camberos, M C; Perez, A; Cresto, J C

    1998-01-01

    The study was done using 39 guinea pigs grouped as followed; 18 were injected with 0.5 mg of porcine insulin emulsified in complete Freund's adjuvant; 12 were injected with saline and 9 were used as control of cardiac bleeding during the assay. Intraperitoneal glucose tolerance tests (IGTT) were carried out on days 0, 11, 32 and 38. Seven of the thirteen guinea pigs immunized with insulin which survived after the study, showed glucose intolerance on day 32 at 90 and 120 min (p < 0.01 and p < 0.001) and on day 38 at 120 min (p < 0.05). Anti-idiotypic IgG partially purified from a sera pool from these animals inhibited 125-Insulin binding to rat hepatocytes, immunoprecipitated 125I-rat insulin receptors and recognized the alpha-subunit of insulin receptor in immunoblotting. We conclude that insulin anti-idiotypes in guinea pigs offer a simple way to produce antibodies against insulin receptor binding site. The methodology for anti-idiotype identification can be applied to patients with insulin resistance.

  18. Insulin Signalling: The Inside Story.

    PubMed

    Posner, Barry I

    2017-02-01

    Insulin signalling begins with binding to its cell surface insulin receptor (IR), which is a tyrosine kinase. The insulin receptor kinase (IRK) is subsequently autophosphorylated and activated to tyrosine phosphorylate key cellular substrates that are essential for entraining the insulin response. Although IRK activation begins at the cell surface, it is maintained and augmented following internalization into the endosomal system (ENS). The peroxovanadium compounds (pVs) were discovered to activate the IRK in the absence of insulin and lead to a full insulin response. Thus, IRK activation is both necessary and sufficient for insulin signalling. Furthermore, this could be shown to occur with activation of only the endosomal IRK. The mechanism of pV action was shown to be the inhibition of IRK-associated phosphotyrosine phosphatases (PTPs). Our studies showed that the duration and intensity of insulin signalling are modulated within ENS by the recruitment of cellular substrates to ENS; intra-endosomal acidification, which promotes dissociation of insulin from the IRK; an endosomal acidic insulinase, which degrades intra-endosomal insulin; and IRK-associated PTPs, which dephosphorylate and, hence, deactivate the IRK. Therefore, the internalization of IRKs is central to insulin signalling and its regulation.

  19. 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.

  20. Insulin Dose and Cardiovascular Mortality in the ACCORD Trial

    PubMed Central

    Rubin, Daniel J.; Riddle, Matthew C.; Miller, Michael E.; Hsu, Fang-Chi; Ismail-Beigi, Faramarz; Chen, Shyh-Huei; Ambrosius, Walter T.; Thomas, Abraham; Bestermann, William; Buse, John B.; Genuth, Saul; Joyce, Carol; Kovacs, Christopher S.; O'Connor, Patrick J.; Sigal, Ronald J.; Solomon, Sol

    2015-01-01

    OBJECTIVE In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality. RESEARCH DESIGN AND METHODS We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment. RESULTS More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation. CONCLUSIONS These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD. PMID:26464212

  1. Insulin regulation of sugar transport in giant muscle fibres of the barnacle

    PubMed Central

    Baker, P. F.; Carruthers, A.

    1983-01-01

    1. Sugar transport in the giant muscle cells of Balanus nubilus is accelerated during contractile activity and exposure to porcine insulin. The characteristics of hexose-transfer regulation in the giant muscle cells have been examined by studying the transport of 3-O-methylglucose (a non-metabolized sugar) in both intact giant fibres and fibres subjected to internal solute control by internal dialysis. 2. Sugar transport in barnacle muscle is mediated by a saturable process which is inhibited by both phloretin and cytochalasin B. Insulin increases the capacity of the transport system with little effect on its apparent affinity for sugar. Under the same conditions insulin increases 3-O-methylglucose-displaceable cytochalasin B binding. The effects of insulin on transport are half-maximal at 5 μM-insulin and are abolished by both insulin antibody and phloretin. The intact barnacle releases an insulin-like material in response to a rise in blood glucose levels. 3. Insulin increases the cyclic GMP (cGMP) content and reduces the cyclic AMP (cAMP) content of barnacle muscle. Experiments with fibres injected with aequorin show that insulin also lowers cytosolic ionized Ca levels. The changes in cyclic nucleotide levels induced by insulin precede the effects on sugar transport and cytosolic ionized Ca. During repetitive contractile activity, cAMP, cGMP and ionized Ca levels are raised. 4. Agents which raise the cAMP content of barnacle muscle normally inhibit sugar transport. Dibutyryl cAMP also inhibits transport. Alterations in cytosolic ionized Ca levels in intact fibres are without effect on sugar transport. Nevertheless, stimulation of transport by insulin is blunted when cytosolic ionized Ca is lowered by intracellular injection of the Ca-chelating agent, EGTA. 5. Sugar uptake in the internally dialysed fibre is inhibited by intracellular application of cAMP. Internal application of Ca and cGMP stimulate sugar uptake in the dialysed fibre. Cyclic AMP reduces the

  2. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat.

    PubMed

    Broca, Christophe; Breil, Vincent; Cruciani-Guglielmacci, Céline; Manteghetti, Michèle; Rouault, Christine; Derouet, Michel; Rizkalla, Salwa; Pau, Bernard; Petit, Pierre; Ribes, Gérard; Ktorza, Alain; Gross, René; Reach, Gérard; Taouis, Mohammed

    2004-09-01

    ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.

  3. Insulin treatment of type 2 diabetes: considerations when converting from human insulin to insulin analogs.

    PubMed

    Griffin, Stacy

    2013-03-01

    Type 2 diabetes mellitus is a highly prevalent disease characterized by insulin resistance, hyperglycemia, and diminished pancreatic β-cell function. Conventional insulin products used to manage this disease include regular human insulin and intermediate-acting human insulin. However, due to several limitations imposed by human insulins, such as onset and duration of action that do not coincide with physiologic needs and increased risk of hypoglycemia, insulin analogs were developed. Because they more closely mimic the physiologic action of endogenous insulin, insulin analogs are associated with more effective glucose control, a lower risk of hypoglycemia, greater convenience, and, in some instances, less weight gain. Switching from human insulin to insulin analogs is easily accomplished. Several studies have demonstrated a high rate of success with patient-initiated, self-adjusted dosing algorithms compared to investigator/clinician-initiated dose adjustments. These studies and several other published guidelines on insulin analogs provide patients and clinicians with information pertaining to better treatment options and can help increase overall patient satisfaction.

  4. Improved Postprandial Glucose Control Using the InsuPad Device in Insulin-Treated Type 2 Diabetes

    PubMed Central

    Raz, Itamar; Bitton, Gabriel; Feldman, Dmitry; Alon, Tal; Pfutzner, Andreas; Tamborlane, William V.

    2015-01-01

    Background: Delays in the time-action profiles of premeal boluses of rapid-acting insulin analogs contribute to early postmeal hyperglycemia in patients with diabetes. We tested whether applying local heat to skin around the injection site to increase the rate of insulin absorption reduces postprandial hyperglycemia in patients with type 2 diabetes. Methods: Fourteen patients with type 2 diabetes (4 females; age 61.6 ± 8.4 years, HbA1c 8.42 ± 1.13%; BMI 29.10 ± 5.61 kg/m2) on intensified insulin therapy underwent 5-hour meal tolerance tests (MTTs) with a standardized liquid meal after an overnight fast on 2 study days. Subjects injected 0.2 U/kg of insulin aspart or lispro subcutaneously into the abdominal skin on both days with and without the use of the InsuPad device. Results: Following the premeal bolus injection of rapid-acting insulin analog, infusion site warming led to a rise in plasma insulin levels to peak concentrations that were significantly earlier than without skin warming (mean ± SD 52 ± 26.7 vs 80 ± 51.3 minutes, P < .005) as well as increase in plasma insulin levels during the first hour after injection (mean ± SD 63.5 ± 32.7 IU vs 48.0 ± 25.0 uU.min/ml, P = .019). As a result, the area under the curve of the postprandial glucose excursion during the first 2 hours (the primary study outcome) and the entire 5 hours after the meal were significantly reduced (P = .007 and P = .03, respectively) with skin warming around the injection site. Discussion and Conclusions: Use of the InsuPad to increase the rate of insulin absorption provides an effective means to achieve better control of postmeal glucose excursions in type 2 diabetic patients receiving premeal injections of rapid-acting insulin analogs. PMID:25883166

  5. 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.

  6. Variability of NPH insulin preparations.

    PubMed

    Belmonte, M M; Colle, E; DeBelle, R; Murthy, D Y

    1971-01-23

    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.

  7. 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

  8. Epidural Injections for Spinal Pain

    MedlinePlus

    ... Physician Resources Professions Site Index A-Z Epidural Injections An epidural injection provides temporary or prolonged relief ... limitations of Epidural Injection? What is an Epidural Injection? An epidural injection is an injection of medication ...

  9. Cold exposure potentiates the effect of insulin on in vivo glucose uptake

    SciTech Connect

    Vallerand, A.L.; Perusse, F.; Bukowiecki, L.J. )

    1987-08-01

    The effects of cold exposure and insulin injection on the rates of net 2-({sup 3}H)deoxyglucose uptake (K{sub i}) in peripheral tissues were investigated in warm-acclimated rats. Cold exposure and insulin treatment independently increased K{sub i} values in skeletal muscles, heart, white adipose tissue, and brown adipose tissue. The effects of cold exposure were particularly evident in brown adipose tissue where the K{sub i} increased >100 times. When the two treatments were combined, it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an insulin-like effect on K{sub i} that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from (1) an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and (2) an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake.

  10. Optimizing insulin therapy in pregnant women with type 1 diabetes mellitus.

    PubMed

    Gottlieb, Peter A; Frias, Juan P; Peters, Kelly A; Chillara, Bhavani; Garg, Satish K

    2002-01-01

    Pregnancy complicated by type 1 diabetes mellitus is associated with an increased risk of complications in the mother and infant. Normal or near normal glycemic control prior to and during pregnancy reduces many of these risks to levels observed in the general population. This degree of glycemic control is generally achievable only with intensive insulin therapy: multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) via an insulin pump. These therapeutic regimens have been found to result in comparable glycemic control, although CSII provides increased flexibility in terms of patient lifestyle, and may reduce the incidence of hypoglycemia. Frequent home blood glucose monitoring is imperative during pregnancy in order to optimize glycemic control and reduce the risk of hypoglycemia. Furthermore, insulin requirements change significantly over the course of pregnancy. The new short-acting insulin analogs, insulin lispro and insulin aspart, have pharmacodynamic properties which make them ideal for use during pregnancy. Although the number of published studies evaluating the use of insulin lispro during pregnancy is limited, the majority support its safety. No studies of insulin aspart in pregnancy have been published in full. In addition to optimization of glycemic control, frequent assessment for development and/or progression of microvascular complications is necessary during pregnancy.

  11. Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats.

    PubMed

    Wisniewski, Miriam S W; Carvalho-Silva, Milena; Gomes, Lara M; Zapelini, Hugo G; Schuck, Patrícia F; Ferreira, Gustavo C; Scaini, Giselli; Streck, Emilio L

    2016-04-01

    Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain α-ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating α-ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of α-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD.

  12. Paradoxical increase in liver ketogenesis during long-term insulin-induced hypoglycemia in diabetic rats.

    PubMed

    Schiavon, Fabiana P M; Gazola, Vilma A F G; Furlan, Maria M D P; Barrena, Helenton C; Bazotte, Roberto B

    2011-02-01

    It is well established that insulin inhibits liver ketogenesis. However, during insulin-induced hypoglycemia (IIH) the release of counterregulatory hormones could overcome the insulin effect on ketogenesis. To clarify this question the ketogenic activity in livers from alloxan-diabetic rats submitted to long-term IIH was investigated. Moreover, liver glycogenolysis, gluconeogensis, ureagenesis and the production of L-lactate were measured, and its correlation with blood levels of ketone bodies (KB), L-lactate, glucose, urea and ammonia was investigated. For this purpose, overnight fasted alloxan-diabetic rats (DBT group) were compared with control non-diabetic rats (NDBT group). Long-term IIH was obtained with an intraperitoneal injection of Detemir insulin (1 U/kg), and KB, glucose, L-lactate, ammonia and urea were evaluated at 0, 2, 4, 6, 8 or 10 h after insulin injection. Because IIH was well established two hours after insulin injection this time was used for liver perfusion experiments. The administration of Detemir insulin decreased (P < 0.05) blood KB and glucose levels, but there was an increase in the blood L-lactate levels and a rebound increase in blood KB during the glucose recovery phase of IIH. In agreement with these results, the capacity to produce KB from octanoate was increased in the livers of DBT rats. Moreover, the elevated blood L-lactate levels in DBT rats could be attributed to the higher (P < 0.05) glycogenolysis when part of glucose from glycogenolysis enters glycolysis, producing L-lactate. In contrast, except glycerol, gluconeogenesis was negligible in the livers of DBT rats. Therefore, during long-term IIH the higher liver ketogenic capacity of DBT rats increased the risk of hyperketonemia. In addition, in spite of the fact that the insulin injection decreased blood KB, there was a risk of worsening lactic acidosis.

  13. Central Renin Injections: Effects on Drinking and Expression of Immediate Early Genes

    NASA Technical Reports Server (NTRS)

    Xu, Zhice; Johnson, Alan Kim

    1998-01-01

    This study investigated the drinking response and the expression of Fos- and Egr-1-immunoreactivity (Fos-ir, Egr-1-ir) in the brain induced by endogenous angiotensin generated by intracerebroventricular (i.c.v.) injection of renin. Renin induced Fos-ir in the subformical organ (SFO), median preoptic (MnPO), supraoptic and paraventricular nuclei (SON and PVN), area postrema (AP), nuclei of the solitary tract (NTS) and lateral parabrachial nuclei (LPBN). Renin-induced Egr-1-ir exhibited a similar pattern of distribution as that observed for Fos-ir. The dose of i.c.v. renin that induced expression of immediate early gene (IEG) product immunoreactivity also produced vigorous drinking. When renin-injected rats were pretreated with captopril, an angiotensin converting enzyme inhibitor, drinking was blocked. With the same captopril pretreatment, both Fos- and Egr-1-ir in the SFO, MnPO, SON, PVN, AP and LPBN were also significantly reduced.

  14. Local application of low-dose insulin in improving wound healing after deep burn surgery

    PubMed Central

    Wang, Chejiang; Wang, Jiazhe; Feng, Jianke

    2016-01-01

    The clinical effects of local application of low-dose insulin in improving wound healing after deep burn self-skin transplantation surgery were examined. Fifty-eight patients with deep burns were selected and randomly divided into 3 groups. In the blank control group, normal saline was injected to the subcutaneous tissue of wounds; in large dose insulin group, 1.0 µ long-term suspended zinc insulin was locally injected; and in the low-dose insulin group, 0.1 µ long-term suspended zinc insulin was locally injected. The healing effects were compared. After 7 and 14 days of treatments, wound surface area in the low-dose group was significantly smaller than in the other groups, and differences were statistically significant (P<0.05); wound healing duration and infection rate for patients in the low-dose group were significantly lower, class A healing rate was significantly improved, and the differences were statistically significant (P<0.05). Insulin resistance index (HOMA-IR) in the low-dose group was significantly lower, insulin secretion index (HOMA-β) and the insulin sensitivity index (HOMA-ISI) significantly increased. The expression levels of vascular endothelial growth factor and tumor necrosis factor-α in local tissue for the low-dose group were significantly higher than those in the other two groups. Differences were statistically significant (P<0.05). In conclusion, local application of low-dose insulin can effectively improve wound healing after deep burn surgeries. PMID:27698753

  15. Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis.

    PubMed

    Pinato, Luciana; da Silveira Cruz-Machado, Sanseray; Franco, Daiane G; Campos, Leila M G; Cecon, Erika; Fernandes, Pedro A C M; Bittencourt, Jackson C; Markus, Regina P

    2015-03-01

    Although melatonin is mainly produced by the pineal gland, an increasing number of extra-pineal sites of melatonin synthesis have been described. We previously demonstrated the existence of bidirectional communication between the pineal gland and the immune system that drives a switch in melatonin production from the pineal gland to peripheral organs during the mounting of an innate immune response. In the present study, we show that acute neuroinflammation induced by lipopolysaccharide (LPS) injected directly into the lateral ventricles of adult rats reduces the nocturnal peak of melatonin in the plasma and induces its synthesis in the cerebellum, though not in the cortex or hippocampus. This increase in cerebellar melatonin content requires the activation of nuclear factor kappa B (NF-κB), which positively regulates the expression of the key enzyme for melatonin synthesis, arylalkylamine N-acetyltransferase (AA-NAT). Interestingly, LPS treatment led to neuronal death in the hippocampus and cortex, but not in the cerebellum. This privileged protection of cerebellar cells was abrogated when G-protein-coupled melatonin receptors were blocked by the melatonin antagonist luzindole, suggesting that the local production of melatonin protects cerebellar neurons from LPS toxicity. This is the first demonstration of a switch between pineal and extra-pineal melatonin production in the central nervous system following a neuroinflammatory response. These results have direct implications concerning the differential susceptibility of specific brain areas to neuronal death.

  16. Insulin pumps in pregnancy: using technology to achieve normoglycemia in women with diabetes.

    PubMed

    Castorino, Kristin; Paband, Rashid; Zisser, Howard; Jovanovič, Lois

    2012-02-01

    Poorly controlled diabetes before conception and during pregnancy among women with pre-existing diabetes can cause major birth defects and spontaneous abortions, as wells as abnormal fetal growth and development including an offspring who is small or large for gestational age, or predisposed to obesity, type 2 diabetes, and metabolic syndrome in his/her lifetime. Conversely, for a woman with pre-existing diabetes, optimizing blood glucose levels before and during early pregnancy can reduce these risks dramatically. As insulin pump technology has evolved, continuous subcutaneous insulin infusion has become a safe and reliable method for treating diabetes during pregnancy. Although pump therapy is often preferred by patients and some experts, insulin pumps have not yet been shown to be superior to multiple daily injections of insulin during pregnancy. In this review of the literature we focus on the use of insulin pumps in the management of diabetes in pregnancy.

  17. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice

    PubMed Central

    Zhang, Yongli; Dai, Chun-ling; Chen, Yanxing; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2016-01-01

    Elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD). At present, there is no treatment that can prevent anesthesia-induced postoperative cognitive dysfunction. Here, we treated mice with daily intranasal administration of insulin (1.75 U/day) for one week before anesthesia induced by intraperitoneal injection of propofol and maintained by inhalation of sevoflurane for 1 hr. We found that the insulin treatment prevented anesthesia-induced deficit in spatial learning and memory, as measured by Morris water maze task during 1–5 days after exposure to anesthesia. The insulin treatment also attenuated anesthesia-induced hyperphosphorylation of tau and promoted the expression of synaptic proteins and insulin signaling in the brain. These findings show a therapeutic potential of intranasal administration of insulin before surgery to reduce the risk of anesthesia-induced cognitive decline and AD. PMID:26879001

  18. Intracerebroventricular administration of Shiga toxin type 2 induces striatal neuronal death and glial alterations: an ultrastructural study.

    PubMed

    Goldstein, Jorge; Loidl, César Fabián; Creydt, Virginia Pistone; Boccoli, Javier; Ibarra, Cristina

    2007-08-03

    Shiga toxin (Stx) from enterohemorrhagic Escherichia coli (STEC) is the main cause of hemorrhagic colitis which may derive to hemolytic-uremic syndrome (HUS). HUS is characterized by acute renal failure, thrombocytopenia and microangiopathic hemolytic anemia. Mortality in the acute stage has been lower than 5% of total affected argentine children with endemic HUS. Common signs of severe CNS involvement leading to death included seizures, alteration of consciousness, hemiparesis, visual disturbances, and brainstem symptoms. The main purpose of the present work was to study the direct involvement of Stx2 in brain cells by intracerebroventricular (i.c.v.) administration of Stx2. Immunodetection of Stx2 was confirmed by immunoelectron cytochemistry in different subsets and compartments of affected caudate putamen cells of corpus striatum. Transmission electron microscopy (TEM) studies revealed apoptotic neurons, glial ultrastructural alterations and demyelinated fibers. The i.c.v. microinfusion was applied for the first time in rats to demonstrate the direct action of Stx2 in neurons and glial cells. The toxin may affect brain neuroglial cells without the involvement of proinflammatory or systemic neurotoxic elements.

  19. Intracerebroventricular administration of leptin increase physical activity but has no effect on thermogenesis in cold-acclimated rats.

    PubMed

    Tang, Gang-Bin; Tang, Xiang-Fang; Li, Kui; Wang, De-Hua

    2015-06-08

    Most small homotherms display low leptin level in response to chronic cold exposure. Cold-induced hypoleptinemia was proved to induce hyperphagia. However, it is still not clear whether hypoleptinemia regulates energy expenditure in cold condition. We try to answer this question in chronic cold-acclimated rats. Results showed that 5-day intracerebroventricular(ICV) infusion of leptin (5 μg/day) had no effects on basal and adaptive thermogenesis and uncoupling protein 1 expression. Physical activity was increased by leptin treatment. We further determined whether ghrelin could reverse the increasing effect of leptin on physical activity. Coadministration of ghrelin (1.2 μg/day) completely reversed the effect of leptin on physical activity. Collectively, this study indicated the regulation of leptin on energy expenditure during cold acclimation may be mainly mediated by physical activity but not by thermogenesis. Our study outlined behavioral role of leptin during the adaptation to cold, which adds some new knowledge to promote our understanding of cold-induced metabolic adaptation.

  20. Effects of Intracerebroventricular Administration of Neuropeptide Y on Metabolic Gene Expression and Energy Metabolism in Male Rats.

    PubMed

    Su, Yan; Foppen, Ewout; Fliers, Eric; Kalsbeek, Andries

    2016-08-01

    Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the central release of NPY has coordinated and integrated effects on energy metabolism in different tissues, resulting in increased energy storage and decreased energy expenditure (EE). We first investigated the acute effects of an intracerebroventricular (ICV) infusion of NPY on gene expression in liver, brown adipose tissue, soleus muscle, and sc and epididymal white adipose tissue (WAT). We found increased expression of genes involved in gluconeogenesis and triglyceride secretion in the liver already 2-hour after the start of the NPY administration. In brown adipose tissue, the expression of thermogenic genes was decreased. In sc WAT, the expression of genes involved in lipogenesis was increased, whereas in soleus muscle, the expression of lipolytic genes was decreased after ICV NPY. These findings indicate that the ICV infusion of NPY acutely and simultaneously increases lipogenesis and decreases lipolysis in different tissues. Subsequently, we investigated the acute effects of ICV NPY on locomotor activity, respiratory exchange ratio, EE, and body temperature. The ICV infusion of NPY increased locomotor activity, body temperature, and EE as well as respiratory exchange ratio. Together, these results show that an acutely increased central availability of NPY results in a shift of metabolism towards lipid storage and an increased use of carbohydrates, while at the same time increasing activity, EE, and body temperature.